Medical Physiology: A Systems Approach (Lange Medical Books)

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Medical Physiology A Systems Approach Hershel Raff, PhD Professor Departments of Medicine and Physiology Medical College of Wisconsin Endocrine Research Laboratory Aurora St. Luke’s Medical Center Milwaukee, Wisconsin

Michael Levitzky, PhD Professor of Physiology and Anesthesiology Louisiana State University Health Sciences Center New Orleans, Louisiana

Medical New York Chicago San Francisco Lisbon London Madrid Mexico City Milan New Delhi San Juan Seoul Singapore Sydney Toronto

Copyright © 2011 by The McGraw-Hill Companies, Inc. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher. ISBN: 978-0-07-176663-0 MHID: 0-07-176663-4 The material in this eBook also appears in the print version of this title: ISBN: 978-0-07-162173-1, MHID: 0-07-162173-3. All trademarks are trademarks of their respective owners. Rather than put a trademark symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the trademark. Where such designations appear in this book, they have been printed with initial caps. McGraw-Hill eBooks are available at special quantity discounts to use as premiums and sales promotions, or for use in corporate training programs. To contact a representative please e-mail us at [email protected]. NOTICE Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confi rm the information contained herein with other sources. For example and in particular, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs. TERMS OF USE This is a copyrighted work and The McGraw-Hill Companies, Inc. (“McGrawHill”) and its licensors reserve all rights in and to the work. Use of this work is subject to these terms. Except as permitted under the Copyright Act of 1976 and the right to store and retrieve one copy of the work, you may not decompile, disassemble, reverse engineer, reproduce, modify, create derivative works based upon, transmit, distribute, disseminate, sell, publish or sublicense the work or any part of it without McGraw-Hill’s prior consent. You may use the work for your own noncommercial and personal use; any other use of the work is strictly prohibited. Your right to use the work may be terminated if you fail to comply with these terms. THE WORK IS PROVIDED “AS IS.” McGRAW-HILL AND ITS LICENSORS MAKE NO GUARANTEES OR WARRANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its operation will be uninterrupted or error free. Neither McGraw-Hill nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill and/or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise.

To our students, mentors, colleagues, and families.

iv

KEY FEATURES

v

About the Authors Hershel Raff

Michael Levitzky

Hershel Raff received his Ph.D. in Environmental Physiology from the Johns Hopkins University in 1981 and did postdoctoral training in Endocrinology at the University of California at San Francisco. He joined the faculty at the Medical College of Wisconsin in 1983, and rose to the rank of Professor of Medicine (Endocrinology, Metabolism, and Clinical Nutrition) and Physiology in 1991. He is also Director of the Endocrine Research Laboratory at Aurora St. Luke’s Medical Center. At the Medical College of Wisconsin, he teaches physiology and pharmacology to medical and graduate students. He was an inaugural inductee into the Society of Teaching Scholars, received the Beckman Basic Science Teaching Award and the Outstanding Teacher Award, and has been one of the MCW’s Outstanding Medical Student Teachers each year the award has been given. Dr Raff was elected to Alpha Omega Alpha (AOA) Honor Medical Society as a faculty teacher in 2005. He is also an Adjunct Professor of Biomedical Sciences at Marquette University. He is Associate Editor of Advances in Physiology Education. He was Secretary-Treasurer of the Endocrine Society and is currently Chair of the Publications Committee of the American Physiological Society. He was elected a Fellow of the American Association for the Advancement of Science in 2005. Dr. Raff ’s basic research focuses on the adaptation to low oxygen (hypoxia). His clinical interest focuses on pituitary and adrenal diseases, with a special focus on the diagnosis of Cushing’s syndrome. Dr. Raff is also a co-author of Vander’s Human Physiology (McGraw-Hill) currently in its 12th Edition, and Physiology Secrets, currently in its 2nd Edition.

Michael Levitzky is Professor of Physiology and Anesthesiology at the Louisiana State University Health Sciences Center and is Director of Basic Science Curriculum at the LSU School of Medicine in New Orleans. He received a B.A. from the University of Pennsylvania in 1969 and a Ph.D. in Physiology from Albany Medical College in 1975. He joined the faculty of the LSU School of Medicine in 1975, rising to the rank of Professor in 1985. He has also been Adjunct Professor of Physiology at Tulane University School of Medicine since 1991. Dr. Levitzky teaches physiology to medical students, residents, fellows, and graduate students. He has received numerous teaching awards from student organizations at both LSU and Tulane. He received the inaugural LSUHSC Allen A. Copping Award for Excellence in Teaching in the Basic Sciences in 1997 and the American Physiological Society’s Arthur C. Guyton Teacher of the Year Award in 1998. He was elected to the Alpha Omega Alpha (AOA) Honor Medical Society as a faculty teacher in 2006. Dr. Levitzky has served the American Physiological Society as a member of the Education Committee and as a member of the Steering Committee of the Teaching Section. He served as a member of the National Board of Medical Examiners United States Medical Licensing Examination (USMLE) Step 1 Physiology Test Material Development Committee from 2007-2011. He is the author or co-author of several other textbooks, one of which, Pulmonary Physiology (Lange/McGraw-Hill), is currently in its 7th edition.

vi

Contents Contributors xi Preface xiii S E C T I O N

I

INTRODUCTION

10. Cardiac Muscle Structure and Function 93 Kathleen H. McDonough

1

1. General Physiological Concepts 1 Hershel Raff and Michael Levitzky

S E C T I O N

David Landowne

3. Cell Membranes and Transport Processes 15 David Landowne

4. Channels and the Control of Membrane Potential 33 David Landowne

5. Sensory Generator Potentials 43 David Landowne

6. Action Potentials 47

12. Introduction to the Nervous System 105 Susan M. Barman

13. General Sensory Systems: Touch, Pain, and Temperature 115 Susan M. Barman

14. Spinal Reflexes 125 Susan M. Barman

15. Special Senses I: Vision 133 Susan M. Barman

16. Special Senses II: Hearing and Equilibrium 147 17. Special Senses III: Smell and Taste 159

7. Synapses 59

Susan M. Barman

David Landowne

18. Control of Posture and Movement 167 Susan M. Barman

III 79

8. Overview of Muscle Function 79 Kathleen H. McDonough

9. Skeletal Muscle Structure and Function 83 Kathleen H. McDonough

105

Susan M. Barman

David Landowne

MUSCLE PHYSIOLOGY

IV

CNS/NEURAL PHYSIOLOGY

9

2. Cells and Cellular Processes 9

S E C T I O N

Kathleen H. McDonough

S E C T I O N

II

CELL PHYSIOLOGY

11. Smooth Muscle Structure and Function 99

19. Autonomic Nervous System 177 Susan M. Barman

20. Electrical Activity of the Brain, Sleep–Wake States, and Circadian Rhythms 185 Susan M. Barman

21. Learning, Memory, Language, and Speech 191 Susan M. Barman

vii

viii

CONTENTS

S E C T I O N

37. Acid–Base Regulation and Causes of Hypoxia 375

V

CARDIOVASCULAR PHYSIOLOGY 199

Michael Levitzky

38. Control of Breathing 385 Michael Levitzky

22. Overview of the Cardiovascular System 199 Lois Jane Heller and David E. Mohrman

S E C T I O N

VII

RENAL PHYSIOLOGY

23. Cardiac Muscle Cells 211 Lois Jane Heller and David E. Mohrman

24. The Heart Pump 223 Lois Jane Heller and David E. Mohrman

25. Cardiac Function Assessments 235 Lois Jane Heller and David E. Mohrman

397

39. Renal Functions, Basic Processes, and Anatomy 397 Douglas C. Eaton and John P. Pooler

40. Renal Blood Flow and Glomerular Filtration 409 Douglas C. Eaton and John P. Pooler

26. Peripheral Vascular System 251 David E. Mohrman and Lois Jane Heller

41. Clearance 417 Douglas C. Eaton and John P. Pooler

27. Vascular Control 263 David E. Mohrman and Lois Jane Heller

42. Tubular Transport Mechanisms 423

28. Venous Return and Cardiac Output 275

Douglas C. Eaton and John P. Pooler

David E. Mohrman and Lois Jane Heller David E. Mohrman and Lois Jane Heller

30. Cardiovascular Responses to Physiological Stress 295

VI

PULMONARY PHYSIOLOGY

44. Basic Renal Processes for Sodium, Chloride, and Water 437 Douglas C. Eaton and John P. Pooler

Lois Jane Heller and David E. Mohrman S E C T I O N

43. Renal Handling of Organic Substances 429 Douglas C. Eaton and John P. Pooler

29. Arterial Pressure Regulation 285

45. Regulation of Sodium and Water Excretion 449 Douglas C. Eaton and John P. Pooler

305

46. Regulation of Potassium Balance 463 Douglas C. Eaton and John P. Pooler

31. Function and Structure of the Respiratory System 305 Michael Levitzky

32. Mechanics of the Respiratory System 313 Michael Levitzky

47. Regulation of Acid–Base Balance 471 Douglas C. Eaton and John P. Pooler

48. Regulation of Calcium and Phosphate Balance 485 Douglas C. Eaton and John P. Pooler

33. Alveolar Ventilation 331 Michael Levitzky

34. Pulmonary Perfusion 341 Michael Levitzky

35. Ventilation–Perfusion Relationships and Respiratory Gas Exchange 353 Michael Levitzky

36. Transport of Oxygen and Carbon Dioxide 363 Michael Levitzky

S E C T I O N

VIII

GI PHYSIOLOGY

491

49. Overview of the GI System—Functional Anatomy and Regulation 491 Kim E. Barrett

50. Gastric Secretion 507 Kim E. Barrett

CONTENTS

51. Pancreatic and Salivary Secretion 517 Kim E. Barrett

52. Water and Electrolyte Absorption and Secretion 527 Kim E. Barrett

53. Intestinal Mucosal Immunology and Ecology 535 Kim E. Barrett

54. Intestinal Motility 543 Kim E. Barrett

55. Functional Anatomy of the Liver and Biliary System 559 Kim E. Barrett

56. Bile Formation, Secretion, and Storage 565 Kim E. Barrett

57. Handling of Bilirubin and Ammonia by the Liver 575 Kim E. Barrett

58. Digestion and Absorption of Carbohydrates, Proteins, and Water-soluble Vitamins 583 Kim E. Barrett

59. Lipid Assimilation 593 Kim E. Barrett S E C T I O N

IX

ENDOCRINE AND METABOLIC PHYSIOLOGY 601 60. General Principles of Endocrine Physiology 601

62. Anterior Pituitary Gland 623 Patricia E. Molina

63. Thyroid Gland 633 Patricia E. Molina

64. Parathyroid Gland and Calcium and Phosphate Regulation 643 Patricia E. Molina

65. Adrenal Gland 655 Patricia E. Molina

66. Endocrine Pancreas 671 Patricia E. Molina

67. Male Reproductive System 683 Patricia E. Molina

68. Female Reproductive System 695 Patricia E. Molina

69. Endocrine Integration of Energy and Electrolyte Balance 715 Patricia E. Molina

S E C T I O N

X

INTEGRATIVE PHYSIOLOGY 70. Control of Body Temperature 729 Hershel Raff and Michael Levitzky

71. Hypoxia and Hyperbaria 735 Michael Levitzky and Hershel Raff

72. Exercise 745 Michael Levitzky and Kathleen H. McDonough

73. Aging 753 Hershel Raff

Patricia E. Molina

61. The Hypothalamus and Posterior Pituitary Gland 613 Patricia E. Molina

729

Answers to Study Questions Index 761

757

ix

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Contributors

Susan M. Barman, PhD Professor Department of Pharmacology & Toxicology and Neuroscience Program Michigan State University East Lansing, Michigan

Kathleen H. McDonough, PhD Professor Department of Physiology Associate Dean, School of Graduate Studies Louisiana State University Health Sciences Center New Orleans, Louisiana

Kim E. Barrett, PhD Professor of Medicine and Dean of Graduate Studies University of California, San Diego La Jolla, California

Patricia E. Molina, MD, PhD Richard Ashman, PhD Professor and Head of Physiology Department of Physiology Louisiana State University Health Sciences Center New Orleans, Louisiana

Douglas C. Eaton, PhD Distinguished Professor and Chair of Physiology and Professor of Pediatrics Department of Physiology and Center for Cell & Molecular Signaling Emory University School of Medicine Atlanta, Georgia Lois Jane Heller, PhD Professor Department of Physiology and Pharmacology University of Minnesota Medical School Duluth, Minnesota David Landowne, PhD Professor Department of Physiology and Biophysics University of Miami, Miller School of Medicine Miami, Florida

David E. Mohrman, PhD Associate Professor, Emeritus Department of Physiology and Pharmacology University of Minnesota Medical School Duluth, Minnesota John P. Pooler, PhD Professor of Physiology Emeritus Emory University School of Medicine Atlanta, Georgia Hershel Raff, PhD Professor Departments of Medicine and Physiology Medical College of Wisconsin Endocrine Research Laboratory Aurora St. Luke’s Medical Center Milwaukee, Wisconsin

Michael Levitzky, PhD Professor of Physiology and Anesthesiology Louisiana State University Health Sciences Center New Orleans, Louisiana

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Preface

Medical Physiology: A Systems Approach is intended to provide first-year medical and graduate students and advanced undergraduate students with the basis of the major physiological processes necessary for understanding both health and disease. The curriculum of many medical schools is changing; most medical schools have undergone, or are in the midst of, a transition from the block approach, with each discipline having its own course, to a vertically integrated structure. One of the goals of an integrated curriculum is the presentation of much more clinical material during the first two years of medical school as well as the reinforcement of basic concepts in the two primarily clinical years. As a result, there is an increasing focus on the essential concepts necessary to understand pathophysiology. Therefore, this book is considerably shorter than the fulllength, standard physiology textbook. It focuses on major physiological concepts and clinical correlates, and leaves the minute details to larger books. Most of this book evolved from the Lange Physiology Series of monographs. The section on the central nervous system arose from the 23rd edition of Ganong’s

Review of Medical Physiology. Finally, the Introduction, Muscle Physiology, and Integrative Physiology sections are new. Each chapter begins with a list of objectives and concludes with a chapter summary. Most chapters also end with a clinical correlation that reinforces the major physiological principles just learned, and illustrates their importance to understanding disease states. Each chapter ends with multiple-choice questions designed to test the knowledge of some of the major concepts covered in the chapter. The authors are indebted to our mentors who provided us with a foundation for advances in physiological education in the 21st century. We also thank our students for providing a sounding board for the pedagogical approaches exploited in this book. The authors are thankful to Michael Weitz, Karen Davis, and Brian Kearns at McGraw-Hill for their outstanding editorial help. Finally, we give special thanks to our families: Judy and Jonathan; and Elizabeth, Edward, and Sarah. Hershel Raff Michael Levitzky

xiii

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SECTION I INTRODUCTION

C

General Physiological Concepts Hershel Raff and Michael Levitzky

1

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■

Understand the general properties of a eukaryotic cell. Explain the general organization of the internal organs of the body. Compare and contrast the composition of extracellular versus intracellular fluid. Describe the different types of membrane transport. Understand the general concepts of pressure, flow, resistance, and compliance. Explain mass balance. Define negative and positive feedback.

INTRODUCTION Physiology is the science of the function of organisms. The object of physiology is to explain how the organ systems, cells, and even molecules interact to maintain normal function. The hallmark of physiology is the concept of homeostasis, which is the maintenance of a normal internal environment in the face of external and internal perturbations so that the functions of the cells and organ systems of the body are maintained. This is accomplished primarily by feedback systems such that when a system is disturbed, a variety of local responses, systemic reflexes (automatic, rapid reactions to stimuli), and long-term adjustments are activated to return the system to its normal set point. By understanding how things work under normal conditions, one can appreciate when and why there is a malfunction. This is called pathophysiology—a lasting disturbance in normal function

Ch01_001-008.indd 1

caused by disease or injury. Therefore, physiology is one of the foundations of the health sciences.

THE CELL The basic building block of the organs of the body is the cell. The details of cell physiology are covered in Section 2. Figure 1–1 shows the general structure of a nucleated (eukaryotic) cell. It is surrounded by a cell membrane that is composed of a lipid bilayer, membrane proteins, and carbohydrates in association with lipids (glycolipids) or proteins (glycoproteins). The cell membrane is the gatekeeper for anything that enters or leaves the cell and is a barrier that helps to maintain the internal composition of the cell. Some membrane proteins and glycoproteins function as sensors, or receptors, which sense the external environment and

1

11/26/10 9:50:25 AM

2

SECTION I Introduction

Secretory granules Golgi apparatus

Centrioles

Rough endoplasmic reticulum

Smooth endoplasmic reticulum

Lysosomes Nuclear envelope

Lipid droplets Mitochondrion

Globular heads

Nucleolus

FIGURE 1–1

Diagram showing a hypothetical cell in the center seen with a light microscope. (Adapted with permission from Fawcett DW, et al.

The ultrastructure of endocrine glands, Recent Prog Horm Res. 1969;25:315–380.)

chemical signals, and then signal the interior of the cell, usually through chemical second messengers or changes in electrical activity of the membrane. Other membrane proteins function as transporters that regulate the entry or exit of substances into or out of the cell. The lipid bilayer structure and associated proteins of the cell membrane are shown in Figure 1–2. The inside of the cell is composed of cytosol, which is a liquid consisting primarily of water in which proteins, metabolites, fuel, and inorganic ions (called electrolytes) are dissolved. Also dispersed in the cytosol are a variety of subcellular particles and organelles. Altogether, the combination of cytosol and the intracellular structures is called the cytoplasm. The organelles include the endoplasmic reticulum, which is an extensive network of membranes inside of which are proteins and other important chemicals. The endoplasmic reticulum is important in many metabolic functions and the packaging of secretory products. The ribosomes are involved in translation, which is the synthesis of proteins from messenger RNA (mRNA). These ribosomes are associated with endoplasmic reticulum in a combined structure called the rough endoplasmic reticulum (RER). The Golgi apparatus is associated with endoplasmic reticulum; the Golgi apparatus packages material synthesized in the RER. Lysosomes are intracellular, membrane-surrounded structures that contain digestive enzymes located in granules that are involved in intracellular metabolism. Secretory granules contain molecules that the cell will release into the extracellular fluid by exocytosis, in

response to stimuli. Some cells contain numerous lipid droplets, because fat is hydrophobic and does not dissolve readily in the aqueous environment of the cytosol. Mitochondria have two lipid bilayer membranes in apposition, and are the energy-

Extracellular fluid Carbohydrate portion of glycoprotein

Transmembrane proteins

Phospholipids

Channel Integral proteins

Peripheral protein Polar regions

Nonpolar regions

Intracellular fluid

FIGURE 1–2 Organization of the phospholipid bilayer and associated proteins in a biological cell membrane. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

CHAPTER 1 General Physiological Concepts

plasm and nucleus that respond to signals that enter the cell. Examples of such signals are steroid hormones such as estrogen and testosterone that are lipophilic (“fat-loving”) and, as a result, can readily diffuse through the cell membrane to exert an intracellular action.

generating organelles. The cytoplasmic organelles are held in position by filaments and microtubules, arising from the centrosomes, which are also important in the movement of chromosomes during cell division. Finally, the nucleus, also surrounded by a lipid bilayer membrane called the nuclear envelope, contains chromatin that is composed of DNA containing the nucleic acid code for cellular differentiation, function, and replication. DNA contains the genes that encode mRNAs that are produced from DNA by transcription. Also contained within the nucleus is the nucleolus, which is the site of ribosome synthesis. As you will learn in many chapters in this book, the cell membrane contains many different types of receptors that sense extracellular signals that are transduced into intracellular signals. In addition, there are receptors within the cyto-

GENERAL STRUCTURE OF THE BODY Figure 1–3 is a diagrammatic representation of the human body. The organs (e.g., brain and heart) receive nutrients and eliminate waste products via the circulatory system. The heart is illustrated as two parts—right and left—as a functional

Central nervous system

Afferent and efferent nerves

Right

Venous blood

O2 CO2

Atmosphere

O2 CO2

Lung

Left Heart

Heart Tissues

Arterial blood

Nutrients

Waste products Endocrine glands Hormones

Liver

GI tract

Synthesis

Metabolism

Kidney

Food & water intake

Nutrients

Bile

Waste

Reabsorption

Filtration Waste Feces Urine

3

FIGURE 1–3 General organization of the major organs of the body. Arrows show the direction of blood flow and flux of gases, nutrients, hormones, and waste products.

4

SECTION I Introduction

depiction even though it is actually one organ. The right side of the heart receives partially deoxygenated blood returning from the tissues and pumps blood to the lungs. In the lungs, oxygen diffuses into the blood from the gas phase for use in cellular respiration in the body, and carbon dioxide, a waste product of cellular respiration, is eliminated by diffusion from the blood into the gas phase. The left side of the heart receives oxygenated blood from the lung and pumps the blood into the arterial tree to perfuse the organs of the body. Nutrients, minerals, vitamins, and water are taken in by the ingestion of food and liquids and absorption in the gastrointestinal (GI) tract. The liver, usually considered part of the GI system, processes substances absorbed into the blood from the GI tract, and also synthesizes new molecules such as glucose from precursors. Metabolic waste products are eliminated by the GI system in the feces and by the kidney in the urine. The two main integrative controllers of the internal environment are the nervous and endocrine systems. The nervous system is composed of the brain, spinal cord, sensory systems, and nerves. The endocrine system is composed of ductless glands and scattered secretory cells distributed throughout the body that release hormones into the blood in response to metabolic, hormonal, and neural signals. It is the function of the nervous and endocrine systems to coordinate the behavior and interactions of the organ systems described throughout this book. Water is the most abundant molecule in the body, constituting about 50–60% of the total body weight. All cells and organs exist in an aqueous environment. The intracellular water is the main component of the cytosol. Water is also the main component of the extracellular fluid. The extracellular fluid includes the interstitial fluid, which bathes the cells of the body, the blood plasma, which is the liquid component of the blood, cerebrospinal fluid, which is found only in the central nervous system, synovial fluid, which is found in joints such as the knee, and lymph, which is a liquid formed from interstitial fluid that flows back to the circulatory system via the lymphatic system. There are significant differences in the composition of intracellular and extracellular fluids that are very important in many aspects of cellular function (Table 1–1).

GENERAL PHYSICAL FACTORS AND CONCEPTS It is not an accident that physiology and physics come from the same Greek word physis (nature). It is important that students of physiology understand the physical forces and factors that govern body function.

MEMBRANE TRANSPORT There are several different mechanisms by which molecules cross the cell membrane either coming into or going out of the cell. These are all described in detail in Section 2. The simplest is diffusion in which the rate at which a molecule crosses

TABLE 1–1 Composition of extracellular and intracellular fluids. Extracellular Concentration (mM)

Intracellular Concentration (mM)

Na+

140

12

+

5

150

1

0.0001

1.5

12

100

7

HCO3

24

10

Amino acids

2

8

Glucose

4.7

1

Protein

0.2

4

K

Ca

2+

Mg Cl

2+

− −

The intracellular concentrations are slightly different for different tissues. The Ca2+ concentrations shown are the free, biologically active ions not bound to proteins. Total Ca2+ (bound plus free) are considerably higher in extracellular (2.5 mM) and intracellular (1.5 mM) fluids. Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.

the cell membrane is governed by the concentration gradient and the ease with which each molecule can go through the cell membrane (permeability); energy expenditure is not directly required for diffusion, which is why it is sometimes called passive diffusion. There are also protein transporters located in the cell membrane that mediate facilitated diffusion of molecules that are too large or hydrophilic to permeate the membrane by simple diffusion. Facilitated diffusion does not require energy and moves molecules down a concentration gradient. By contrast, active transport is a process of moving molecules across a cell membrane against a concentration gradient; it can be thought of as a pump that uses energy to do work. The movement of water molecules across the cell membrane also occurs by diffusion from a higher to a lower water “concentration.” This is termed osmosis; water moves from a compartment with fewer osmotically active particles (higher water concentration) to a compartment with more osmotically active particles (lower water concentration). Examples of osmotically active particles are ions such as sodium, potassium, and chloride, and organic molecules such as glucose and amino acids.

BUFFERING AND pH One of the most tightly controlled variables in the body is the hydrogen ion concentration of the intracellular and extracellular fluids. This is because most proteins have optimal function within a very narrow range of pH. Remember that the pH is the negative logarithm (base 10) of the hydrogen ion concentration in molar units—when pH is low, the fluid is acidic; when pH is high, the fluid is alkaline. The body has several mechanisms for

CHAPTER 1 General Physiological Concepts maintaining a normal pH. These are extensively covered in Sections 6 and 7. The body can rid itself of acid by increasing the elimination of carbon dioxide from the lungs. This is because carbon dioxide and hydrogen ion are linked through chemical reactions to bicarbonate, one of the main buffers in the body. A buffer is an ionic compound that attenuates changes in pH by combining with or releasing hydrogen ions. The kidneys can also remove hydrogen ion from the body via the complex processes involved in producing urine. Finally, changes in intracellular and extracellular pH can be prevented by a variety of buffers in addition to bicarbonate.

HYDROSTATIC FORCES AND PRESSURE, RESISTANCE, AND COMPLIANCE Pressure is defined as force per unit of area. The pressure at the bottom of a column of liquid increases with the height of the column and is also dependent on the density of the liquid and on gravity. The pressure at any point in a column of liquid is called the hydrostatic pressure, and is the pressure difference between that point and the top of the column. Hydrostatic pressure differences have many important physiologic consequences, particularly in blood vessels, as will be seen in Section 5. The flow of a fluid (a liquid or a gas) is quantified as the volume of the fluid moving through a vessel per unit of time. The relationships among pressure, flow, and the resistance offered by the vessels through which a fluid flows can be complex, but are simplified as follows. The rate of flow of liquid through a tube is proportional to the difference in pressure between the two ends of the tube and inversely proportional to the resistance to flow through the tube. Resistance cannot be determined directly, but is calculated from the pressure and flow. If the resistance does not change, increasing the pressure difference through a tube will increase the flow. If the pressure difference from one end of the tube to the other does not

NET GAIN TO BODY

change, increasing the resistance will decrease the flow. If the flow through the tube does not change, increasing the resistance will increase the pressure difference between the ends of the tube. The pressure difference between the two ends of the tube represents energy conversion to heat by the internal friction of the fluid with itself and with the wall of the vessel. You will notice that the relationship between pressure, flow, and resistance for liquid flowing through a tube is analogous to Ohm’s law for electricity in which the voltage drop across a circuit (analogous to a pressure drop in a tube with liquid flowing through it) is proportional to the product of current (analogous to flow) and resistance. Most of the vessels or chambers in the body will stretch passively if the pressure difference across their walls increases. This results in an increased volume of the vessel. This ability to stretch in response to an increased transmural (across the wall) pressure difference is called compliance. A less specific term for compliance is distensibility. The inverse of compliance is elastance. Elastance can therefore be thought of as the resistance to stretch when the transmural pressure difference increases or as the ability of a vessel to return to its original volume after the increased transmural pressure difference is removed. It is directly related to Hooke’s law of elasticity for mechanical springs.

MASS BALANCE AND METABOLISM In order to achieve the steady state that defines homeostasis, any substance taken in by the body must be nearly equal to the amount of the substance leaving the body plus that removed by metabolism (Figure 1–4). The influx of a substance is the sum of uptake in the lung, absorption in the GI tract, synthesis in the body (e.g., liver synthesis of glucose from molecular precursors), and release from cells (e.g., fatty acid release from adipose tissue). The efflux of a substance is

DISTRIBUTION WITHIN BODY

NET LOSS FROM BODY Metabolism

Food

GI tract

Storage depots

Air

Lungs

POOL

Synthesis in body

Reversible incorporation into other molecules

Excretion from body via lungs, GI tract, kidneys, skin, menstrual flow

FIGURE 1–4 Concept of mass balance. The central compartment is usually extracellular fluid (which includes blood plasma). It receives substances from intake, synthesis, and release from cells. It loses substances by excretion, metabolism, and uptake into cells. In the steady state, when a substance is said to be “in balance,” intake and excretion are nearly equal. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

5

6

SECTION I Introduction

the sum of metabolism, uptake into cells, losses via the GI tract, respiratory system, sweat, and urinary excretion. In the steady state, the difference between total influx and efflux should be very close to zero. From minute to minute, there are obviously large differences between influx and efflux, but over days to weeks when the substance is usually in balance, the difference should be close to zero. Examples of this are sodium balance described in Section 7 and calcium and phosphate balance described in Section 9.

EXCITABILITY As you will learn in Sections 2–4, living cells have an electrical charge difference across the cell membrane created primarily by differences in ion concentration and movement between the outside and inside of the cell (see Table 1–1). As a result, the membranes have a resting electrical potential that can be changed by a variety of inputs. Dramatic changes in ion flux across the cell membrane lead to large changes in electrical potential that can result in major cellular responses. For example, muscular contraction described in Section 3 results from the depolarization of the muscle cell membrane that is transduced into a chemical signal within the cell that leads to the generation of force and movement.

CELL–CELL INTERACTIONS As you will learn in Sections 2–4, 8, and 9, cells interact with each other locally. One mechanism is by direct contact between cells via tight junctions and gap junctions. Another is the synapse, in which neurons can release chemicals called neurotransmitters to alter the function of a neighboring cell. Finally, there are a variety of chemical signals by which cells can communicate with neighboring cells by diffusion. An example of this is paracrine signaling by which humoral factors are released by one cell, diffuse through the interstitial fluid, and bind to a receptor on a neighboring cell within the same tissue.

The main focus of physiology is the understanding of the mechanisms by which cells, organs, and organ systems maintain homeostasis. This is accomplished primarily by negative feedback. The general concept is that the body tries to increase a variable when it is below its optimum (termed the set point), and decrease a variable when it is above its optimum. This is analogous to the thermostat that controls room temperature by adjusting the heating and/or cooling of the room. For example, if you open a window on a cold day, the room temperature decreases from the set point of the thermostat. This is called perturbation. The thermostat contains a sensor that detects the difference between the room temperature and the set point. The thermostat signals the furnace to generate heat, and the room temperature is returned toward normal. The difference between the low point in room temperature and the final room temperature at steady state is called the correction. Because the window is left open in this example, room temperature does not quite return to the set point; the remaining difference between the final room temperature and its thermostatic set point is called the error. The ability of the control system to restore the system to its set point is called gain, which is represented by the following equation: Correction Gain = ____________ Remaining error

Final blood pressure

100 95

100-95=5 Remaining error 95-75=20 Correction due

to reflexes

75

Mean arterial blood pressure (mm Hg)

Nadir

(1)

A classic example of this is shown in Figure 1–5 that shows the response of the cardiovascular system to rapid blood loss (hemorrhage). In this example, the rapid loss of 1 L of blood leads to a decrease in mean blood pressure from the set point of 100 to 75 mm Hg. As you will learn in Chapter 29, there are sensors in the cardiovascular system called baroreceptors that detect blood pressure. These sensors change their neural input to the brain to activate systemic reflexes to restore blood pressure to normal. In this example, these reflexes restore blood pressure to 95 mm Hg. The correction, therefore, is 20 mm Hg and the remaining error is 5 mm Hg. Using equation (1), this gives a gain of about 4. Although clinicians do not usually calculate gain when taking care of patients, it is a convenient way

Rapid blood loss

Set point

FIGURE 1–5 Moderate hemorrhage as an example of the gain of a feedback control system. The higher the gain of a system, the better able it is to restore a controlled variable to its set point in response to a perturbation.

CONTROL SYSTEMS

Gain=

Correction 20 = =4 5 Remaining error

Time (min)

Original perturbation

CHAPTER 1 General Physiological Concepts to think of the ability of reflexes to restore a perturbed system to normal via negative feedback. The higher the gain, the higher the ratio of correction to remaining error and the better the control system is at restoring the system to its set point. For example, as you will learn in Chapter 70, the control of body temperature has a very high gain. Included in many feedback systems is a change in behavior. For example, drinking extra water when blood volume is decreased helps to restore plasma volume. Putting on warm clothes and curling up helps to minimize heat loss in a cold environment. Finally, set points of control systems can change. Examples of this are resetting of the baroreceptor set point during chronic increases in blood pressure (hypertension) that you will learn about in Chapter 29, and during the acclimatization to the low ambient oxygen of high altitude (hypoxia) that you will learn about in Chapter 71. Although most control systems of the body are negative feedback, there are a few examples of positive feedback, which are feedback loops that amplify themselves. You will learn about several examples of this in Chapter 68. One is the stimulation of the anterior pituitary hormone LH by estrogen just before ovulation that causes a large increase in LH, which then stimulates more estrogen release, and so on. Another example is the birth of a baby during which stretch of the cervix stimulates the release of oxytocin from the posterior pituitary gland that, in turn, stimulates stronger uterine contractions. This causes additional cervical stretch, more oxytocin release, and greater uterine contractions. Positive feedback is also responsible for detrimental effects in the body. One example is heart failure during which the pumping of the heart decreases due to, for example, an infection of the heart muscle. The resultant decrease in blood pressure leads to reflexes that stimulate the heart to pump harder in an effort to raise blood pressure. This additional stress on the heart actually makes it work less well, and the heart failure feeds on itself. Another important concept in homeostatic control is potentiation. This is when one substance augments the response to another substance, even though the first substance does not exert a significant response on its own. An example of this that you will learn in Chapters 49 and 66 is the release of the GI hormones from the intestine in response to a meal. These hormones can potentiate the pancreatic insulin response to absorbed glucose. This is an example of feedforward potentiation, because these GI hormones “announce” the impending increase in blood glucose before glucose absorption actually occurs in the small intestine. When glucose finally arrives via the bloodstream at the pancreas, there is a potentiated insulin response such that hyperglycemia is prevented.

CHAPTER SUMMARY ■

■

The cell is surrounded by a membrane that regulates the intracellular composition and the flux of molecules in and out of the cell. Water is the most abundant molecule in the body, and its concentration and balance is highly regulated.

■

■

■

■ ■

7

There are significant concentration gradients between intracellular and extracellular fluid for sodium, potassium, calcium, magnesium, chloride, and bicarbonate, as well as organic compounds. Molecules can enter the cell by passive diffusion, and through transporters that do not (facilitated transport) and do directly use cellular energy (active transport). The rate of flow of a liquid through a tube is determined by the pressure difference between the inflow and outflow, and the resistance to flow of the tube. Most important substances in the body are in balance, with the influx and efflux being approximately the same over time. Most systems are controlled by negative feedback with the controlled variable being able to shut off its own release much like a thermostat controls room temperature.

STUDY QUESTIONS 1. Which of the following organelles is primarily response for generation of energy? A) Golgi apparatus B) mitochondria C) lysosomes D) ribosomes 2. Which of the following has an intracellular fluid concentration much higher than its extracellular fluid concentration? A) sodium ion B) chloride ion C) glucose D) potassium ion 3. Which of the following would result in an increase in flow of a liquid through a tube? A) increase in resistance B) increase in pressure at the downstream end of the tube C) increase in pressure at the inflow end of the tube D) increase in length of the tube 4. Which of the following has the highest feedback gain? A) starting blood pressure = 100; low point in blood pressure = 70; final blood pressure after feedback correction = 90 B) starting body temperature = 37.2°C; high point in body temperature = 38.9°C; final body temperature after feedback correction = 37.4°C C) starting blood glucose = 80 mg/dL; high point in blood glucose = 110 mg/dL; final blood glucose after feedback correction = 85 mg/dL D) starting plasma osmolality = 280 mOsm/kg; low point in plasma osmolality = 270 mOsm/kg; final osmolality after feedback correction = 278 mOsm/kg

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SECTION II CELL PHYSIOLOGY

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Cells and Cellular Processes David Landowne

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O B J E C T I V E S ■ ■ ■

Recognize and describe the types of electrophysiological events. Describe the types of membrane channels and their roles. Describe physiological control systems.

INTRODUCTION Life is cellular, and cells are the fundamental units of life. Without cells, there would be no living beings. All the cells of a given individual are ultimately derived from a single fertilized ovum. Most of the cells of multicellular organisms reside within their tissues and organs. This chapter concentrates on the cellular processes and leaves the discussion of their higher organization to chapters concerned with the various organ systems. Drugs, toxins, and diseases are introduced to illustrate the cellular processes.

COMMUNICATION Dynamic cell processes support sensory perception of the environment, communication, and the integration of information within and between cells, as well as their expression, or actions on the environment. These are the processes that enable the cell to contribute to the functioning of tissues, organs, and individuals. These processes make up one of the phenomena of cells—excitability. The others, reproduction and metabolism, are not covered in depth here. Perception, integration, and expression can be best considered as physio-

Ch02_009-014.indd 9

logical events in terms of inputs, processes, and outputs (Figure 2–1). Complex processes can be broken down into simpler ones, with the outputs of one or more processes becoming the inputs to the next one. In order to survey the processes discussed here, it is useful to consider a three-cell model of the body. Figure 2–2 shows a sensory neuron or nerve cell, a motor neuron, and a skeletal muscle cell. These cells represent the hardware the body uses to carry out the dynamic cell processes described in the previous paragraph. The cells have specialized portions for the different processes. Starting from the left, the sensory cell has one end that is specialized for the transduction of a stimulus into a cellular signal. The various senses have different specializations to accomplish this transduction. Besides the classic five senses (touch, hearing, vision, taste, and smell), there are sensors or proprioceptors inside the body that sense internal parameters—for example, body temperature, blood pressure, blood oxygen levels, or the lengths of various muscles. If it is sufficiently large, the initial signal causes another signal to propagate over the axon (the long cylindrical portion of the nerve cell) until it reaches the other end, where the sensory neuron makes a synaptic connection with dendrites of the motor neuron, located in the central nervous system (CNS). The message is transmitted from the presynaptic cell

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SECTION II Cell Physiology

Input

Output

Process

FIGURE 2–1 The input–process–output structural framework is a specification of causal relationships in a system. Complex systems can be considered as composed of simple units. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

to the postsynaptic cell, where it is integrated or evaluated along with messages from other neurons that synapse on the same motor neuron. In the complete organism, this integration and comparison occurs in many cells and at different levels within the CNS, so the decision to move or not move can be made considering more than one input and also anything the organism has learned from the past. If the motor neuron is sufficiently excited, it will send another message along the axon that leads to a synapse on a muscle cell. In healthy people, this neuromuscular synapse leads to a signal that propagates over the length of the muscle cell and activates contraction, which can act on the environment. Other actions on the environment are effected by the secretions of various glands; these too may be controlled by synaptic connections. These muscles and glands may act internally (e.g., to control heart rate or blood pressure) or externally (for locomotion or communication with other people). These signals are all electrical; they all represent changes in the electrical potential difference across the various cell mem-

branes. Every living cell has a surface membrane that separates its intracellular and extracellular spaces. All cells, not just those of nerve and muscle, are electrically negative inside the cell with respect to outside. This is called the membrane potential. When the cells are “resting”—that is, not signaling—their membrane potential is called the resting potential. Chapter 4 is about the origins of the resting potential. Even though the signals described above are changes in potential, they are generally referred to as named potentials. On the left in Figure 2–2, there is the sensory generator potential, which has two properties to distinguish it from the next signal, the action potential. The sensory generator potential is local; it occurs only within a few millimeters of the sensory ending. The action potential is propagated; it travels from the sensory ending to the presynaptic terminal, perhaps more than a meter away. The sensory generator potential is also graded; a larger-amplitude stimulus produces a larger-amplitude sensory generator potential. In contrast, the action potential has a stereotyped amplitude and duration; it is all-or-none. The information about the stimulus is encoded in the number of action potentials, or the number per second. A larger-amplitude stimulus will result in a higher frequency of action potentials, each with the same stereotyped amplitude. Because the all-or-none character of neurons is similar to the true-or-false character of logical propositions, cyberneticists (people who study control and communication in the animal and the machine) have considered that neural events and the relations among them can be treated by means of propositional logic. Chapters 5 and 6 are about sensory generator potentials and action potentials, respectively. The presynaptic terminals contain a mechanism to release the contents of vesicles containing chemical transmit-

Hardware

Sensory ending

Axon

Synapse

Axon

Muscle

Signals (potentials)

Sensory generator Local

Action

Synaptic

Action

Endplate

Propagated

Local

Propagated

Local

Graded

All-or-none

Graded

All-or-none

Graded

Channels

Mechano sensitive

Voltage sensitive

Chemo sensitive

Voltage sensitive

Chemo sensitive

Cybernetics

Input

Transmission

Process

Transmission

Output

FIGURE 2–2 The cellular processes of a hypothetical three-celled organism. Different types of channels underlie different physiological processes that support the input–process–output functions of animals, including humans. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 2 Cells and Cellular Processes ters that diffuse across the narrow synaptic cleft and react with the postsynaptic cell to produce a postsynaptic potential. The postsynaptic potential is also local and graded. It is only seen within a few millimeters of the site of the presynaptic ending and its amplitude depends on how much transmitter is released. There are excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs), depending on whether the postsynaptic potential makes the cell more or less likely to initiate an action potential. If there is sufficient excitation to overwhelm any inhibition that may be occurring, an action potential will be initiated in the postsynaptic cell. There are many presynaptic cells ending on each postsynaptic neuron as well as various different transmitters in different synapses. These transmitters, the release mechanism, and the resulting postsynaptic potentials are discussed in Chapter 7. The action potential in the motor neuron and the synapse with the muscle cell are very similar to the neuron to neuron synapse discussed above. In the light microscope, the neuromuscular junction looks like a small plate; hence, the junction is often called an endplate and the postsynaptic potential an endplate potential. The neuromuscular junction differs from most other synapses because there is only one presynaptic cell, its effect is always excitatory, and—in healthy people—the endplate potential is always large enough to initiate an action potential in the muscle cell. The muscle action potential propagates along the length of the cell and into the interior by small transverse tubules, whose membranes are continuous with the surface membrane. The action potential excitation is coupled to the muscular contraction by processes described in Chapter 10. That chapter also discusses the control of cardiac and smooth muscle cells. The resting potential, the sensory generator potentials, the action potentials, and the synaptic potentials all occur by the opening and closing of channels in the cell membranes. These channels are made of proteins that are embedded in and span the membrane connecting the intracellular and extracellular spaces. Each has a small pore through the middle, which may be opened or closed and is large enough to allow specific ions to flow through and small enough to keep metabolites and proteins from flowing out of the cell. There are many channels, and a good part of Chapter 3 is devoted to their description. They are generally named either for the ion that passes through them or for the agent that causes them to open. There are three classes of channels that act to produce the changes in potential described in Figure 2–2. All these channels will be discussed individually in Chapter 3 and then again in the context of the various potentials in subsequent chapters. Mechanosensitive channels subserve the sensations of touch and hearing and the many proprioceptors that provide information on muscle length, muscle tension, joint position, the orientation and angular acceleration of the head, and blood pressure. These channels open when the membrane of the sensory ending is stretched, sodium ions flow through the channels, and the membrane potential changes.

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Voltage-sensitive channels underlie action potentials. They open in response to a change in membrane potential. When they are open, ions flow through them, and this changes the membrane potential as well. The generator potential or the synaptic potentials activate these channels, and then they open the remaining adjacent voltage-sensitive channels. This accounts for the propagation and all-or-none, stereotyped quality of the action potentials. Nerve and skeletal muscle action potentials are produced by the successive activation of voltage-sensitive sodium channels, followed by voltage-sensitive potassium channels. There are also voltage-sensitive calcium channels in the presynaptic nerve endings. When the action potential reaches the presynaptic terminal, these calcium channels open and permit calcium to enter the cell. The calcium binds to intracellular components and initiates the release of synaptic transmitters. Chemosensitive channels are responsible for the synaptic potentials. The transmitters bind to these channels, causing them to open. There are different channels for different transmitters and also different channels for EPSPs and IPSPs. Chemosensitive channels also subserve the chemical senses of smell and taste. There are also channels that open or close in response to intracellular chemicals such as adenosine triphosphate (ATP) or the cyclic nucleotides, cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP). Vision is supported by a reaction series whereby light absorption leads to a decrease in cGMP, which produces a closure of cyclic nucleotide–gated (chemosensitive) channels. When sodium ions stop flowing through these channels, the membrane potential changes. From a cybernetic viewpoint, Figure 2–2 indicates that the body has mechanisms to input information, to transmit it within the body, to process the information, and to provide output. This type of analysis appears frequently in physiology. Much of what you will learn can be broken into various steps where the output of one process becomes the input for the next. For example, the sensory generator potentials are an input to the action potential–generation process and the action potential is the input to the voltage-sensitive calcium channel, which permits calcium to enter the presynaptic terminal. This calcium is the input for the transmitter release process, and so on.

CONTROL Although most of this book focuses on isolating the different processes so as to analyze them more easily, an understanding of the value and true significance of each physiological quality must refer to the whole organism. A recurring theme throughout all of physiology is the maintenance of a stable internal environment through homeostasis. Many internal properties (e.g., body temperature or blood glucose levels) are homeostatically controlled within narrow limits by feedback control systems. Homeostasis is a property of many complex open systems. Feedback control is the central feature of organized activity.

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SECTION II Cell Physiology

Desired value

Comparator Effector

Controlled parameter

Sensor A From higher centers

Motoneuron Muscle

Sensory neuron

Muscle spindle

B

FIGURE 2–3 Homeostasis and feedback control. A and B) By having inputs that sense the output and feed information back to the controller, machines and humans can gain control of their operating conditions. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

A homeostatic system (e.g., a cell, the body, an ecosystem) is an open system that maintains itself by controlling many dynamic equilibria. The system maintains its internal balance by reacting to changes in the environment with responses of opposite direction to those that created the disturbance. The balance is maintained by negative feedback. Perhaps the most familiar negative feedback control system is the thermostat that controls the temperature of a room, which was described in Chapter 1. The basic steps (Figure 2–3A) in negative feedback control of any measurable parameter are the measurement by a sensor, communication of that measurement to a comparator, making the comparison, and communicating the comparison to an effector that changes the parameter of interest. The feedback is called negative because the signal to the effector is in the opposite direction to any disturbance and reduces the difference between the measured value and the desired value. The three cells in Figure 2–2, arranged as a negative feedback loop (Figure 2–3B), represent the process used to control the length of muscles both to maintain posture and to achieve movement in response to signals from the brain. This feedback loop can be easily demonstrated by the stretch reflex—that is, the knee-jerk reflex (see Chapter 14). When a muscle is

stretched, mechanosensitive channels in sensory organs open, changing membrane potentials in the sensory endings that induce action potentials to propagate to the spinal cord. Transmitter is released, which excites the nerve leading back to the muscle, where the synaptic process is repeated and the muscle shortens to compensate for the initial stretch. There are a few positive feedback systems that are physiologically important. A positive feedback system is unstable; the signal from the sensor increases the effect, which increases the signal from the sensor in a “vicious cycle,” which is limited only by the availability of resources. The all-or-none property of action potentials is due to a positive feedback loop. Some other examples of positive feedback were described in Chapter 1.

CHAPTER SUMMARY ■

■

Communication in excitable cells occurs via electrical signals within the cells and via chemical signals at synapses between the cells. There are two classes of electrical signals: those that are local and graded and those that are propagated and stereotyped, or all-or-none.

CHAPTER 2 Cells and Cellular Processes ■ ■

■ ■

The chemical transmitters are released presynaptically and produce an electrical signal in the postsynaptic cell. Three classes of ion channels produce the electrical signals: mechanosensitive, chemosensitive, and voltage-sensitive channels. Homeostasis by negative feedback control is an important feature of living systems. There are three basic elements of a negative feedback loop: a sensor, a comparator, an effector, and two communication links connecting them.

STUDY QUESTIONS 1. Which of the following changes in electrical potential require voltage-sensitive channels? A) excitatory synaptic potentials B) mechanical sensory generator potentials C) propagated action potentials D) light sensory generator potentials E) inhibitory synaptic potentials

2. Negative feedback control systems do not A) improve the reliability of control. B) require the sensing or measurement of the controlled process. C) require communication between separate parts of the system. D) regulate blood pressure and body temperature. E) cause the all-or-none property of the action potential.

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Cell Membranes and Transport Processes David Landowne

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Describe the molecular composition of biological membranes. Describe the functional biophysical properties of biological membranes. Describe classes of ion channels, their molecular structure, and their biophysical properties. Describe the molecular organization, properties, control, and functional roles of cell–cell channels. Describe the movement and transport of substances across biological membranes by passive processes. Describe the movement and transport of substances across biological membranes by active processes. Describe the physiological importance of two examples of active transport and two examples of passive transport. Define osmotic pressure. Calculate the osmolarity of simple solutions. Calculate the changes in osmolarity in body compartments caused by drinking various simple solutions. Describe physiological mechanisms to regulate osmolarity.

Every living cell has a surface membrane that defines its limits and the connectivity of the intracellular and extracellular compartments. Cell membranes are about 10-nm thick and consist of a 3–4-nm-thick lipid bilayer with various embedded proteins that may protrude into either compartment (see Figure 1–2). Membranes also delimit intracellular organelles, including the nuclear envelope, Golgi apparatus, endoplasmic reticulum (ER), mitochondria, and various vesicles (see Figure 1–1). The lipid bilayer is impermeable to charged or polar substances. The proteins handle the transport of specific ions or molecules across the membranes and thus control the composition of different solutions on either side. They support communication across the membranes and along the surface of the cell and provide mechanical coupling between cells.

Ch03_015-032.indd 15

LIPIDS Most of the membrane lipids are glycerophospholipids, which have a glycerol backbone with two of its three –OH groups esterified by fatty acids and the third esterified to a phosphate group, which is in turn esterified to a small molecule that gives its name to the whole molecule (Figure 3–1). The most common glycerophospholipids are phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS). Membranes also contain phosphatidylinositol (PI), which plays an important role in signaling within the cytoplasm. Notice that PS and PI have a net negative charge. Animal cell membranes may also contain sphingolipids, including the phosphosphingolipid, sphingomyelin, which has

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16

SECTION II Cell Physiology

R O O P O– O

+

N(CH3)3 HCH

Phosphatidylcholine (PC)

HCH O

O

C=O

C=O

+

NH3 HCH

Phosphatidylethanolamine (PE)

HCH +

NH3

COO–

Phosphatidylserine (PS)

HCH

OH OH OH

HO

OH

Phosphatidylinositol (PI)

FIGURE 3–1 Glycerophospholipids. Along with cholesterol, these form the bilayer that separates the inside of cells and supports the embedded membrane proteins. (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

two acyl chains and a phosphate-linked choline head linked to a serine backbone, and glycosphingolipids, which have sugars in the head group. Membranes also contain cholesterol, which has a steroid ring structure. All of these lipids are amphipathic because they have hydrophilic, or “water-loving,” head groups and hydrophobic, or “water-fearing,” acyl tails. The –OH group of cholesterol is hydrophilic and the rest is hydrophobic. A hydrophobic effect arises from the lack of interactions of hydrocarbons with water and the strong attraction of water for itself. Thus, when placed in an aqueous environment, these lipids spontaneously assemble into closed bilayer membrane vesicles. The lipids are relatively free to diffuse laterally within the plane of the membranes, but—with the exception of cholesterol—they are unlikely to flip-flop from one half of the bilayer to the other owing to the hydrophilicity of the head groups. The bilayer is asymmetrical, with the cholinecontaining phospholipids, PC and sphingomyelin, in the outer half and the amino-containing phospholipids, PE and PS, in the inner half. In addition, the glycosphingolipids are in the noncytoplasmic half and PI is facing the cytoplasm. The asymmetrical arrangement is produced as the membranes are assembled in the ER. The phospholipids are synthesized and inserted on the cytoplasmic side of the membrane; then a phospholipid translocator or “flippase” transfers PC to the noncytoplasmic side. Sphingomyelin and the glycosphingolipids are produced in the Golgi apparatus on the noncytoplasmic side.

The ease of lateral diffusion, or membrane fluidity, is increased by the presence of unsaturation or double bonds in the hydrocarbon tails. This forms a kink in the tail and therefore looser packing. At the concentrations generally found in biological membranes, cholesterol reduces the fluidity because of its rigid ring structure. Glycosphingolipid head groups tend to associate with each other and reduce fluidity. Lipid protein interactions may also reduce fluidity. There are cholesterol– sphingolipid microdomains, or “lipid rafts,” involved in intracellular trafficking of proteins and lipids.

PROTEINS The intrinsic proteins of the membrane support the selective movement of ions and small molecules from one side of the membrane to the other, sense a ligand on one side of the membrane and transmit a signal to the other side, and provide mechanical linkage for other proteins on either side of the membrane. The proteins that move materials across the membrane can be functionally divided into channels, pumps, and transporters. Channels may be specific and may open and close, but, when open, they facilitate the movement of materials only with their electrochemical gradients. Ion channels control the flow of electrical current through the membrane. Pumps move ions against their electrochemical gradient at the expense of consuming ATP. The pumps maintain the gradients that allow the channels and transporters to do their jobs. Transporters can link the

CHAPTER 3 Cell Membranes and Transport Processes movement of two (or more) substances and can move one of them against its gradient at the expense of moving the other one with its gradient. A protein is the product of translating a gene; it is a folded, linked sequence of alpha amino acids chosen from a palette with 20 possible different side chains. The peptide link between amino acids –CO–NH– has a planar transconformation; the folding occurs according to the torsion angles between the amino group and the alpha carbon (Φ) and between the alpha carbon and the carboxyl group (ψ). The alpha helix axis and the beta sheet are secondary structures, with particular torsion angles, that are found in proteins. The conformation or tertiary structure of the entire protein is the three-dimensional relationship of all its atoms. Proteins have regions of various secondary structures connected by linkers with less easily characterized structure. Most of the proteins discussed in this book have more than one conformation. For example, a channel may be open or closed. The local secondary structures do not change very much during these conformational changes; rather, change occurs in the relationship between larger portions of the molecule. There is also a supermolecular or quaternary level of organization. Some channels are made of a single polypeptide chain, while others are made of four to six chains. Many channels also have accessory proteins that modulate their function. In addition, the lipid matrix imposes structural restrictions on the embedded proteins. In general, proteins are amphipathic and have regions that are more hydrophobic or hydrophilic, depending on the nature of the side chains. The membrane proteins discussed here have one or more transmembrane (TM) alpha-helical segments with hydrophobic side chains in contact with the hydrocarbon of the lipid. If more than one helix is involved, it is possible to have hydrophobic residues facing the lipid and other groups facing each other in the more interior parts of the protein. The general pattern is for the protein to cross the membrane several times, with intracellular and extracellular loops between TM segments. There is also an N-terminal region before the first segment and a C-terminal region after the last; an example is shown in Figure 3–3. The N-terminal region can be on either side, but the C-terminal region is usually cytoplasmic. Either or both terminal regions can be quite large compared to the TM regions. The TM folding occurs as the protein is synthesized in the ER. The noncytoplasmic portions of the protein may be glycosylated in the Golgi apparatus before being inserted in the surface membrane. Subunit assembly may also occur in the ER or Golgi apparatus. For most membrane proteins, only the primary sequence is known. Secondary structure can be predicted by sequence analysis. The presence of putative hydrophobic helices of sufficient length is taken as a suggestion of a TM segment. A topology or pattern of loops and TM segments can be predicted; such a prediction has been tested for many proteins by preparing antibodies for the putative extracellular portions. Sequence

17

analysis of entire genomes suggests that about 20% of the proteins contain one or more TM segments and are thus membrane proteins. Only a few membrane proteins have been crystallized and subjected to x-ray diffraction analysis. These crystals must include lipid or detergent molecules to satisfy the hydrophobic needs of the TM segments. Most of the solved structures are of bacterial proteins that have been genetically modified to enhance crystallization. A strong sequence homology between the crystallized molecule and part of the human protein is taken to indicate that they have similar structures. Channels, pumps, transporters, receptors, and cell adhesion molecules come in many varieties to serve many roles. The following five sections will describe a taxonomy and the anatomy of examples of each functional class. It may be useful to return to this section while reading the later part of this chapter and those parts of the rest of the book that describe the role of these molecules in physiological processes.

CHANNELS In the previous chapter, channels were distinguished by the mechanism by which they open. There are mechanosensitive channels involved in sensory processes, voltage-sensitive channels involved in action potential propagation, and chemosensitive channels involved in synaptic transmission. There are also channels that are usually open, such as channels that maintain resting potential, water channels, and specialized cell–cell channels that connect the cytoplasm of one cell with the cytoplasm of another. This section describes some channels that support various cell processes discussed later in the book. It is not exhaustive; many channels and many classes of channels are not mentioned. This is a “golden age” for ion channels. Electrophysiology and molecular and structural biology are revealing some amazing membrane proteins. Many ion channels are selective and are named according to the ion that passes through them. The first channel to be crystallized is the resting potential potassium channel, also known as the inward rectifier or Kir. The reason for this name is discussed in the next chapter, along with its function. Kir is a tetramer with four identical subunits arranged with radial symmetry and a pore that permits ion flow at the axis (Figure 3–2A). Each monomer has two TM segments with an extracellular P loop in between (Figure 3–2B; see also Figure 3–4, segments 5 and 6). The four P loops dip back into the membrane and together form the lining of a pore that goes about one third of the way through the membrane. This pore empties into a larger intramembranous cavity that communicates with the cytoplasmic space. The eight helices form a wall for the cavity and also surround the inserted P loops. The TM helices form a conical structure with the point toward the cytoplasm. The selectivity of the pore for potassium ions depends on the specific amino acids forming the lining. VGYGD is the

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SECTION II Cell Physiology

A

B

C

FIGURE 3–2 The crystal structure of an inward rectifier K channel (Kir). A) Top view of a ribbon-structure representation with stick-and-ball for the GYG sequences. B) Side view with two monomers removed; the GYG sequence is a space-filling representation. C) Close-up view of two VGYGD sequences and an ion. (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

K-channel signature sequence (Figure 3–2C); it has been found in K channels from more than 200 organisms. This portion of the molecule is the selectivity filter because it accepts K+ ions and excludes other ions. The pore is lined with the carbonyl oxygen groups; these are in the same relation to each other as the oxygen of the water molecules that coordinate around K+ ions in solution because of its positive charge and the oxygen’s electronegativity. Two of the coordinating oxygens from glycines just below the tyrosines can be seen in Figure 3–2C. Ions with different charges or radii will coordinate water differently and thus will be less likely than K+ ions to leave the water and enter the K channel. It is thought that Figure 3–2 represents a closed Kir channel. The structure of another prokaryotic 2-TM channel has been solved; its inner helices are bent and splayed open, creating a wide entryway. This second Kir channel responds to Ca2+ on its intracellular side by increasing its open probability. The Ca2+ binds to the regulator of K conductance (RCK) domain in the C-terminal part of the protein, not shown in Figure 3–2, inducing a conformational change that splays the inter-

nal helices. Ca2+ and cyclic nucleotides increase the open probability of some other 2- and 6-TM channels by a similar mechanism. There are eight subfamilies of 2-TM Kir channels in the human genome. Several are important in cardiac electrophysiology. Kir2 (or IK1) is the original inward rectifier discovered in cardiac muscle; it is responsible for maintaining the resting potential. Kir3 channels open via G protein–coupled receptors (GPCRs); in the heart, they are referred to as KACh. Kir6 channels open when the ADP/ATP ratio rises. In the heart, they are referred to as KATP.

MECHANOSENSITIVE CHANNELS Mechanosensitive channels are a diverse class of structurally unrelated channels that subserve many different functions in different cells. Mechanosensation is important for touch and hearing and also for sensing blood pressure and for proprioception, providing information about position,

CHAPTER 3 Cell Membranes and Transport Processes

G Y G

P S1

S2

+ + S4 + +

S3

S5

19

S6

C N

FIGURE 3–3 The topology of one monomer of voltage-dependent K channels (KV). The six transmembrane helices (S1–S6) are characteristic of all voltage-dependent ion channels. (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/ McGraw-Hill, 2006.)

orientation, velocity, and acceleration of the body and its parts. The channels are associated with accessory molecules and cellular structures that enhance their particular functions. Somatic nonsensory cells also respond to mechanical stress without informing the nervous system—for instance, to compensate for osmotic swelling or modulate secretion or contraction. Many mechanosensitive channels are relatively nonselective cation channels. Some are very large and permit electrolytes and small metabolites, but not proteins, to cross the membrane. The two structures that have been solved are bacterial. One is a homopentamer, with each subunit containing two TM helices. The other is a heptamer, with each subunit containing three TM helices. These are beautiful structures, but they do not shed much light on the many other forms of mechanosensitive channels.

VOLTAGE-SENSITIVE CHANNELS Voltage-sensitive K channels (KV) are responsible for the return to the resting state, which ends an action potential. KV has a core structure similar to that of Kir and an additional four TM helices on each subunit (see Figure 3–3). The fourth TM segment (S4) is distinguished because it has between four and eight positively charged side chains (Arg or Lys). S4

P S1

S2

S3

+ + + +

S4

S5

S6

is a signature feature of voltage-sensitive channels. It is thought to be the voltage sensor that moves toward the extracellular surface when the membrane potential changes and causes the conformational changes that lead to channel opening. There are nine subfamilies of KV channels and several more 6-TM-channel subfamilies, including the Ca-activated K channels, the hyperpolarization-activated channels important for pacemaker activity in the heart, and cyclic nucleotide–gated channels. The last two families are nonselective cation channels. Voltage-sensitive Na channels (NaV) are responsible for the upstroke of the action potential and support its propagation. Voltage-sensitive Ca2+ channels (CaV) couple membrane potential changes with an increase in intracellular Ca2+ concentration, which acts as a second messenger to control a variety of intracellular processes. NaV and CaV channels have a structure similar to the KV channels except that they are single larger molecules incorporating four domains, each with slightly different 6-TM segments (Figure 3–4). The selectivity filters have four different walls. The CaV channel has four characteristic glutamates (EEEE) in its pore lining, one on each domain. The NaV channel has a DEKA pattern on the four walls of its pore. These side chains must be exposed to the lumen of the pore. The charges they expose to the lumen and the size of the pore determine the selectivity of the channel.

P S1

S2

S3

+ + + +

S4

S5

S6

P S1

S2

S3

+ + + +

S4

S6

P S1

S2

S3

S4

S5

S6

C

N

FIGURE 3–4

S5

The topology of voltage-dependent Na channels (NaV). Four slightly different domains are linked together in one protein.

(Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

20

SECTION II Cell Physiology

CHEMOSENSITIVE CHANNELS There are many different chemosensitive or ligand-gated channels. These control the flow of ions and thus generate electrical signals in response to specific chemicals, such as acetylcholine (ACh), glutamate, or ATP. They can be grouped into three different superfamilies according to the stoichiometry and membrane topology of their subunits. Many of these were first discovered pharmacologically by noticing that certain compounds, called agonists, produced membrane currents or altered the electrical activity of cells and other compounds; antagonists could block these effects. For some agonist-induced currents, the ligand binds the same molecule that contains the pore. These are the ligand-gated channels, which are sometimes called ionotropic ligand receptors to distinguish them from metabotropic ligand receptors, where the ligand binds a GPCR and triggers a biochemical cascade that may include opening of other channels, for example, KACh, described above. The ACh receptor channels (AChRs) are referred to as nicotinic AChRs, or nAChRs. The term nicotinic indicates these receptor bind nicotine, which also opens the channels. nAChRs are distinguished from muscarinic AChRs, which are not channels but rather GPCRs. nAChRs are found on the postsynaptic membranes at skeletal neuromuscular junctions and in the autonomic and central nervous systems. The best-studied nAChRs are heteromeric pentamers (Figure 3–5). The monomers have four TM segments each and

a large extracellular N-terminal region. At the neuromuscular junction, the nAChR has two alpha subunits, with Ach-binding sites at the interface between subunits and far from the lipid membrane. ACh binding induces a conformational change that opens the pore formed at the level of the lipid membrane and lined by the second TM segment of each of the monomer’s five subunits. The open channels are highly permeable to both Na+ and K+, slightly permeable to Ca2+, and not permeable to anions. They are not as selective as the Kir or voltage-sensitive channels. Functionally, the Na permeability is most important, as discussed in Chapter 7. The CNS postsynaptic receptors for glycine (glyR), gammaaminobutyric acid (GABAAR), and serotonin (5HT3R) have similar pentameric architecture, although some are homomeric, as are some nAChRs. glyRs and GABAARs are selectively permeable to anions and produce inhibitory postsynaptic potentials (IPSPs.) 5HT3Rs are cation-selective, similar to nAChRs, and produce excitatory postsynaptic potentials (EPSPs). The most common CNS EPSP channels are glutamate receptors (gluR), which have an architecture (Figure 3–6) reminiscent of an inverted Kir molecule with extra TM segments. gluRs are heteromeric tetramers with three TMs per subunit. They have a large extracellular region with four glutamatebinding sites and a cytoplasmic-facing P loop. Several functionally different gluRs are discussed in more detail in Chapter 7. They are all cation-selective; some allow Ca2+ entry and others do not.

N N

C Out Out

In In

C β

α γ

α δ

FIGURE 3–5 The topology of one monomer of nicotinic acetylcholine receptor channels (nAChR), with a top view showing the arrangement of the five monomers. (Modified with permission from

FIGURE 3–6 The topology of one monomer of glutamate receptor channels (gluR), with a top view showing the arrangement of the four monomers. (Modified with permission from Landowne D: Cell

Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 3 Cell Membranes and Transport Processes The ATP-sensitive channels or P2X receptors (P2XRs) have two TMs per subunit and three subunits per channel. “P” refers to the purine sensitivity; adenine is a purine. P2 distinguishes them from P1 receptors, which are sensitive to adenosine and act through adenylyl cyclase (AC). The P1 receptors are often referred to as A receptors (A for adenosine); they are GPCRs. Caffeine is an antagonist of some of the A receptors. P2 receptors prefer ADP or ATP to adenosine. P2XRs are channels and P2YRs are GPCRs. Purinergic receptors are best known as regulators of blood flow in tissues; they have also been implicated in several sensory processes. Two additional channel families have chemosensitive members but also have important members without known ligands. These are the epithelial sodium channel (ENaC) and the inositol triphosphate (IP3) receptor (IP3R) family. ENaCs are important in the reabsorption of sodium from the nascent urine in the tubules of the nephron. They are thought to be heteromeric tetramers each with two TM segments; they are not voltage-dependent. It is known that they are regulated by control of their insertion and removal from the membrane, and there may be an unknown ligand for this channel. There are structurally related channels in invertebrates that have known ligands. IP3Rs and the related ryanodine receptors (RyR) are found in the membrane of the ER. When open, they permit the release of Ca2+ from the ER. IP3 is a second messenger produced by the action of phospholipase C (PLC) on the membrane lipid phosphotidylinositol, which has been previously phosphorylated to be PIP2. RyRs also control the release of calcium, primarily in muscle, from the sarcoplasmic reticulum. Ryanodine refers to a toxin that partially opens these channels. RyRs are opened by direct interaction with a modified CaV channel in skeletal muscle and by intracellular Ca2+ in cardiac muscle. The functions of IP3Rs and RyRs are discussed in further detail in Chapters 9 and 10. RyRs are homotetramers with an enormous 20-nm-diameter cytoplasmic N-terminal region. The total molecular weight for the tetramer is above 2,000 kDa, about 10 times larger than NaV or KV channels. IP3R channels are also homotetramers about half the size of RyRs. It has been predicted that IP3Rs have 6 TM segments per monomer and RyRs have 4–12.

CELL–CELL CHANNELS In most tissues, there are channels that connect the cytoplasm of one cell to the cytoplasm of its neighbor. The exceptions are free-floating cells in the blood and skeletal muscle cells. These channels are mostly between cells of the same type, but there are some cells of different type with junctions between them. These channels were originally detected electrically by showing that current could pass from one cell to another through an electrical synapse. Later they were associated with an anatomic structure called the gap junction, named for its appearance in electron micrographs. Actually this gap is spanned by matching arrays of proteins from each cell, with up to thousands of cell–cell channels per gap junction. Each cell–cell channel is made of two hemichannels, one from each cell (Figure 3–7). They are also called connexons. A hemichannel is a homomeric or heteromeric hexamer of proteins called connexins. There are more than 15 different connexins with molecular weights between 25 and 50 kDa. They all have four TM segments and two extracellular loops and their N- and C-terminals are in the cytoplasm. Some but not all connexins can form hybrid channels joining different hemichannels on the two cells.

Out

In

N

C

In

WATER CHANNELS Some cells require more permeability to water than is provided by the lipid bilayer. Red blood cells, which must quickly change shape to pass through narrow capillaries, and many epithelial cells, most notably those in the kidney, have specialized water channels or aquaporins (AQPs), which permit the passage of water but exclude ions. The AQPs are found as tetramers with four functional pores, one in each subunit. The subunits have six TM segments and two regions similar to the P loop of KV channels. One of the loops faces the extracellular surface and the other faces the cytoplasm, and they meet in the middle of the membrane. The functions of AQPs and ENaCs are discussed toward the end of this chapter.

21

Out

In

FIGURE 3–7

The topology of connexin, a monomer of cell–cell channels, top view showing the arrangement of six monomers in a hemichannel and side view showing two cell membranes with aligned hemichannels. (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/ McGraw-Hill, 2006.)

22

SECTION II Cell Physiology

The pore is much larger than the ion channels described above. It is about 1.2 nm and is permeable to anions, cations, and small metabolites as well as second messengers such as ATP, cAMP, or IP3 but not proteins. Experimentally, the pore is permeable to molecules with molecular weights below 1 kDa. Cell–cell channels allow cells in a tissue to work in a coordinated manner. If a cell is damaged, it can close its cell–cell channels leading to its neighbors and thus prevent the loss of small molecules from the whole tissue. This gating is controlled by intracellular Ca2+, H+, or transjunctional voltage. Different connexons have relatively different sensitivity to these three changes. Gating can also be induced by octanol and anesthetics such as halothane. In some situations unpaired connexons, or the related pannexons, can open and allow small molecules to move from the cytoplasm to the extracellular space. Pannexons have been suggested to have a role in inflammation and the response to ischemia by allowing the release of ATP to signal to cells near a site of tissue insult.

Out

Na/K PUMP The Na/K pump, often referred to more simply as the Na pump, moves three Na+ ions out of the cell and two K+ ions into the cell in a cycle that converts one ATP molecule to ADP + Pi. At maximum speed, the pump completes about 100 cycles per second (cps), which means the movement of ions per molecule is much less than a NaV channel, which may allow 1,000 ions/ms to flow into the cell. The NaV channels are open only briefly when the cell is active; the pump runs continuously to recover from the activity. Pump activity increases when intracellular Na+ or extracellular K+ increase and the pump acts homeostatically to restore the original levels. The Na pump is a heterodimer with an alpha subunit that has the Na+, K+, and ATP-binding sites and a beta subunit thought to be important for membrane insertion. The beta subunit has 1 TM segment; the alpha subunit probably has 10. Intracellular

3Nao

E2 3Na

2K

In P

P

P

Out Occluded 3Na

In

2K

P ATP

ADP

PUMPS Ions move across cell membranes via channels, pumps, and transporters. These are three fundamentally distinct mechanisms and the student should be careful not to confuse them. Pumps create and maintain ionic gradients, moving ions against the gradient at the expense of ATP. Channels use these gradients to produce the various electrical signals. Transporters use one or more gradients; the with-gradient movement of an ion (often Na+) is coupled to the against-gradient movement of another substance. Because they consume ATP, pumps are often referred to as ATPases. Five pumps will be described in detail: the Na/K pump, the Ca pump, and three types of proton pump. The first three of these are called P-type pumps, because they are autophosphorylated during the reaction cycle, or E1–E2 pumps, because they have two major conformational states.

2Ko

Out E1 In

2Ki

3Na

ATP

3Nai

2K

ATP

FIGURE 3–8 The Na/K pump cycle. Operating in the clockwise direction the pump moves three Na+ out and then moves two K+ in at the expense of converting one ATP to ADP. (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/ McGraw-Hill, 2006.)

Na+ and ATP bind to the E1 form of the alpha subunit, which is then phosphorylated and converts to the E2 form (Figure 3–8, lower left, proceeding clockwise). The E2 form releases the Na+ into the extracellular space and binds extracellular K+. The crystal structure of the E2-2K+–Pi form has recently been solved. The overall structure of domains and helices is similar to the Ca pump described below but there are differences related to the specific functions of each pump. The cycle continues when the phosphate is hydrolyzed off the protein; the protein changes back to the E1 form, releases the K+ inside the cell, and then binds the next Na load. As the Na+ and K+ alternately move through the membrane, the pump passes through an occluded state where the ions are not accessible to either solution. Digitalis and ouabain, a related cardiac glycoside, stop the action of the pump by binding extracellularly to the E2 form near the K+-binding location. Digitalis is used to treat a variety of cardiac conditions. It is a relatively dangerous drug and must

CHAPTER 3 Cell Membranes and Transport Processes be used cautiously so as to block only some of the pump molecules and leave others functional. The danger is complicated because extracellular K+ antagonizes the binding of digitalis by driving the pump toward the E1 form; the prudent clinician will monitor blood potassium levels during digitalis treatment. The Na pump is electrogenic, because each cycle moves one net charge out of the cell. This current has only a small effect on the membrane potential compared to ion flow through channels, which is discussed in the next chapter. The net movement of Na+ out of the cell prevents NaCl from accumulating in the cell. If the pump is blocked with cardiac glycosides, the cell will swell because of the osmotic influx of water following the NaCl.

Ca PUMP There are two important Ca pumps, one that pumps Ca2+ from the cytoplasm into the extracellular space and another, the SERCA pump, that pumps Ca2+ from the cytoplasm into the lumen of the sarcoplasmic or ER. They are thought to have similar mechanisms; both are P-type E1–E2 pumps that move two Ca2+ ions out of the cytoplasm and two or three H+ ions into the cytoplasm for each ATP consumed. The SERCA pump structure has been solved in several different states. It is a tall molecule, about 15-nm high and 8-nm thick, mostly extending out of the membrane on the cytoplasmic side. There are 10 TM segments. The cytoplasmic headpiece consists of the actuator (A), nucleotide binding (N), and phosphorylation (P) domains. The three cytoplasmic domains are widely split in the E1 • 2Ca state but gather to form a compact headpiece in the other states. This motion is transmitted to the membrane portion through helices 1–3, attached to the A domain, and 4 and 5, attached to the P domain, to allow the Ca2+ to be released on the noncytoplasmic side. The distance between the Ca2+-binding sites and the phosphorylation site is greater than 5 nm.

H/K PUMP The H/K pump secretes acid into the stomach by pumping two H+ ions out of the parietal cells of the gastric glands and two K+ ions into the cell while splitting one ATP molecule. Similar pumps also operate in epithelial cells in the intestine and kidney. This is an E1–E2 P-type pump and has a beta subunit, similar to the Na/K pump. The H/K pump is inhibited by omeprazole (Prilosec) and other similar drugs used in the treatment of frequent heartburn.

F-TYPE H PUMPS The most significant F-type H pump usually runs in reverse as the F0–F1 ATP synthase found in mitochondria. This protein complex allows protons to flow with their electrochemical gradient and converts the flow of 10 protons to form three ATPs from ADP. The hydrogen gradients are produced by oxidative metabolism in mitochondria.

23

TABLE 3–1 Localization of membrane pumps. Pump

Cell Type

Membrane

Inhibitor

Na/K

All

Surface

Digitalis

Ca

All

Surface and ER

Thapsigargin

H/K

Gut, kidney

Surface

Omeprazol

F-type H

All

Mitochondria

Oligomycin

V-type H

All

Surface and vesicles

Bafilomycin

The pump has 8 different subunits and more than 20 polypeptide chains. The F0 portion spans the membrane and carries the H ions; the F1 extends into the mitochondrial matrix. Part of the complex rotates about an axis perpendicular to the plane of the membrane, similar to a turbine, as the H ions flow through. Another portion, the stator, stays fixed in position, and the interaction between the rotator and the stator produces a sequence of conformational states that favor the synthesis of ATP. In the presence of high ATP, low ADP, and no proton gradient, the process can be reversed to pump H+.

V-TYPE H PUMPS V-type H pumps are also protein complexes of up to 14 subunits with rotors and stators. They move protons into vacuoles and other intracellular organelles such as lysosomes, the Golgi apparatus, and secretory vesicles. The H+ gradient produced across synaptic vesicle membranes is used to drive the packaging of neurotransmitters (see Figures 7–3 to 7–5). These pumps are responsible for the H+ that is secreted by osteoclasts to dissolve bones and also for H+ secretion in the kidney and epididymus (Table 3–1).

TRANSPORTERS Transporters move ions and other small molecules across the membrane and are not channels or pumps. Sometimes the word transporter is used in the general sense to include all transport mechanisms and secondary transporter is used to distinguish this group. Transporters undergo a conformational change as they transport; in this aspect they are similar to pumps and different from an open channel. Unlike a pump, they do not consume ATP. Most transporters are thought to have 12 TM segments in two groups of 6 with a larger cytoplasmic loop between them. Some have a 2-fold pseudosymmetry and P loops facing both surfaces. There are three general categories of transporters: uniporters, symporters or cotransporters, and antiporters or exchangers (Figure 3–9). The glucose transporter (GLUT) is a uniporter that facilitates the diffusion of glucose with its concentration gradient into many cells that are consuming glucose. It also facilitates movement of glucose from cells that are releasing

24

SECTION II Cell Physiology The Cl/HCO3 exchanger, also known as the anion exchanger (AE), is important for moving CO2 from the tissues to the lungs. CO2, produced by metabolism in the cells, is converted to bicarbonate by carbonic anhydrase in the red blood cells, and the HCO3– moves into the plasma exchanging for chloride via AE. The process is reversed as the blood passes through the lungs and the CO2 moves into the air to be exhaled. This process will be covered in Chapter 37. Uniporter

FIGURE 3–9

Symporter

Antiporter

Three types of transporters. (Modified with

permission from Landowne D: Cell Physiology, New York: Lange Medical Books/ McGraw-Hill, 2006.)

glucose by breaking down glycogen and from basal surfaces of epithelial cells that line the intestines and kidney tubules (see Figure 3–14). The Na–glucose cotransporter (SGLT) is a symport that carries glucose into intestinal and kidney epithelial cells across their apical surfaces against the glucose concentration gradient. The energy required for this transport comes from the movement of one or two sodium ions with their electrochemical gradient for each transported glucose molecule. A Na/glutamate cotransporter recovers glutamate that is used as a neurotransmitter at CNS synapses (see Figure 7–4). It couples the downhill movement of three Na+ ions and one K+ ion to the uphill transport of one glutamate. The structure of a bacterial glutamate transporter, which is thought to be similar to that of humans, has recently been solved. It has eight TM segments and two P loops, one facing the cytoplasm and one facing the outside. It is thought that relatively small movements of the protein can transfer the glutamate from one P loop to the other and thus across the membrane. There is an H/glutamate antiporter that uses the H+ gradient, established by a V-type pump, across the membrane enclosing synaptic vesicles to concentrate glutamate inside the vesicle (see Figure 7–4). There are many other Na-driven cotransporters to move other small molecules into cells and H-driven transporters to move some material into vesicles. Some of these transporters are targets for pharmacologic intervention. For example, fluoxetine (Prozac) acts on a Na/serotonin cotransporter. Others are discussed further in Chapter 7. Some anions are cotransported with sodium; for example, the Na/I symporter concentrates iodine into thyroid follicle cells. The Na/Ca exchanger (NCX) is an important regulator of intracellular Ca2+ concentration. Three sodium ions moving with their electrochemical gradient into the cell can move one calcium ion out, or vice versa; all of the exchangers can run either way depending on the relative gradients. The effect of digitalis on cardiac muscle is to raise intracellular Na by inhibiting the Na/K pump. Elevated Nai+ means that there is less inward gradient for Na+ and therefore less Ca2+ efflux via NCX. This increases Cai2+ and produces a stronger contraction (see also Chapter 23).

ABC TRANSPORTERS This mixed group of 12 TM transport proteins contains a characteristic ATP-binding cassette (ABC) amino acid sequence and, in the absence of more specific information, is assumed to consume ATP while transporting some material across the membrane. Two ABC transporters deserve mention here, the multidrug resistance (MDR) transporter, which is a pump, and the cystic fibrosis transmembrane regulator (CFTR), which is a channel. MDR1 extrudes hydrophobic drugs across the cell membrane. It is thought to act somewhat like the flippase and extrudes the drugs without much specificity. A wide variety of cells in the GI tract, liver, and kidney express MDR proteins. These can frustrate the physician who is attempting to provide drugs to treat cancer among these cells. CFTR is a protein that, when mutated, leads to cystic fibrosis. The wild-type protein is a chloride channel that requires phosphorylation by protein kinase A (PKA) and additional ATP hydrolysis by the activated CFTR protein in order to open. The Cl− moves with its electrochemical gradient. Cystic fibrosis occurs because of the lack of Cl− transport in the pancreatic duct (hence cystic). The decreased Cl− leads to decreased water and the protein-rich secretion thickens and can block the ducts that then become fibrotic. Before the development of oral replacement therapy for the missing pancreatic enzymes, many CF patients died of complications of malnutrition. Now the major problem is the thickening of mucus in the lungs because of insufficient fluid secretion.

MEMBRANE RECEPTORS The word receptor comes from pharmacologic studies, where it designates the site of action or the molecule that a small molecule of interest, perhaps a hormone or neurotransmitter, acts on. Here it is used in a more restrictive sense to mean molecules that span the membrane, are acted on the external surface by the small molecule, and trigger some action inside the cell when the small molecule is present. There are also intracellular receptors, for example, the steroid hormone receptor. Steroid hormones and related drugs can cross the lipid bilayer and bind these intracellular proteins. Chemosensitive channels are excluded as well, although some pharmacologists like to call them ionotropic receptors. There are two major categories of these membrane receptors: the GPCRs and the enzyme-linked or catalytic receptors.

CHAPTER 3 Cell Membranes and Transport Processes

Agonist

AC

Effector

GPCR

P

β/γ G protein

25

α ATP

cAMP

PKA

FIGURE 3–10 The Gαs signaling pathway. Binding of agonist to the G protein–coupled receptor causes the dissociation of the α subunit, which causes adenylyl cyclase to raise cAMP levels. This, in turn, causes protein kinase A to phosphorylate an effector protein (in this case a channel). (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

G PROTEIN–COUPLED RECEPTORS GPCRs have seven TM segments with an extracellular N terminus. They are coupled to a trimeric GTP-binding protein complex. When a hormone or neurotransmitter interacts with a GPCR, it induces a conformation in the receptor that activates a heterotrimeric G protein on the inner membrane surface of the cell (Figure 3–10). In the inactive heterotrimeric state, GDP is bound to the Gα subunit. On activation, GDP is released, GTP binds to Gα, and subsequently Gα–GTP dissociates from Gβγ and from the receptor. Both Gα–GTP and Gβγ are then free to activate other membrane proteins. Most Gα and Gγ are lipidated; they have a covalently attached lipid anchor into the membrane bilayer. The duration of the G-protein signal is determined by the intrinsic GTP hydrolysis rate of the Gα subunit and the subsequent reassociation of Gα–GDP with Gβγ. There are more than 2,000 predicted GPCRs in the human genome, more than 5% of all the genes. More than 800 are olfactory receptors; others detect almost all neurotransmitters and many hormones. Light also is detected by GPCRs in the eye (Figure 5–2). Different cells have different palettes of GPCRs coupled to different G proteins controlling different sets of intracellular reactions. There are only about 16 different Gα subunits and even fewer Gβγ. Three classes of Gα subunits initiate most of the subsequent events described in this book. Gαs stimulates adenylyl cyclase (AC), Gαi inhibits AC and its associated βγ directly activates KAch channels, and Gαq stimulates a phospholipase (PLCβ). AC produces cAMP that can directly influence some channels. cAMP also activates protein kinase A (PKA) by dissociating the regulatory subunits from the catalytic subunits. The PKA phosphorylates many proteins, thus altering the activity of the cells. PLCβ splits the membrane

phospholipid PI to produce IP3 and diacylglycerol (DAG). As described above, IP3 binds the IP3R channels, which increases Cai, which in turn triggers various reactions. Several examples of GPCR-initiated cascades are described more fully in later chapters. The toxins that underlie two infectious diseases, cholera and pertussis, ADP-ribosylate Gα subunits leading to constitutive activation. In cholera, activated Gα in intestinal epithelial tissue stimulates AC, cAMP levels increase, and CFTR chloride channels open, leading to a watery diarrhea. People with cystic fibrosis can be resistant to cholera because they have fewer functional chloride channels. The cellular pathogenesis of pertussis is not clear.

ENZYME-LINKED RECEPTORS Most enzyme-linked receptors are receptor tyrosine kinases (RTK) and act by phosphorylating tyrosine side chains on other proteins, which may in turn phosphorylate other proteins. Some enzyme-linked receptors are not kinases themselves but are coupled to an associated protein that phosphorylates other proteins. Some enzyme-linked receptors are guanylyl cyclases, tyrosine phosphatases, or serine kinases. Most growth and differentiation factors act by binding specific RTKs. The insulin receptor is an RTK that phosphorylates a family of substrates known as insulin-receptor substrates; these stimulate changes in glucose, protein, and lipid metabolism and also trigger the Ras signaling pathway, activating transcription factors that promote growth. Interferon receptors and the CD4 and CD8 molecules on the surface of T lymphocytes are examples of receptors that are coupled to cytoplasmic tyrosine kinases.

26

SECTION II Cell Physiology

CELL ADHESION MOLECULES Most cells except red blood cells have integral membrane proteins that attach to the extracellular matrix or with adhesion molecules on neighboring cells. These molecules hold the tissue together and can allow the transmission of mechanical forces from one cell to another. They can act as signals during development, so one cell can recognize another. Many also act as receptors, informing the inside of the cell that they have bound something. Some are controlled from the inside, binding only when some signal has been received. The integrins are examples of cell-matrix adhesion molecules. They have a single TM segment and link cells to fibronectin or laminin in the extracellular matrix. Cadherins are Ca-dependent cell–cell adhesion molecules; they are glycoproteins with a single TM segment and are thought to bind homophilically (to another copy of the same molecule) to cadherins on the other cell. Cadherins have been found at many neuron–neuron synapses. There is a large family of cell adhesion molecules, of which the N-CAMs are the best understood. N-CAMs are found on a variety of cell types and most nerve cells. Like cadherins, N-CAMs have a single TM segment and bind homophilically, but they differ in that they do not require Ca2+ for binding. Intercellular adhesion molecules (ICAMs) are a related class expressed on the surface of capillary endothelial cells that have been activated by an infection in the surrounding tissue. They bind heterophilically (to a different molecule) to integrins on white blood cells and help them move to the site of infection. Selectins are carbohydrate-binding proteins on the endothelial cell membrane that recognize sugars on the surface of the white blood cell and form the initial binding, which is strengthened by the ICAMs.

TRANSPORT ACROSS CELL MEMBRANES From a functional point of view, discussion of the transport of materials across cell membranes can be divided into passive transport, where the materials move with their concentration

Flux

gradient, and active transport, which creates or maintains these gradients.

PASSIVE TRANSPORT Simple Diffusion Some materials can move with their concentration gradient by simple diffusion though the lipid bilayer. Small, uncharged molecules such as O2, CO2, NH3, NO, H2O, steroids, and lipophilic drugs can enter or leave cells by simple diffusion. The net flux of these compounds through the membrane is proportional to difference in their concentrations on the two sides, or as expressed in the following equation: J1→2 = –P(C2 – C1) = –PΔC

(1)

Using the centimeter–gram–second (CGS) system of units, J1→2 is the number of moles that move through a square centimeter of membrane from side 1 into side 2 each second and C1 and C2 are the numbers of moles of the material per cubic centimeter of solution on the two sides. P, the proportionality constant, is called the permeability of the membrane to this material in centimeters per second. The equation is written with the leading minus sign as an aid to remembering that the flux is moving with the concentration gradient. This relationship is shown graphically in Figure 3–11. Equation (1) is Fick’s first law. It can be used to describe the flux by simple uncharged substances through any membrane. For example, it is useful to describe the movement of oxygen from the air into the alveoli of the lungs and into the blood, across the cells of the alveolar epithelium and the capillary endothelium. A charged species will also be influenced by the electrical potential difference across the membrane in a manner to be discussed in the next chapter. If there is no potential difference across the membrane, Fick’s law is also applicable to charged substances. Permeability describes a property of a particular membrane in relation to a particular substance. The membrane is considered permeable, while the substances are said to be permeant or to permeate. The permeability will be proportional to the ability of the substance to partition into the

Flux

Vmax

Concentration

FIGURE 3–11

Km

Concentration

The concentration dependence of simple diffusion (left) and facilitated diffusion (right). (Reproduced with permission from

Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 3 Cell Membranes and Transport Processes membrane and to diffuse within the membrane. The permeability will be inversely proportional to the thickness of the membrane. It is usually not easy or necessary to know these three factors separately, but one should appreciate that thickening of the complex membrane between the alveolus and the pulmonary capillary blood will reduce the movement of oxygen into blood. It is sometimes convenient to think of Fick’s law as saying that the net influx of a substance is equal to the unidirectional influx (PC0) minus the unidirectional efflux (PCi). The permeability is a measure of the ease with which a solute crosses through a membrane. Plain lipid bilayers are relatively permeable to small, uncharged molecules; the permeability to water is about 10−3 cm/s. Thus, water equilibrates across a cell membrane in a few seconds. Urea is moderately permeable (P = 10−6 cm/s), and its equilibration time is a few minutes. Hydrophilic small organic molecules such as glucose or uncharged amino acids are less permeable, with P = 10−7 and equilibration times of hours; ions are essentially impermeable, with P = 10−12 cm/s and equilibration times of many years.

27

ACTIVE TRANSPORT Pumps provide primary active transport, moving materials against their electrochemical gradients at the expense of ATP. The Na/K pump moves Na+ out of the cell and K+ into the cell; both ions are moving against their respective gradients. The SERCA pump moves Ca2+ against its gradient from the cytoplasm into the lumen of the ER. Cotransporters and exchangers can provide secondary active transport, using a gradient produced by primary active transport to move another material against its gradient. Many transporters couple the movement of Na+ or H+ with its electrochemical gradient with the movement of another substance against its gradient. The Na-GLUT and the H/glutamate antiporter are two examples of secondary transport mechanisms. The flux by pumps and transporters can be described by equations similar to equation (2), modified to include the affinity for each substance and for ATP. When more than one ion at a time is involved in the reactions at one pump or transporter molecule, the equation must also be modified to reflect this cooperativity. Thus, the efflux of sodium through the Na/K pump has a sigmoidal relationship to the internal Na+ concentration.

Facilitated Diffusion Many substances, such as glucose or urea, easily enter cells in spite of the fact that the lipid bilayer is relatively impermeable to them. The flux of these materials is described by Fick’s law only for low concentrations. At higher concentrations, the flux saturates at a maximum value (see Figure 3–11). This behavior can be described by the Michaelis–Menten equation, which is also used to describe enzyme kinetics. The unidirectional flux is given by the following equation: J

C

max J = _____ C+K

(2)

m

where Jmax is the maximum flux and Km the affinity or the concentration at which the flux is half its maximum value. This saturable property of the flux suggests that there are a fixed number of sites at which the flux can take place. Also, as in the case of enzymes, it may be possible to demonstrate the competition of different substances for the same site or noncompetitive inhibition of the transport sites. The sites are selective for a particular substance or group of substances that they will transport or that allow competition for transport. Selectivity, affinity, and Jmax are three independent qualities of the sites; they will be found with different values in different systems. Facilitated diffusion is now understood in terms of channels or transporters. Most channels have low affinity or high Km values; they are not saturated under normal physiological conditions. Three glucose uniporters, GLUT1, GLUT3, and GLUT4 (which is regulated by insulin), are found in many tissues and have a high affinity for glucose; they are saturated at all physiological concentrations. GLUT2, which is found in tissues carrying large glucose fluxes (such as intestine, kidney, and liver), has a low affinity for glucose, and the influx through GLUT2 transporters increases as the glucose concentration increases.

OSMOSIS Life is intimately associated with the movement of water. Our bodies are mostly water and are vitally dependent on its supply. Water is a small but abundant molecule. It is not much larger than an oxygen atom, about 0.2 nm across—small enough to intercalate between other molecules, even in some crystals. A mole of water is 18 mL; thus, pure water is 55 mol/L. This concentration is several hundred-fold higher than the Na+, K+, or Cl− concentrations in the body that are the next highest. More than 99% of the molecules in the body are H2O. Because the molecules are small, they move easily; because they are so abundant, their movements are important to our health. There are two or three distinct mechanisms for water movement: bulk flow, molecular diffusion, and, perhaps, molecular pumping. When you pull the plug in a bathtub or your heart beats, there is bulk flow of fluid in response to an external mechanical force—a push or a pull. The driving force for bulk flow is the mechanical pressure commonly produced by pushing or by gravity. Molecular diffusion or osmosis is a passive process by which water diffuses from areas of high water concentration to those of low. There is a high water concentration where there is low solute concentration, and vice versa. Water can diffuse across most cell membranes directly through the lipid bilayer or by traveling through AQPs. Many cells produce AQPs, because simple diffusion does not permit adequate water flux. Some kidney cells insert AQPs in response to antidiuretic hormone (ADH), so as to increase water flow from the forming urine back into the blood, thereby conserving water. This passive type of water movement is called osmotic flow, and the associated driving force is the concentration gradient of the water.

28

SECTION II Cell Physiology

Water may also be transported across membranes at the expense of energy by the Na–glucose cotransporter (SGLT). The TM transport of two Na+ ions and one sugar molecule has been associated with the influx of 210 water molecules, independent of the osmotic gradient. The energy could come from allowing Na+ to move with its concentration gradient. This molecular pumping would be a secondary active transport mechanism and might account for almost half the daily uptake of water from the small intestine. Osmotic pressure is the mechanical pressure needed to produce a flow of water equal and opposite to the osmotic flow produced by a water concentration gradient. In animal cells, this pressure does not develop across the cell membrane because the cells will change their volume in response to osmotic flow. The concept of osmotic pressure is similar to (and historically preceded) the Nernst equilibrium potential, an electrical potential that produces a flow of ions equal and opposite to a flow produced by a concentration gradient. The Nernst potential is discussed in Chapter 4. If two different solutions are in contact, the osmotic pressure, π, between them is: π = RTΔc

(3)

where R is the molar gas constant (Avogadro’s number times Boltzmann’s constant), T the absolute temperature, and Δc the concentration difference of all of the impermeable solutes. The concentration difference refers to the summated molar concentration of all the particles created when the solute is dissolved in water. It is measured as the osmolarity, that is, the sum of the moles of each component of the solution. A 2-mM solution of MgCl2 contains 6 milliosmoles (mOsm) per liter of solution, 2 for the Mg2+ and 2 for each Cl−. The osmolarity of this solution is 6 mOsm. A 3-mM NaCl solution and a 6-mM urea solution have the same osmolarity because they have the same number of particles per liter of solution. They are said to be isosmotic. The osmolality of a solution can be measured by the change it produces in the freezing point or vapor pressure. Osmolality refers to moles of solute per kilogram of solvent, whereas osmolarity refers to moles of solute per liter of solution. Because 1 L of any body fluid contains very close to 1 kg of water, the distinction is moot in clinical situations, and you may hear

300 mM NaCl

150 mM NaCl

300 mM urea

Cell volume

150 mM NaCl

the terms used interchangeably. Also, the actual pressures are rarely discussed; rather, the osmoles are mentioned directly. Tonicity is a concept that is related to osmolarity but is a special case for cells. A solution is said to be isotonic if it causes neither shrinking nor swelling of cells. A 150-mM NaCl solution (9 g/L or 0.9%) is isotonic for mammalian cells and also isosmotic to the cell contents. A 300-mM urea solution is also isosmotic to the cell contents, but a cell placed in this solution will swell and eventually lyse or burst (Figure 3–12). The urea solution is hypotonic; it has insufficient tonicity to keep the cell from swelling. It differs from the NaCl solution because the urea can cross the cell membrane. The addition of a permeable material to a solution increases its osmolarity but not its tonicity. The addition of more impermeable solutes makes a hypertonic solution; a 300-mM NaCl solution is hypertonic and will cause cells to shrink. If a moderately permeable solute is added to an isotonic solution (e.g., 300-mM urea + 150-mM NaCl), the cells will transiently shrink and then return to their original volume (Figure 3–13). The rate at which they shrink is proportional to the water permeability of the membrane; the rate at which the volume recovers is proportional to the urea permeability. If the original 150-mM NaCl solution is replaced, the opposite effects will occur. The cells will swell as water rushes in and then return to their original volume as the urea (and water) leaves the cell. In some cases, it is convenient to consider a reflection coefficient as a description of the permeability of solutes. Water movement across capillary walls depends on the mechanical or hydrostatic pressure difference and on the difference in colloid osmotic pressure due to differences in protein concentration in the plasma and the interstitial fluid. If the capillary wall is completely impermeable to the proteins, it is said to have a reflection coefficient of 1.0. If the walls become leaky, the reflection coefficient decreases, proteins enter the interstitial space, and water follows. Water movement in the whole body is concerned with two compartments, intracellular and extracellular. The extracellular compartment has two subcompartments: the plasma fluid in the blood vessels and the interstitial fluid that bathes the rest of the cells. The plasma and the interstitial fluid are separated by the capillary walls, which are freely permeable to all the small molecules and ions but normally prevent the plasma

Time

FIGURE 3–12

Cells shrink in hypertonic solutions and swell in hypotonic solutions. (Modified with permission from Landowne D: Cell Physiology,

New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 3 Cell Membranes and Transport Processes

150 mM NaCl + 300 mM urea

150 mM NaCl

Cell volume

150 mM NaCl

29

Time

FIGURE 3–13

The addition of urea causes transient shrinking but does not change the steady-state tonicity. (Modified with permission

from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

proteins from entering the interstitial fluid. The proteins have an overall net negative charge at blood pH. The equilibrium that arises with impermeable proteins and freely permeable ions is called the Gibbs–Donnan equilibrium. This effect produces small ion concentration gradients (> gNa, the membrane potential will be near EK; if gNa >> gK, it will be near ENa, and if they are equal, it will be halfway between. If the membrane is permeable only to these two ions and there is no external source of electrical current, the membrane potential will always be between EK and ENa. These concepts will become more useful when the conductances change, as seen in the next three chapters. Because the resting membrane is preferentially permeable to potassium, the resting potential is sensitive to the external potassium concentration (Figure 4–6). Increasing external K will bring the membrane potential closer to zero or depolarize the membrane. The resting membrane in its normal ionic environment is considered polarized. A change of potential in the positive direction, toward 0 mV, is a depolarization. A change in the other direction, making the membrane potential more negative, is a hyperpolarization.

Increased Ko depolarizes membranes because it reduces the K+ gradient across the membrane and makes EK closer to zero. This reduces the tendency for K+ to leave the cell, so the balance is reached at a less negative potential. Increased Ko+ is a dangerous, potentially lethal condition because excitable cells require the normal resting potential to remain excitable. Doubling the blood K+ level (hyperkalemia) is likely to compromise cardiac muscle function.

Kir CHANNELS SUPPORT THE RESTING POTENTIAL Some cells, notably cardiac and skeletal muscle cells, have Kir channels that are open, thus conducting, at the resting potential and are thought to be the major contributor to the resting K conductance. These were named inward rectifiers when experiments demonstrated that the inward current through them, when the membrane potential was hyperpolarized beyond EK, was larger than the outward current seen when the membrane was depolarized. It is perhaps an unfortunate name because, in normal life, the membranes never experience such a large hyperpolarization. The important aspects of this channel’s function are to be open for outward movement of potassium near the resting potential and then to become nonconducting when the cell is depolarized. This blocking in the depolarized state will be seen to be important for cardiac muscle action potentials, as described in Chapter 6. Kir is not a voltage-sensitive channel. The blocking comes about because Mg2+ or other polyvalent cations in the cytoplasm attempt to go through the channel when they are depolarized and get stuck, thus preventing K+ from using the channel. If the channels are studied under conditions without polyvalent cations, they conduct K+ equally well in both directions.

0

Membrane potential (mV)

−20 −40 −60 −80 −100

EK = 60 mV log [K]o/155

−120 −140 −160

1

10 [K]o mM (note log scale)

100

FIGURE 4–6 The observed membrane potential as a function of the external K+ concentration. The solid line is the theoretical prediction for a membrane that is permeable only to K+. Notice the logarithmic concentration scale. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 4 Channels and the Control of Membrane Potential

GOLDMAN–HODGKIN–KATZ EQUATION If permeabilities are known, rather than conductances, a membrane potential can be calculated using the theoretical Goldman–Hodgkin–Katz (GHK) or constant field equation: P Na + + P K + + P Cl − PNaNai + PKKi + PClClo

Na o K o Cl i V = 60mV log10_________________ + + −

(7)

As in equation (6), the GHK equation simplifies to the Nernst equation if only one permeability is greater than zero. The GHK equation has been useful to describe experimental results when some of the concentrations are set to zero, which makes the Nernst potentials in equation (6) meaningless. The relationship between permeability and conductance can be set on a quantitative basis by considering the condition when the membrane potential is zero and then, after multiplying the chemical flux by Faraday’s constant, equating equations (3–1) and (4–2) to obtain the electrical current. Thus, we have: gxEx = PxF ΔCx

(8)

CHANGES IN MEMBRANE POTENTIAL The membrane potential will change if current is injected into the cell by opening channels that allow ions to flow with their electrochemical gradients. It takes time to change the membrane potential; it will not jump instantaneously to a new value. Many nerve and muscle cells are quite long, more than 1 m for some nerve cells. The effect of a localized current will spread passively from the site of injection but may not change the potential of the entire cell. These temporal and spatial effects are shared by electrical cables and are referred to as the cable properties. They can be understood by considering the membrane capacitance, the membrane resistance, and the longitudinal cytoplasmic resistance between different parts of the cell. The passive spread by cable properties must be distinguished from the active spread by action potentials. The passive effects occur without any change in the number of open channels. If sufficient current enters a nerve axon and depolarizes it above threshold, an action potential will be elicited and will propagate without loss of amplitude over the entire length of the cell. The action potential is regenerated as it propagates. As the wave of opening sodium channels moves, energy is supplied to the process from the Na+ gradient all along the axon. In contrast, a smaller depolarization or a hyperpolarization that does not open Na channels will spread only a few millimeters, becoming progressively smaller when measured at a greater distance from the stimulus. The membrane capacitance is the ratio of the charge separated to the membrane potential—equation (1). The capacitance is related to the membrane geometry by the following equation: K × area C = ________ Thickness

(9)

39

where K is a constant describing the material composition of the membrane. If the area is larger, it will take a greater amount of charge to change the potential. The thinner the membrane, the closer the charges are to each other and the more charges will have to be moved to change the potential. The capacitance of a typical membrane is about 1 μF/cm2; this value is often used to estimate the size of a cell by measuring its capacitance. The membrane resistance is the reciprocal of the membrane conductance: 1 Rm = __ g m

(10)

The longitudinal resistance is proportional to the length and inversely proportional to the cross-sectional area: ρ × length

Rl = ________ Area

(11)

where ρ is the resistivity of the cell contents.

PASSIVE PROPERTIES OF A SMALL ROUND CELL When pulse of current is injected into a small round cell (which can be assumed to have the same membrane potential over its entire surface), the membrane potential does not change instantaneously. Instead, it changes with an exponential time course with a characteristic time constant (τ), the time it takes to discharge the change in voltage to 1/e = 37 percent of its value (or the time it takes to charge to 63 percent of its final value) (Figure 4–7). Initially the injected charges are adding to the stored charges that were causing the original membrane potential. Later, when the membrane potential has reached a new steady state, current equal to the injected current is leaking back out through membrane channels. When the pulse is terminated, the excess stored charge leaks out through the channels and the membrane potential decays exponentially to its original value. The time constant of these exponential changes is the product of the cell’s membrane resistance and capacitance. Many cells have time constants in the range of 1–20 milliseconds. These time constants limit how rapidly the membrane potential can change and permit temporal summation of synaptic events in the central nervous system (see Chapter 7).

PASSIVE PROPERTIES OF A LONG CYLINDRICAL CELL An extended cell or a tissue with cells that are electrically connected by gap junctions may have different membrane potentials at different locations. If there is a local change in permeability, current will flow into or out of the cell and the membrane potential will change at that location and, to a lesser extent, at nearby locations. With a prolonged steady current, which lasts much longer than the time constant described in the previous

40

SECTION II Cell Physiology

I

V

In C

I

R

V

Out A

B

I

ΔV = IR[1 −exp(−t/τ)] V

63%

37%

τ

ΔV = IR exp(−t /τ)

τ

C

FIGURE 4–7 A spherical cell (A), its equivalent circuit (B), and the voltage response to an injected pulse of current (C). (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

section, there will be a steady change in potential that is largest at the point of current entry and falls off exponentially with distance with a characteristic length constant (λ) or space constant, the distance it takes for the potential to drop to 37 percent of its

I

value at the site of injection (Figure 4–8). Typical length constants for nerve and muscle cells are 0.1–2.0 mm. A 10-μm cell is approximately isopotential, but a 150-cm-long nerve cell requires an active propagation mechanism to be able to communicate electrical activity from end to end. The voltage change declines because some of the injected current leaks out of the cell and is not available to depolarize the adjacent regions. The amount that leaks out is proportional to the voltage change, so the decline is exponential. The length constant depends on the ratio of the membrane resistance to the longitudinal axoplasmic resistance. As the distance from the injection increases, the amplitude of the transient response decreases and the rise time becomes longer and more sigmoidal (Figure 4–9). Initially most of the charge entering the cell goes to the membrane immediately adjacent to the source; only later it is enough available to charge the distal membrane. When the pulse is terminated, all responses decay at the same rate. Synapses are distributed on the dendritic tree at different distances from the cell body. The more distant synapses will have less effect on the cell’s activity; the amplitude of the effect will be lower and its time course will be slower. Passive spread is important for action potential propagation; it is the mechanism of connection between the active region and the adjacent resting region. Action potentials propagate more rapidly in larger-diameter axons because they have lower longitudinal resistance and longer length constants. The passive properties, membrane capacitance, membrane resistance, and longitudinal resistance, are referred to as cable properties because they also determine the ability of under-

V1

V2

V3

A RI

In

I

C

RI

Rm

RI

Rm

Rm

RI

Rm

Out B 1

ΔV(x) = ΔVo exp(−x/λ) 2

3

37% λ

Distance x

C

FIGURE 4–8

A long cell (A), its equivalent circuit (B), and the steady-state distribution of its membrane potential in response to a steady injection of current (C). (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 4 Channels and the Control of Membrane Potential

I

V2

V1

41

V3

I 1 2 V

FIGURE 4–9

3

The transient voltage responses at three distances from the site of an injected pulse of current. (Modified with permission

from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

water cables to transmit signals. The length constant for undersea cables is several kilometers; for nerve axons it ranges from about 0.1 to 20.0 mm depending on the diameter. Undersea cables rely on repeater amplifiers for longer distances; nerves use voltage-dependent sodium channels, as described in Chapter 6. When cell–cell junctions join cells, they can operate electrically as if they were all one cell. Many of the cells in the heart are coupled and action potentials propagate from one cell to another supported by the passive spread of depolarization via the cell–cell junctions. There are also cell–cell junctions between some neurons in the CNS. For some it is helpful to visualize a hydraulic analogy of these electrical phenomena. Electrical voltage is analogous to water pressure and electrical current to solution flow. The long cell is similar to a leaky hose, with lower membrane resistance corresponding to more leaks and lower longitudinal resistance corresponding to larger hose diameter.

CHAPTER SUMMARY ■

■ ■

■

An electrical membrane potential is directly proportional to the separation of positive and negative charges across the cell membrane. The ratio of separated charge to voltage is the membrane capacitance. Cell membranes separate solutions with quite different ionic compositions. The movement of ions is directly proportional to the net driving force on the ions. The net driving force is the electrochemical gradient or the difference between the effect of the membrane potential and the effect of chemical gradient. The effect of the chemical gradient can be expressed by the Nernst equilibrium potential.

■

■

■

■

■

■

Only a very small number of ions must be separated to produce the membrane potential. This is negligible compared with the concentrations available on both sides. The resting membrane potential is a steady state with ions moving with their electrochemical gradient through channels and an equal number being pumped against their electrochemical gradient at the expense of ATP. The GHK equation can be used to calculate the membrane potential if the permeabilities to the various ions and their concentrations are known. When current flows through the membrane, the membrane potential changes in time and in space, governed by the “cable properties.” When a pulse of current is injected into a cell, there is a characteristic time required for the membrane potential to change. When a steady current is injected into a long cell, the potential change is largest at the injection site and decreases characteristically away from the site.

STUDY QUESTIONS 1. If all the Na–K pumps in the membrane of a muscle cell were stopped, all of the following changes would be expected for the muscle cell except A) immediate loss of the ability of the cell to carry action potentials B) gradual decrease in internal K+ concentration C) gradual increase in internal Na+ concentration D) gradual decrease in resting membrane potential (the potential would become less negative) E) gradual increase in internal Cl− concentration.

42

SECTION II Cell Physiology

2. If the potassium ion concentration on the outside of a resting skeletal muscle cell is doubled to twice of the normal value by adding K+ and Cl− in equal amounts, what would be the best estimate of the effect on the resting membrane potential? A) hyperpolarize about 100 mV B) depolarize about 5 mV C) hyperpolarize about 15 mV D) depolarize about 20 mV E) no measurable effect 3. The following cell in an organism called the Europa louse was recovered from a moon of Jupiter with a space probe. The intracellular and extracellular concentrations of all the ions are given as follows: Extracellular +

Intracellular

Rb = 100 mM

Rb+ = 1 mM

SO42− = 50 mM

SO42− = 0.5 mM

The cell membrane is permeable to Rb+ and not to SO42− or water. What is the resting membrane potential? (The sign refers to the potential inside of the cell.) A) +30 mV B) +60 mV C) +120 mV D) −30 mV E) −60 mV

4. A scientist is recording from the soma of a neuron with an intracellular microelectrode to study synaptic inputs on the dendrites. The letters a, b, and c below indicate the synaptic potentials recorded from three different synaptic inputs. For identical synaptic inputs to the dendrites, which synaptic potential was generated by the synapse at a location on the dendrites closest to the soma?

A)

B)

C)

C

Sensory Generator Potentials David Landowne

5

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■

■

List eight sensations and the names of the specialized sensory receptor cells responsible for generating these sensations. Describe sensory adaptation in these receptors. Draw a schematic cartoon of (a) a Pacinian corpuscle and its sensory ganglion cell (including cell body and central process); (b) a cochlear hair cell and its synapses; and (c) a photoreceptor and its synapses. List three or more differences between ion channels that underlie action potentials, resting potentials, and receptor potentials.

Animals have developed a wide variety of sensory organs capable of monitoring chemicals, light, sound, and other mechanical events in the external and internal environments. In all of these organs there are mechanisms to convert information about the environment into electrical signals within the nervous system. This chapter is concerned about the conversion process and some general properties of all receptors. More details about the sensory organs and the systems that process the nerve signals are provided in Section 4: Chapters 13, 15, 16, and 17. Transducers can convert one type of energy to another. The cells or portions of cells that perform the initial step of sensory transduction convert light or mechanical energy or the presence of specific chemical conditions into a change in the membrane potential called the receptor potential or sensory generator potential. In small sensory cells, this generator potential directly controls the synaptic release process to be described in Chapter 7. In longer cells, the generator potential will initiate an action potential that propagates to a distant presynaptic ending and then trigger the release process. The information about the stimulus energy that was transduced into a generator potential is then encoded in the frequency of action potentials. Each sensory cell has an appropriate stimulus, called its adequate stimulus. The CNS interprets signals coming from this cell in terms of its adequate stimulus. The adequate stimulus for photoreceptors in the eye is visible light. If an electric

Ch05_043-046.indd 43

shock or sufficient pressure is applied to the eye, a person will report flashes of light, even if the room is dark. Each cell also has a receptive field that is the region in stimulus space that evokes a response in that cell. The receptive field of a photoreceptor in the retina is a particular location in the visual space in front of the eye and a range of colors to which that receptor is sensitive. The receptive field for a somatosensory nerve in the skin is the area of skin that elicits a response. The receptive field for an olfactory neuron is the range of chemicals it can detect. Cells in the CNS concerned with sensory information also have receptive fields. Different cells handle sensory information from the feet than that from the hands. The incoming information arrives on “labeled lines”; the CNS processors know from whence it comes. There are several locations in the brain that have receptive fields including the same location in visual space. The receptive fields of these higher-order cells are more complex, as signal processing has occurred comparing the output from one lowerorder cell with that of others. Mechanosensory transduction is direct, by mechanosensitive channels in the membrane. The sensory cell often has molecules or structures to focus the mechanical energy or filter out undesired mechanical disturbances, and there may be an elaborate organ—such as that comprising the outer, middle, and inner ear—to deliver the desired mechanical energy to the appropriate cell. In the end, a relatively nonspecific cation channel opens and both Na+ and K+ move with their concentration

43

11/26/10 9:41:42 AM

44

SECTION II Cell Physiology

FIGURE 5–1

The changes in membrane potential of a mechanosensory nerve ending to stimuli of three different amplitudes. (Modified with permission from Landowne D: Cell Physiology, New

York: Lange Medical Books/McGraw-Hill, 2006.)

gradients. In skin mechanoreceptors, such as the Pacinian corpuscle discussed below, there is a greater driving force on Na+, so more Na+ than K+ moves and the cell depolarizes. The number of mechanosensitive channels that open is proportional to the amount the membrane is stretched by the stimulus. A larger stimulus will open more channels and produce a larger depolarization (Figure 5–1). If the depolarization is large enough, action potentials will be initiated and will propagate toward the CNS. The situation is more complex in the ear, because the sensory cells (called sensory hair cells, for the hairlike appearance of the modified cilia on their apical surface) are part of an epithelium that separates two different solutions. However, mechanical

disturbance of these cells by the appropriate sound also leads to inward current carried by K+ through mechanosensitive channels on the cilia and depolarizes the cell. The sensory hair cells are short and synapse with auditory nerve cells in the ear. The hair cells do not have action potentials; they are short compared to their length constant, so they can rely on passive spread to open CaV channels to release transmitters. Some taste chemosensation is supported directly by chemosensitive channels, as in the glutamate receptors for the umami taste (the distinctive savory taste of glutamate); these are relatively nonselective cation channels that depolarize the cells. Others use channels even more directly; Na+ moving through epithelial sodium channels (ENaCs) depolarizes cells to provide the salty taste sensation. Odors are detected by G protein– coupled receptors (GPCRs) whose G proteins activate adenylyl cyclase, thus elevating levels of cyclic adenosine monophosphate (cAMP). The cAMP opens a cyclic nucleotide–gated (CNG) nonspecific cation channel that depolarizes the cell. CNG channels are tetramers with six TM segments and are structurally similar to KV channels but lack the latter’s exquisite selectivity for K ions and the voltage sensitivity. Light transduction also involves GPCRs with seven TM segments: rhodopsin in the rods and three other opsins in the cones tuned for short, medium, and long (or blue, green, and red) wavelengths. The chromophore that absorbs the light is 11-cis retinal (MW 284). Absorption of a photon triggers conversion of the retinal to the all-trans isomer, which causes a conformational change in the opsin protein informing the G protein that

Disk membrane

Rhodopsin (GPCR)

Phosphodiesterase

β/γ Transducin (G protein)

α

cGMP

hν

GMP

cGMP Na

FIGURE 5–2 The processes linking light absorption by rhodopsin and the closing of cyclic nucleotide–gated channels. Light induces a conformational change in rhodopsin that causes the subunits of transducin to dissociate. The alpha subunit stimulates a phosphodiesterase that degrades cGMP. In the absence of cGMP a channel that was allowing the entry of Na+ closes and the cell hyperpolarizes. (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 5 Sensory Generator Potentials an event has taken place (Figure 5–2). The G protein is called transducin; it was the first G protein to be identified and was named before the family was well known. Transducin activates a phosphodiesterase that hydrolyzes cyclic guanosine monophosphate (cGMP). In the dark, there is a CNG channel that is open and carrying inward current. The channel closes when the cGMP level drops; when the light is on, the dark current decreases and the cell hyperpolarizes. There is amplification along this chemical pathway, so one photon leads to the closure of many CNG channels. The hyperpolarization reduces a steady output of synaptic vesicles to pass the message on to the next cell in the pathway to the brain. The sensation of uncomfortably hot skin temperature has been linked to the direct activation of a channel called VR1, for vanilloid receptor. It is also known as the capsaicin receptor because it can be activated by the vanilloid capsaicin, the major piquant ingredient in hot peppers. VR1 is a member of the transient receptor potential (TRP) channel family; it has a six-TM architecture and is permeable to cations. Raising the temperature into the range of 42°C (107.6°F), which many human observers identify as painfully hot, opens this channel, depolarizes the sensory ending, and initiates a train of action potentials. Other members of the TRP family have been associated with temperature sensation and other functions, though not all with pain. Our everyday experience of our sense is not a direct representation of the stimuli but rather the result of processing that occurs in the nervous system. We do not see the world as flashes of light at different positions in our visual fields but rather as objects and surroundings. Pain is an experience that can arise from a wide variety of stimuli without necessarily telling us anything definite about the stimulus. A few specific nociceptors have been identified, but there are also many other receptors that may be associated with pain. Elevated K+ from damaged cells or the direct cutting of a nerve cell can induce action potentials that may be interpreted as pain. Acid-sensing ion channels (ASICs) in the ENaC family respond to lactic acid released in the heart and depolarize nerves that provide the sensory pathway for the painful experience of angina. P2X3 receptor channels, which can be activated by adenosine triphosphate (ATP) released by damaged cells, have been associated with pain from overstretched bladders, and P2X4 receptors have been associated with a neuropathic pain generated within the nervous system without obvious outside stimuli.

SENSORY ADAPTATION All senses except pain adapt; if they are presented with a maintained stimulus, the response will diminish in time. The Pacinian corpuscle adapts rapidly and responds to a sustained stimulus with only one or two action potentials at the start (Figure 5–3). When the stimulus is released, there is an offresponse and another action potential is initiated. Most of this adaptation takes place in the onionlike capsule of accessory

45

FIGURE 5–3

Fast and slow sensory adaptation. The colored bars indicate a steady level of stimulation. The rapidly adapting receptor on the left adapts completely after two impulses have occurred. In the slowly adapting receptor on the right, the rate of firing declines less rapidly. (Modified with permission from Landowne D: Cell Physiology, New York: Lange Medical Books/McGraw-Hill, 2006.)

cells that surrounds the nerve ending. When one side of the capsule is distorted by the stimulus, at first the distortion is transmitted to the nerve ending and the nerve depolarizes. Then the capsule balloons out to the sides, the forces on the nerve are relieved, and the nerve stops firing. When the stimulus is removed, the capsule rebounds to its original shape, transiently pushing the sides of the nerve in the process. The Pacinian corpuscle is tuned to provide maximum information about vibratory stimuli and to ignore steady pressure. Muscle spindle organs are sensory structures embedded in skeletal muscles, which provide information about the length of the muscle to the CNS (see Figure 2–3 and Chapter 14). Muscle spindles adapt rapidly to changes in length but also continue to fire during a sustained stimulus. The firing rate decreases slowly during the stimulus; muscle spindles are said to be slowly adapting (Figure 5–3). The nervous system responds to changes in the environment, and by reducing the messages indicating that a stimulus is still present, more attention can be given to any changes. Adaptation takes place at many levels—accessory tissue before the receptor potential, the receptor potential itself, the encoding mechanism that initiates action potentials, and at many higher synapses where the incoming message is integrated with other signals. Adaptation to light occurs by constricting the pupils, by photobleaching the pigments, and by feedback regulation of the steps in the biochemical cascade. Many senses have some form of efferent control. The sympathetic nervous system can release norepinephrine onto the Pacinian corpuscle, which will increase its sensitivity to mechanical stimuli. Muscle spindle organs (see Chapter 14) have efferent nerves (γ motor nerves) that set the range of lengths to which the sensory nerve is most sensitive. There are also motor hair cells in the ear that can selectively enhance the sensitivity of sensory hair cells to particular sounds (see Chapter 16). There are many controls on the eye to assure that the object of interest is suitably focused on an appropriate portion of the retina even as the head changes its position in space (see Chapter 15).

CHAPTER SUMMARY ■ ■

Each sensory cell has an adequate stimulus. Touch, hearing, and other mechanosensation occur via mechanosensitive channels.

46 ■ ■ ■ ■

SECTION II Cell Physiology Taste is mediated by chemosensitive channels and odor by GPCRs and CNG channels. Vision is also mediated by GPCRs—for example, rhodopsin—and CNG channels. Pain is mediated by ASICs and purine-activated channels. All senses except pain adapt.

10

Response impulse/s

Response impulse/s

STUDY QUESTIONS

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10 5

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30 50 Seconds A) Response impulse/s

Response impulse/s

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10

50 30 Seconds C)

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30 50 Seconds B)

10

50 30 Seconds D)

10 5

1. The graphs above show the frequency of action potentials (y-axis) recorded from a primary sensory afferent fiber during sensory stimulation. Which one of these graphs shows the response from a typical sensory fiber (excluding pain fibers) to a constant maintained stimulus applied beginning at 10 seconds and lasting throughout the recording (i.e., until 50 seconds)?

2. Which of the following sensory cells has a hyperpolarizing generator potential in response to its adequate stimulus? A) Pacinian corpuscle nerve ending B) muscle spindle nerve C) taste bud cell D) retinal cone cell E) olfactory nerve ending 3. Hair cells are the sensory receptor cells in the cochlea. They are excited by the vibration of the hair bundle. Vibration of the hair bundle causes which one of the following events? A) influx of K+ through mechanosensitive cation channels in the tips of the cilia B) influx of Ca2+ through cyclic nucleotide–gated (CNG) channels in the tips of the cilia C) long-lasting hyperpolarization of the hair cell D) a train of action potentials propagated from the cilia to the cell body of the hair cell

C

Action Potentials David Landowne

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O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■ ■ ■

Describe the activation of action potentials. Explain the propagation of action potentials. Describe the membrane currents underlying action potentials. Describe the activity of channels producing action potentials. Explain the membrane basis of the action potential threshold and refractory period. Explain actions of calcium, local anesthetics, and neurotoxins on action potentials. Describe the relationship between channel activity and cardiac muscle contraction. Describe the membrane basis of intrinsic cardiac pacemakers. Describe the effects of acetylcholine and NE on cardiac action potentials.

ROLE OF VOLTAGE-SENSITIVE SODIUM CHANNELS Action potentials are changes in membrane potential that propagate along the surface of excitable cells. They are best known in nerve and muscle cells but also occur in some other cells, including egg cells associated with fertilization. Unlike some other changes in membrane potential, action potentials are characterized as being “all-or-none”; they have a threshold for excitation and a stereotyped duration. Immediately following an action potential, the excitable cell has a refractory period when it is more difficult or impossible to elicit a second action potential. Like most changes in membrane potential, action potentials are the result of changes in membrane permeability due to the activity of channels, or proteins embedded in the membrane lipid bilayer that facilitate the passive movement of specific ions with their electrochemical gradients. An action potential is a change in membrane potential from a resting potential of about –70 mV (the inside of the cell is negative) to about +30 mV and then back to the resting potential. Their duration

Ch06_047-058.indd 47

in nerve and skeletal muscles is on the order of 1 millisecond; in cardiac ventricular muscle cells, their duration is several hundred milliseconds. In nerve and skeletal muscles, the underlying permeability changes are a transient increase in sodium permeability followed, after a delay, by an increase in potassium permeability due, respectively, to the activation of sodium and potassium channels (Figure 6–1). Cardiac action

25 mV 10 mS/cm2 1 ms

FIGURE 6–1 An action potential (red trace) and the underlying changes in membrane conductance for Na+ (blue trace) and K+ (beige trace). (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

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potentials are more complex and also involve the activation of calcium channels. Action potentials are all-or-none and propagate because the sodium channels are voltage-sensitive. Depolarization, the reduction of the membrane potential, from –70 to 0 mV, induces a conformational change within a few hundred microseconds in the sodium channel protein, which leads to in increase in permeability to sodium ions. Sodium ions rush into the cell through these open voltage-dependent Na (NaV) channels and bring positive charge with them, which further depolarizes the cell, opening more NaV channels (Figure 6–2). This positive feedback loop persists until all of the sodium channels have opened. Once the loop is started, it continues to completion. The depolarization spreads passively to adjacent regions of the membrane and activates nearby sodium channels. This wave of molecular conformational change and electrical activity propagates over the length or surface of the cell at velocities up to 120 m/s. Potential energy that is stored in the sodium concentration gradient is sequentially used along the propagation path. The propagation velocity is determined by the rate of molecular change and the electrical properties of the cell that control the spread of potential changes (cable properties). About 1 millisecond later, the sodium channels undergo a second conformational change and inactivate. In this third conformation, they are closed and sodium no longer passes

Change of channel conformation

Depolarization of membrane potential

Increase of sodium permeability

Entry of sodium into cell

FIGURE 6–2 The action potential’s positive feedback cycle. The cycle is started by a depolarization and continues until all of the sodium channels have been activated. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

through. In addition, the NaV channels are unable to open again until the membrane is repolarized to the resting potential for a few milliseconds to allow recovery from inactivation (Figure 6–3). This automatic closing of the sodium channels limits the duration of nerve and skeletal muscle

Open

Activated

Resting closed

Inactivated closed

FIGURE 6–3 Sodium channels can be in different functional states. A depolarization first causes the channel to change from the resting state to the activated and open states and later to the inactivated state. Repolarization is required to go from the inactivated state back to the resting state. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 6 Action Potentials

Vi

Vm

49

Axon

Axial wire Vo Vc

I

FIGURE 6–4 A simplified voltage-clamp circuit for a squid giant axon. The membrane potential, Vm, is sensed as the difference between the inside potential, Vi, and the outside potential, Vo. Vm is compared to the command potential, Vc, and, if they are different a current flows through the axial wire and the cell membrane to make Vm equal to Vc. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

action potentials. Loss of the ability to open again produces the refractory period. The outward movement of K+ carrying positive charge out of the cell produces the repolarization (the falling phase of the action potential). In some cells, voltage-dependent K channels (KV) channels—whose activation is slower than that of sodium channels—facilitate repolarization. In mammalian myelinated axons, the repolarizing current passes through the (nonvoltagesensitive) potassium channels that produce the resting potential. The axons seem to be an exception; the presynaptic nerve terminals and the cell bodies of most neurons have KV channels.

VOLTAGE CLAMPING This understanding of the action potential mechanism comes from the work of Alan Hodgkin and Andrew Huxley about 50 years ago. Working with giant nerve axons isolated from squid, they were able to break the positive feedback loop and

measure the effect of a change in membrane potential in the ionic permeabilities without any change to the membrane potential due to the movement of ions. Their technique was to include the nerve membrane in a negative feedback circuit (Figure 6–4). A pair of electrodes measures the membrane potential; this is then compared with a desired command potential. If the membrane potential is different from the command potential, a current is made to flow through the membrane in a direction that reduces the difference. Thus, the voltage across the membrane is clamped at a desired value. When the controlled voltage is a pulse from the resting potential to 0 mV, four different kinds of current can be identified (Figure 6–5). The first is the charge movement necessary to change the potential or change the charge on the membrane capacitance. Second, there is a small outward current called the gating current. Then there is an inward current that is replaced in a few milliseconds by an outward current, which lasts as long as the pulse.

0 mV −70 mV Ic

“Voltage clamped” membrane potential

IK

Ig

Outward INa Inward

Current with both potassium and sodium ions

FIGURE 6–5 The membrane currents (lower trace) in response to a voltage-clamp pulse (upper trace). Ic, capacity current; Ig, gating current; INa, sodium current; IK, potassium current. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

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SECTION II Cell Physiology

0 mV −70 mV

“Voltage clamped” membrane potential

IK Outward Current without sodium ions Inward

Current without potassium ions

INa 1 ms Ig

Current without either ions

FIGURE 6–6

The separation of the currents by changing the solutions. The labels have the same significance as Figure 6–5.

(Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

One can replace the contents of a segment of squid axon with a simple salt solution and maintain functioning channels. By changing the solutions bathing both sides of the membrane, one can separate the currents carried by Na+ (INa) and K+ (IK) and also see the gating current (Ig) still present in the absence of either ion (Figure 6–6). Notice that at 0 mV, the Na current is inward and the K current outward. The Na current activates or increases more rapidly than the K current. It inactivates or decreases during the pulse, even though the membrane potential is kept at 0 mV, whereas the K current remains for the duration of the pulse. If the potential is pulsed to other depolarized potentials, all four components of the current are present, although their amplitude and time course and, in the case of INa, direction may change (Figure 6–7). The Na current becomes more inward between the resting potential and about 0 mV. Larger pulses

produce less inward Na current until, at about +60 mV, no net current passes through the Na channels. Still larger pulses can drive outward Na current through the Na channels. The reversal of the current occurs at the sodium equilibrium potential, ENa. If the ratio of the sodium concentrations bathing both sides of the membrane is changed, this reversal potential also changes. With modest depolarizations, the inward current increases because larger pulses open more sodium channels. However, the less negative potential decreases the inward driving force on the sodium ions; after most of the NaV channels have been opened, still larger depolarizations decrease the Na current. When the membrane potential exceeds the sodium equilibrium potential, Na is forced out of the cell through the open NaV channels. In a free-running action potential, the membrane potential never exceeds the sodium equilibrium potential and there is always a net entry of Na into the cell.

+80 mV +60

1 mA/cm2 1 ms

+40

0 −20

−70

+80 mV +60 +40 0 −20

FIGURE 6–7 The current’s responses (upper traces) to voltage steps of varying amplitude (lower traces). Capacity current transients not shown. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 6 Action Potentials

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The Hodgkin–Huxley equations are available in a commercial computer program called Neuron. The Web site (http://nerve.bsd.uchicago.edu/nerve1.html) has a JavaScript rendition that will allow you to manipulate the equations with most modern Web browsers.

1 mA/cm2 10 ms 0 mV −70

FIGURE 6–8

The recovery from inactivation shown by a two-pulse experiment with different amounts of time at the resting potential between pulses. Capacity current transients not shown. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

The Na current activates and inactivates more rapidly as the size of the pulse is increased. If a second pulse is given immediately after the first, the gating current and the sodium current during the second pulse are smaller than during the first pulse (Figure 6–8). They both recover in parallel as the duration between pulses is increased. The rate of recovery from inactivation is also voltage-dependent, as the channels recover more rapidly at more hyperpolarized potentials. The K current increases and becomes more rapid as the membrane potential is increased. Above about +20 mV, the increase in amplitude becomes proportional to the change in potential, indicating that all of the channels are open and that only the driving force continues to increase. The gating current is a direct sign of the conformational changes in the NaV channel proteins. These molecules contain charged groups and dipoles that move or reorient when the electrical field changes, specifically the S4 TM helices shown in Figures 3–3 and 3–4. This movement can be measured as the gating current. As the pulse is made progressively more positive and more sodium channels open, the amplitude of the gating current grows and the currents become more rapid. Above about +20 mV, these two changes are complementary and the area under the gating current trace is constant, indicating that all of the channels are undergoing conformational changes and are doing so more rapidly at more positive potentials. The capacitance current increases linearly with the size of the pulse because it requires more charge to change the voltage by larger amounts. Hodgkin and Huxley separated the currents and showed how the ionic currents were proportional to the driving force on the ions. They created mathematical equations that emulated the amplitude and time course of the permeability changes and showed that these equations could predict the amplitude and time course of action potentials as well as their threshold, conduction velocity, refractory period, and several other features. Their concept of describing ionic current as the product of conductance times driving force is used to describe most of the remaining electrophysiological phenomena in all cells and tissues.

THRESHOLD The threshold arises because there are two different effects of small depolarizations. On the one hand, depolarization will increase the probability that NaV channels open and permit inward current, which will lead to further depolarization. On the other hand, depolarization moves the membrane potential further away from the potassium equilibrium potential, increasing the net driving force on potassium ions and thus producing an outward current through the resting potential potassium channels, which will lead to repolarization. If a sufficient number of sodium channels are opened so that the inward sodium current exceeds the outward potassium current, the cell has exceeded threshold and will continue to depolarize until all of the available sodium channels have opened. Treatments that reduce the sodium current—for example, reducing extracellular sodium concentration or reducing the number of NaV channels—will elevate the threshold.

REFRACTORY PERIODS During an action potential, most of the NaV channels activate or open and then inactivate and close into a state that differs from their condition before the action potential. In order to recover from inactivation and be available to open again, the NaV channels must spend some time with the membrane potential near the resting potential. They will not recover if the membrane remains depolarized. During this recovery, the axon is said to be refractory because it is resistant to stimulation. The refractory period is divided into two segments: an absolute refractory period when no stimulus, however large, can elicit a second action potential, followed by a relative refractory period when the axon can be stimulated again but requires a larger stimulus to elicit the second response than was needed for the first (Figure 6–9). During the absolute refractory period, so few NaV channels have recovered that even if all of the recovered channels were opened, there would be insufficient sodium current to exceed the outward potassium current, which tends to restore and maintain the resting potential. During the relative refractory period, a larger depolarization is required because a larger fraction of the available NaV channels must be opened to obtain the same number of channels opened in the first stimulus. In addition, in many nerve and muscle cells, there are more open potassium channels immediately following an action potential, which also makes the cell more difficult to excite a second time.

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3

Relative threshold

Absolute

Relative

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FIGURE 6–9 The absolute and relative refractory periods. The time axis begins with the occurrence of an action potential. During the absolute refractory period no stimulus, however large, can elicit a second action potential. During the relative refractory period a second action potential can be elicited but it requires a larger stimulus than that in the resting state. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

MYELINATION

DISEASES

Vertebrate nervous systems present a specialization of nervous function not seen in invertebrates, namely myelination (Figure 6–10). Accessory cells wrap nerve axons with many layers of their own membrane, electrically insulating most of the cell. NaV channels cluster in the regions between these wraps, in the nodes of Ranvier. The Na current enters the cell only at these nodes; excitation “jumps” from node to node in what is called saltatory conduction. The spread between nodes is the same passive spread seen in unmyelinated nerve cells, but it is more effective, that is, it produces a more rapid conduction velocity. The myelin wraps increase the resistance between the axoplasm and the surrounding media, which, in turn, increases the length constant for passive spread. The myelin also increases the effective thickness, which decreases the effective capacitance and reduces the amount of charge required to change the potential. Both effects speed conduction.

There are many diseases or conditions of reduced or excessive excitation of cells. Perhaps the most familiar is the conduction of acute pain information, which is frequently treated with local anesthetics; these act by blocking the NaV channels. Some forms of epilepsy and some cardiac arrhythmias are also treated with NaV channel blockers. One type of long-QT (LQT) syndrome, a cardiac arrhythmia, has been linked to a mutation in one of the Na+ channel genes, and a hyperkalemic periodic paralysis (HyperKPP) has been linked to another. Other LQT syndromes have been associated with KV channels. Hypocalcemia is associated with increased excitability of nerves and skeletal muscle and may produce uncontrollable muscle contraction (tetany). Hypercalcemia renders nerves and muscles less excitable. Calcium binds to the membrane near the S4 voltage sensor (Figure 3–4) of the NaV channel and has an effect similar to hyperpolarization. The positive charge on the calcium ion repels the positively charged S4 helix, making it

FIGURE 6–10

The effect of myelination on the longitudinal spread of current. In the upper diagram Na+ is shown entering (colored arrow) at a node of Ranvier and the associated current loops are shown in black. In an unmyelinated nerve (lower diagram) the same current loops occur but over a shorter distance; hence, the action potential propagates more slowly. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 6 Action Potentials

DRUGS AND TOXINS

more difficult for the S4 to move outward and open the channel. The result is that, in low calcium conditions, the sodium channel opens in response to a smaller stimulus or even spontaneously at the resting potential. The calcium binding does not change the resting potential as measured with electrodes in the bulk compartments on both sides of the membrane. There are demyelinating diseases, such as multiple sclerosis (MS), where myelin is lost and conduction can become slower or fail altogether. MS is an autoimmune disease and is generally treated with synthetic corticosteroids such as prednisone. The symptoms can be eased by providing air conditioning or moving to a cooler climate. Cooling helps, somewhat paradoxically, because although it slows the opening of sodium channels and thereby slows the propagation velocity, it also slows the inactivation of NaV channels and increases the duration of the action potentials; thus, the greater Na+ influx makes the propagation more reliable. Reliability is often discussed in terms of the safety factor for propagation. In healthy individuals, the 100-mV action potential that arrives at the next node of Ranvier is about five times larger than the 20-mV depolarization required for initiating a new impulse at that node. In patients with MS, the action potential reaching the next node may be diminished to near or below the size needed to reinitiate the impulse. One effect of cooling nerves is to increase the safety factor for propagation.

1

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++++−−−−+++++++++++++++ −−−−++++−−−−−−−−−−−−−−−

++++++++++−−−−+++++++++ −−−−−−−−−−++++−−−−−−−−−

+++++++++++−−−−++++++++ −−−−−−−−−−−++++−−−−−−−−

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After the identification of these specific Na+ and K+ conductances, they were shown to be molecularly separate because they differ in pharmacology and respond differently to various drugs. Tetrodotoxin (TTX), a poison found in the internal organs of puffer fish, selectively blocks nerve NaV channels at nanomolar concentrations. Local anesthetics such as lidocaine or benzocaine also block NaV channels. There is a greater diversity among KV channels and also among the drugs that block them. Tetraethyl ammonium (TEA) ions and 4-aminopyridine are among the KV channel blockers. There are also compounds that chronically activate NaV channels, such as veratridine, pyrethroid insecticides, and brevetoxin, one of the red-tide toxins.

EXTRACELLULAR RECORDINGS— COMPOUND ACTION POTENTIALS Action potentials can be recorded with a pair of wires placed on the surface of a nerve bundle, typically about 1 cm apart. When a nerve impulse passes these wires, a biphasic action potential is seen on the display (Figure 6–11). This is a differential recording of the same nerve impulse that would

++++−−−−++++ −−−−++++−−−−

++++ ++++−−−− −−−− −−−−++++

+++++++++++++ −−−−−−−−−−−−−

++++++++++++++−−−−+++++ −−−−−−−−−−−−−−++++−−−−−

+++++++++++++++−−−−++++ −−−−−−−−−−−−−−−++++−−−−

2

1

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FIGURE 6–11 Externally recorded action potentials. Left: Biphasic action potential recorded from an intact axon. Right: Monophasic action potential recorded near the site of a crush injury. The potential is measured between the two circles above each diagram. The numbers on the traces indicate the timing of the associated diagram above. The colored region inside the nerve cell is propagating from left to right. (Modified with permission from Landowne D: Cell Physiology. New York:

4

Lange Medical Books/McGraw-Hill, 2006.)

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SECTION II Cell Physiology α δ

1 mV 10 ms

β

B 1 μV 50 ms C

γ

δ

FIGURE 6–12 A compound action potential. Left: High sweep speed. Right: Lower sweep speed, higher vertical gain. The letters refer to specific groups of axons within the nerve. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

appear as in Figure 6–1 if the recording were made with an intracellular microelectrode. One deflection occurs as the impulse passes the first wire and the second occurs as it passes the second wire. They are in opposite directions because the two wires lead to opposing inputs for the display. If the nerve is crushed between the electrodes so that the impulse does not reach the second electrode, the response becomes monophasic. This type of recording with external electrodes is used clinically to test nerve integrity. A nerve bundle can also be stimulated with another pair of wires on a remote stretch of the same bundle. With appropriate equipment, stimulation and recording can be made through the skin without dissecting out the nerve bundle. When a nerve bundle is stimulated, more than one axon may be excited. The electrical recording of the combination of the action potentials produced is called a compound action potential. The compound action potential is also biphasic if the nerve is intact between the recording wires. Besides being biphasic, there are many differences between compound action potentials recorded with external electrodes and the single-cell action potential recorded with an electrode inside the cell and a reference electrode outside the cell. The compound action potentials are much smaller, on the order of 1 mV, and there is no sign of the resting potential because both wires are outside the nerve. The compound action potential is not all-or-none because a larger stimulus will bring more individual axons above threshold and the compound action potential’s amplitude is proportional to the number of axons firing. The compound action potential becomes smaller and longer at greater distances from the stimulating electrodes because the conduction velocity of the various axons is not exactly the same and the action potentials disperse as they travel away from the stimulation site. The threshold and conduction velocity of the various axons within a nerve bundle vary with the diameter of the axons. Large axons have a lower threshold to stimulation by external electrodes. (Of course, in life they are usually stimulated more selectively by a specific receptor or synaptic input.) The larger-diameter fibers have a lower threshold; more of the stimulating current flows through them because they have a lower internal resistance. Larger axons also have a more rapid conduction velocity, again because of their lower internal resistance.

Vertebrate peripheral axons are classified by their diameter (or conduction velocity or threshold to external stimulation). There are groups of nerve fibers with similar diameters. The groups of different diameters can be distinguished as separate elevations in the compound action potential (Figure 6–12). There is some correlation of function with diameter. For example, large myelinated motoneurons leading to skeletal muscles are Aα fibers and small unmyelinated fibers carrying pain information are C fibers. The larger fibers have faster conduction velocities and lower thresholds to external electrical stimuli.

CARDIAC ACTION POTENTIALS The heart is a pump made up of excitable muscle cells. The electrical activity of these cells controls their contraction. The function of these cells will be discussed further in the context of function of the heart in Chapter 23. The overall control of the heart’s pattern of contraction is by the spread of action potentials through a special conducting system of modified heart muscle cells (Purkinje fibers) and through the atrial and ventricular muscle cells themselves (see Figure 23–3). There are two types of action potentials in the heart distinguished by their rate of depolarization and their conduction velocity. The fast action potentials, with a rapid rate of depolarization and a rapid propagation velocity, are found in atrial and ventricular muscle cells and Purkinje fibers. The slow action potentials are normally found in the sinoatrial (SA) node and the atrioventricular (AV) node.

CARDIAC MUSCLE ACTION POTENTIALS In cardiac muscle action potentials, current from adjacent cells depolarizes the cell to a level where fast, voltage-dependent NaV channels open and rapidly depolarize the membrane toward the sodium equilibrium potential (phase 0 in Figure 6–13). These channels are similar to the sodium channels of nerve and skeletal muscle; they open in response to depolarization. They are also blocked by local anesthetics. After opening, they inactivate quickly and the membrane potential starts to return. However, the depolarization also opens voltage-activated L-type CaV channels that do not inactivate. This maintains the

CHAPTER 6 Action Potentials

1 2 Vm 50 mV 0

3

50 ms

4 IK

ICa 1 mA/cm2 INa

FIGURE 6–13 A ventricular muscle cell action potential (upper trace) and its underlying ionic currents. The INa and ICa currents are inward and the IK current is outward. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/ McGraw-Hill, 2006.)

action potential in the plateau phase (phase 2). Reducing external Ca2+ concentration or adding drugs that block calcium channels will reduce the plateau phase and also reduce the strength of muscle contraction. Cardiac muscle, unlike skeletal muscle, requires external Ca2+ for contraction (Figure 6–13). Cardiac muscle cells also differ from nerve and skeletal muscle by lacking the fast KV channel for quick repolarization. The potassium conductance system of the heart is rather complex; at least five different components have been identified on the basis of their kinetics and voltage dependence. Two of these are important to understand the plateau phase. During the plateau phase, the conductance is less than that during diastole, the period between action potentials. This is because of the inward rectifier channel (Kir), which is responsible for maintaining the resting potential and has a high conductance near and below the resting potential (at more negative potentials); it does not conduct during the plateau phase when the membrane is depolarized. The Kir channel rectifies, allowing current to flow and maintain the resting potential, but it does not allow much current to flow out during depolarization. The rectification is caused by Mg2+ or other polyvalent cations from the internal solution moving into the channel and plugging it when the cell is depolarized. The low conductance to K+ during the plateau phase means that the modest conductance to Ca2+ through the CaV channels maintains the membrane potential at depolarized levels during the plateau. Slow KV channels open very slowly during the action potential and are responsible for the downward slope during the plateau phase. When the membrane potential falls below a certain level, the CaV channels close and the repolarization toward the potassium equilibrium potential accelerates (phase 3). Since the membrane is no longer depolarized, the KV channels close.

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The description above is a simplified view of cardiac muscle action potentials. The complete story has several more K channels and must account for differences among muscle action potentials in different regions of the heart as well as age-related changes. There are two KV channels that open transiently just after the NaV channels and produce the initial partial repolarization (phase 1) from the peak to the plateau (IKto). There are at least two different slow voltage-dependent K channels with similar kinetics but distinct pharmacology (IKR and IKS). Some cardiac muscle cells have T-type calcium channels. In all cardiac cells, some current is carried by the sodium–calcium exchanger and by the Na/K pump. The regional and age-related differences in the action potentials are functionally and clinically important. The ventricular muscle’s action potentials near the endocardial (inner) surface have a longer duration than those near the epicardial (outer) surface. More work is done by the inner fibers, and they are more likely to be damaged in a heart attack. These differences must arise because of a different balance of Na, Ca, and K channel activities. The interactions between the effects of different channels are complex and are best explored with computer models. Clearly more research is necessary to understand the details.

SA AND AV NODE ACTION POTENTIALS The overall control of the heart’s pattern of contraction is normally initiated by action potentials that spontaneously arise 60–80 times/min from modified muscle cells in the SA node. Similar action potentials are also seen in the AV node, where they regulate the activation of the ventricles. In the absence of stimulation from the atria, the AV node’s cells spontaneously produce about 40 action potentials/min; in healthy hearts, however, the atrial cells drive them at the rate set by the SA node. The action potentials in the nodes lack the rapid upstroke and do not have as pronounced a plateau phase as the cardiac muscle action potentials. They are further characterized by the slow depolarization between action potentials: the pacemaker potential. These cells fire rhythmically; they are never at rest and have no true resting potential. The upstroke of the action potential is produced by a slow inward current carried primarily by Ca2+ (Figure 6–14). There is an initial phase through T-type CaV channels and a major phase through L-type CaV channels. The T-type channels are transient and have a low threshold for opening, near –60 mV. The L-type channels are long-lasting and have a higher threshold, near –30 mV. The L-type channels are similar to the CaV channels that maintain the plateau of the cardiac muscle action potentials; they are blocked by dihydropyridines. T-type channels have a different pharmacology. Reducing external Ca2+ concentration or adding Ca2+ channel blockers reduces the amplitude of the node’s action potentials. Outward K+ current gradually replaces the slow inward current and the cells repolarize toward EK. As the potential passes –50 mV, an inward hyperpolarization-activated current, If , appears,

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SECTION II Cell Physiology

Vm

50 mV 50 ms

IK

If 1 mA/cm2 ICa

FIGURE 6–14 The SA node’s action potentials (upper trace) and their underlying currents. The If and ICa currents are inward and the IK current is outward. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.) competes with IK, and eventually begins to depolarize the cell again. If is carried mainly by sodium ions. When the potential again passes –60 mV, the CaV channels are again activated and the cycle is repeated.

EFFECTS OF SYMPATHETIC AND PARASYMPATHETIC INNERVATIONS The heart can beat spontaneously without neural input. In healthy individuals, however, the autonomic nervous system and circulating hormone levels regulate the heart rate and its strength of contraction. The autonomic nervous system controls many internal organs through its two divisions, the sympathetic and the parasympathetic nervous systems. These release norepinephrine (NE) and acetylcholine (ACh), respectively, into the heart. The autonomic nervous system can also cause the adrenal medulla to release epinephrine into the blood. Epinephrine has effects on the heart similar to those of NE. Some of the details about the autonomic synapses and their pharmacology are described in the next chapter. The cells in the SA and AV node cells have GPCRs that produce a stimulation (via Gαs) or inhibition (via Gαi) of adenylyl cyclase, which, in turn, raises or lowers cAMP levels in response to NE and ACh, respectively. The cAMP enhances the activity of the If channels. The end result is that NE increases If and thus depolarizes the cells more rapidly and increases the heart rate. ACh reduces If , slows the rate of depolarization, and reduces the heart rate (see Figure 23–4). Changing If also leads to a speeding or slowing of conduction through the AV node. These effects are discussed further in terms of heart function in Chapter 23. High ACh levels lead to the opening of another potassium channel (KACh). (It is a G protein–activated inward rectifier GIRK channel.) This channel further reduces the tendency to

depolarize between action potentials and can temporarily stop the heart.

NOREPINEPHRINE ALSO INCREASES CONTRACTILITY In the presence of NE, the plateau of the muscle action potentials is elevated and has a shorter duration (Figure 6–15). This shortening of the action potential shortens the duration of the muscle contraction, which is functionally important for the heart. At high heart rates, the time required to refill the heart limits its performance. By reducing the time that muscle force is being generated (systole), more time is left for filling (diastole). The shortening of the ventricular action potentials can be seen in the ECG as a shortening of the QT interval. NE increases the amplitude of the plateau by causing the action potential to open more L-type Ca2+ channels. This drives the membrane closer to the Ca equilibrium potential. The increased Ca influx leads to a greater strength of contraction by a mechanism described in Chapter 10. NE shortens the

NE elevates plateau NE shortens duration

50 mV 50 ms

FIGURE 6–15 The effects of norepinephrine on ventricular muscle cells’ action potentials. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 6 Action Potentials duration by making the KV channels open more rapidly. The effects on the K and Ca2+ channels are mediated via cAMP acting as a second messenger, stimulating protein kinase A (PKA) and phosphorylating the channels. This pathway also enhances the calcium reuptake mechanism by phosphorylating phospholamban. This speeds up muscle relaxation.

ACETYLCHOLINE REDUCES ATRIAL CONTRACTILITY The ACh-activated K channel (KACh) remains open during the action potentials; in atrial muscle and Purkinje fibers, it makes the plateau phase shorter and lower. The atrial contractions are weaker. ACh receptors are relatively sparse on ventricular muscle cells.

57

It is caused by mutations of the NaV channel of skeletal muscle that make them slowly inactivating; the myotonia results from abnormal reopenings of the NaV channels. Moderate elevation of extracellular potassium favors aberrant gating with persistent and prolonged reopenings. The Na current through these channels may cause skeletal muscle weakness by depolarizing the cells, thereby inactivating normal NaV channels, which are then unable to generate action potentials. Patients with HyperKPP are at increased risk for malignant hyperthermia induced by anesthesia during surgery. Other NaV channel mutations in heart muscle are linked to sudden death syndromes. Attacks can be stopped by ingesting a high sugar load or by thiazide diuretics, both of which reduce extracellular potassium. They can be prevented by a diet low in potassium and high in carbohydrates, and also with thiazides. The disease is a lifelong condition.

CLINICAL CORRELATION Since early childhood, a 42-year-old woman experienced stiffness of her muscles, particularly when loosening a tight handgrip or starting to walk. Cold exposure exacerbated these symptoms. Outdoors on a cold and windy day, her face stiffened in a grimace and she could not open her eyes or move them from side to side. These symptoms disappeared within a few minutes after she had entered a warm room. When she ate ice cream, her throat stiffened and she could not swallow. From age 16, she also had attacks of generalized weakness unrelated to cold. Sometimes she woke up at night severely paralyzed. She was more liable to have an attack when hungry. During pregnancy she had daily attacks of weakness; within a few days after delivery she improved. A neurologist performed diagnostic testing. The patient was given 60 mEq of potassium orally with a mixture of anions. Forty-five minutes later, she was so stiff that she could make no quick movements. About an hour later, she noticed increasing weakness and had to lie down. The paralytic attack reached its peak roughly half an hour later. At that time, she could not lift her head, arms, or legs, nor could she move her limbs on the examination table. Myotonia (difficulty of relaxing muscles) of her facial and extraocular muscles was intense. Respiration was mildly impaired. Reflexes were unchanged and sensation was normal. Improvement started half an hour later and was complete 3.5 hours from the start. Before, during, and after, her serum potassium values were: 4.5, 7.3, and 3.9 mEq/L (normal is 3.5–4.5 mEq/L). This disease also affected her son, sister, mother, maternal aunt, and maternal grandfather. The inheritance was due to a single autosomal, dominant gene with probably complete penetrance. This patient was suffering from familial HyperKPP, which occurs in approximately 1 in every 200,000 people.

CHAPTER SUMMARY ■

■ ■

■ ■ ■ ■ ■

■ ■ ■ ■

■

Depolarization opens NaV channels, which allows Na+ to rush in and produce further depolarization. This positive feedback loop produces the all-or-none quality and the propagation of action potentials. K+ leaving the cell repolarizes the membrane potential and terminates action potentials. Voltage clamping, or negative feedback control of the membrane potential, facilitates understanding of the currents underlying the action potential. The amplitude and direction of the sodium current vary with the amplitude of voltage-clamp steps in membrane potential. Depolarizing steps first activate and then inactivate Na+ current. They also activate K+ current after a delay. The gating current is a direct sign of the conformational changes in the sodium channel proteins. There is a threshold for action potential initiation. Following an action potential, excitable cells have an absolute refractory period when they will not produce a second action potential and then a relative refractory period when a larger stimulus is required to produce a second action potential. Myelination increases conduction velocity by increasing the length constant. Hypocalcemia (low extracellular calcium) makes excitable cells more excitable. Demyelinating diseases slow the conduction velocity and may block the propagation of action potentials. Action potentials appear differently when they are recorded with a pair of wires placed on the outside of a nerve bundle. Compound action potentials, the sum of many externally recorded action potentials, have properties that differ from those of single action potentials recorded with intracellular electrodes. In the heart, action potentials arise automatically in the SA node and then spread from cell to cell over the heart via gap junctions.

58 ■

■

■

■

SECTION II Cell Physiology Cardiac muscle cells have KIR channels to maintain the resting potential, NaV channels for the upstroke of the action potential, CaV channels for the plateau phase, and slow KV channels for the repolarization. SA node cells use CaV channels for the upstroke of the action potential, KV channels for the repolarization, and a hyperpolarization-activated If channel to produce the slow “pacemaker” depolarization between action potentials. ACh and NE slow or speed the heart rate, respectively, via G protein–coupled receptors, which leads to a decrease or increase in If. NE increases the amplitude of the plateau and decreases the duration of ventricular muscle action potentials.

STUDY QUESTIONS 1. Hyperkalemia (high extracellular potassium concentration) can stop the heart because A) potassium ions bind to sodium channels, preventing their activity. B) potassium ions stimulate the sodium–potassium pump and thereby prevent cardiac action potentials. C) the membrane potential of heart cells depolarizes and its sodium channels inactivate. D) potassium ions rush out through the inward rectifier. E) potassium ions block the actin–myosin interaction in the heart. 2. Myelination of axons A) reduces conduction velocity to provide more reliable transmission. B) forces the nerve impulse to jump from node to node. C) occurs in excess in multiple sclerosis (MS). D) leads to an increase in effective membrane capacitance. E) decreases the length constant for the passive spread of membrane potential. 3. Consider the following three channels in ventricular muscle cells: sodium channel (NaV), inward rectifier potassium channel (Kir), and calcium channel (CaV). Choose the answer that best describes which of these channels is open during the plateau phase of the ventricular action potential. A) all three B) NaV and Kir only C) CaV and Kir only D) Kir only E) CaV only

4. There is an inward current (If ) associated with pacemaker activity in cells of the sinoatrial node. Stimulation of sympathetic nerves leading to the heart or application of norepinephrine produces A) a decrease of If , a decrease in heart rate, and an increase in strength of contraction. B) a decrease of If , an increase in heart rate, and an increase in strength of contraction. C) an increase of If , an increase in heart rate, and an increase in strength of contraction. D) an increase of If , a decrease in heart rate, and a decrease in strength of contraction. E) an increase of If , an increase in heart rate, and a decrease in strength of contraction. 5. Propagation of a nerve impulse does not require A) closure of potassium channels that maintain the resting potential. B) a conformational change in membrane proteins. C) a membrane depolarization that opens Na+ channels. D) current to enter the axon and flow within the axon. E) entry of sodium ions into the axon. 6. The compound action potential recorded with a pair extracellular electrodes from an intact bundle of nerve fibers A) propagates without change in size or shape. B) is all-or-none. If a threshold is exceeded, further increase in stimulus does not increase the response. C) has an amplitude of about 100 mV. D) is biphasic, showing both upward and downward deflections from the baseline. E) is not blocked by tetrodotoxin (TTX).

C

Synapses David Landowne

7

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P

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O B J E C T I V E S ■ ■

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Describe the steps in chemical synaptic transmission. Describe the biosynthesis and actions of acetylcholine, catecholamines (dopamine, norepinephrine, epinephrine), serotonin, histamine, and excitatory and inhibitory amino acids. Describe the biosynthesis and actions of neuropeptides. Describe the structure of the neuromuscular junction and the functions of the various substructures. Describe and explain the steps involved in neuromuscular transmission. Describe the actions and explain the mechanisms for the effects of Ca2+ and Mg2+ on transmitter release. Describe how acetylcholine interacts with receptors on the postsynaptic membrane and the fate of the acetylcholine. Describe the generation of the endplate potential and the effects and mechanisms of action of acetylcholine esterase inhibitors and blockers of acetylcholine receptors. Describe facilitation and posttetanic potentiation of transmitter release and how these processes can be used to explain certain features of myasthenia gravis and recovery from receptor blockade. Describe the structures and explain the functions of the various parts of neurons. Describe transport of materials up and down axons (orthograde and retrograde axonal transport) including mechanisms and materials. Calculate the time required for the regeneration of peripheral nerves. Describe the differences and similarities between synaptic transmission at a central synapse and at neuromuscular junctions. Describe the generation of IPSPs and EPSPs by ionotropic and metabotropic receptors. Describe the integration of information and repetitive firing in neurons and the concept of presynaptic inhibition.

INTRODUCTION A synapse is a specialized region where a neuron communicates with a target cell: another neuron, a muscle cell, or a gland cell. Most synapses are chemical; the presynaptic neuron releases a transmitter substance that diffuses across the

Ch07_059-078.indd 59

synaptic cleft and binds to a receptor on the postsynaptic cell. The postsynaptic receptor may be ionotropic, in which case it will open a selective pore and allow ions to flow to produce a postsynaptic potential (PSP), or it may be metabotropic and inform a G protein to initiate a chemical cascade, which may include the opening or closing of 59

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channels. A few synapses are electrical; current passes through cell–cell channels directly into the postsynaptic cell. Chemical synapses offer the possibility of amplification, signal inversion, and persistent effects; electrical synapses are faster and seem to be used when synchronization is more important than computation (information processing). Chemical synapses may be excitatory or inhibitory, depending on their effect on the postsynaptic cell. In the CNS, neurons receive both types of synapses and integrate the information coming into them before sending the processed message on to another cell. Chemical synapses are major pharmaceutical targets.

PRESYNAPTIC PROCESSES The presynaptic terminal must provide for the synthesis, packaging, and release of the various transmitters (Figure 7–1). The nonpeptide transmitters are concentrated inside vesicles by specific H/transmitter cotransporters. A V-type H+ pump, which consumes ATP, produces the H+ gradient. The transmitter concentration inside the vesicle can be quite high, on the order of 20,000 molecules in a 20-nm radius sphere, or about 30 mM. After release, transmitters are degraded or transported back into the presynaptic terminal for reuse. The vesicular membranes are also recycled. Some transmitters are small polypeptides that are synthesized on rough endoplasmic reticulum near the nucleus, packaged by the Golgi apparatus, and then transported in vesicles the length of the axon by an active process called axoplasmic transport. This process also brings other proteins to the presynaptic terminals.

Neurotransmitters can be chemically classified into five groups (Figure 7–2). They are all hydrophilic and contain groups that are charged at physiologic pH. Thus, they do not readily pass through lipid membranes and can be compartmentalized as needed.

ACETYLCHOLINE Acetylcholine (ACh) was the first recognized transmitter. It is used by spinal motoneurons to excite skeletal muscles; by the parasympathetic nerves to communicate with various end organs, including the vagus nerve slowing pacemaker regions of the heart; in sympathetic and parasympathetic ganglia; and in various locations in the CNS. There are two classes of postsynaptic ACh receptors (AChRs), which are named for other agonists that can also bind to them. Nicotinic AChRs are at neuromuscular junctions, sympathetic and parasympathetic ganglia, and in the CNS. Nicotinic AChRs are ionotropic receptors or heteromeric pentamers (see Figure 3–5). They are chemosensitive channels that are opened by nicotine and blocked by curare. Muscarinic AChRs occur in the heart, smooth muscles, gland cells, and CNS. They are metabotropic 7-TM GPCRs that are activated by muscarine and blocked by atropine. nAChRs tend to excite the postsynaptic cell; mAChRs may be excitatory or inhibitory. ACh is synthesized from acetyl-CoA and choline by the enzyme choline acetyl transferase (CAT), found in the presynaptic cytoplasm. ACh is concentrated into vesicles by an H/ ACh cotransporter (Figure 7–3). A Ca2+-activated process releases the vesicles. It is described below, after all of the transmitters have been discussed.

Fill

Dock

Fuse and release

Recycle

FIGURE 7–1

Synaptic vesicle docking, releasing of contents, and recycling. (Modified with permission from Landowne

D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 7 Synapses

Cholinergic

Biogenic Amines

O

+

O

N(CH3)3

NH2 HOOC

HO

Dopamine HO

Peptidergic

Amino Acids COOH

HO

Acetylcholine

61

NH2 Glutamic acid

NH2 HOOC

HO

NH2

OH Endorphin Enkephalin Dynorphin Calcitonin gene related peptide (CGRP) Substance Y Substance P Vasopressin (ADH) Oxytocin Cholecystokinin (CCK) Vasoactive intestinal peptide (VIP)

γ-aminobutyric acid (GABA)

Norepinephrine HO

N(CH3)

HO

HOOC

NH2

OH Epinephrine

Glycine

NH2

HO

Purinergic ATP

NH Adenosine

Serotonin NH2

HN N NH N Histamine

Poisoning by botulinum toxin (Botox) blocks ACh release and results in a failure of neuromuscular transmission. Recently Botox injections have been used to treat dystonia, a movement disorder characterized by involuntary muscle contractions, and cosmetically to locally block facial muscles that wrinkle the skin. Excessive doses or systemic toxin delivery from contamination during food canning can lead to death. Black (or brown) widow spider venom (BWSV) also blocks neuromuscular transmission. It makes the presynaptic membranes permeable to Ca2+ and causes a massive release of vesicles, followed by a failure of transmission due to the lack of stored ACh. After release, ACh may be broken down into acetate and choline by acetylcholinesterase (AChE) in the extracellular space. A Na/choline cotransporter recaptures most of the choline; then ACh is resynthesized by CAT and repackaged. AChE inhibitors or anticholinesterases are used for medical purposes, as insecticides, and as nerve gases in chemical warfare. Their effect is to increase the amount and duration of ACh interaction with the postsynaptic receptors. The battlefield countermeasures are to block the postsynaptic receptors on the heart with atropine. The nerve

FIGURE 7–2

The neurotransmitters.

(Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

gases are organofluorophosphates that irreversibly bind AChE but can be displaced by pyridine aldoxime methyl iodide (PAM).

AMINO ACIDS GLUTAMATE Glutamate is the major excitatory neurotransmitter of the CNS. It is a nonessential amino acid, but, because it cannot pass the blood–brain barrier, it must be synthesized in the CNS. There are several synthetic pathways but none specific for neurons. Ionotropic glutamate receptors, gluRs, are classified as NMDA-type if the synthetic agonist N-methyl-daspartate activates them or non-NMDA-type if it does not. Both types are heteromeric tetramers (see Figure 3–6) and permit the passage of Na+ and K+, but the NMDA gluRs also allow Ca2+ to enter the cell and have a special role in synaptic plasticity, described later. There are also metabotropic gluRs (mgluRs). All of these are normally activated by glutamate (Figure 7–4).

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SECTION II Cell Physiology

Glia Cholinesterase

H+

Muscarinic GPCR

ATP ACh

Nicotinic channel

Presynaptic

ACh ATP

Choline Na

Cholinesterase Postsynaptic

K Na

FIGURE 7–3

A generalized schematic acetylcholine synapse. The presynaptic terminal has transporters for choline reuptake and ACh packaging. The postsynaptic membrane has ACh receptors and cholinesterase. The nearby glial cell membrane also has cholinesterase. ACh is hydrolyzed by the esterases and the choline part is taken back by the presynaptic terminal. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

Glutamate is removed from the extracellular space by a Na/ glu cotransporter, the excitatory amino acid transporter (EAAT), which also countertransports K+. EAATs are in the presynaptic terminal membrane and also in the postsynaptic

membrane and nearby glial cell membranes. Inside the glia, glutamate can be converted to glutamine, released, and taken up by the presynaptic terminal by a Na/Cl-coupled cotransporter and finally reconverted into glutamate.

Na glu K gln Na

gln

Glia

mgluR GPCR

H+ ATP

Ionotropic channel

Presynaptic

glu ATP

K glu Na Postsynaptic

K Na

FIGURE 7–4

A generalized schematic glutamate synapse. In addition to the reuptake and packaging transporters, glutamate synapses have uptake transporters in the postsynaptic and glia cell membranes. There is also a glutamine (gln) pathway to move glutamate in the glial cell back to the presynaptic terminal. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 7 Synapses

63

Na GABA Cl Glia

GABAB GPCR

H+ ATP

GABAA channel

Presynaptic

GABA ATP

Cl GABA Na Postsynaptic

K Na

FIGURE 7–5

A generalized schematic GABA synapse. This is similar to the glutamate scheme but has GABA receptors and transporters.

(Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

Excess extracellular glutamate kills neurons by allowing excess Ca2+ into the cells, which can lead to necrosis (cell death). This neurotoxicity is postulated to play a role in ischemic stroke, amyotrophic lateral sclerosis (ALS), Huntington’s disease, Alzheimer’s disease, and possibly some forms of epilepsy. Ischemia can raise extracellular glutamate by limiting oxidative metabolism, ATP, and sodium gradients, thus the movement of glutamate away from the receptors.

GABA AND GLYCINE Gamma-aminobutyric acid (GABA) and glycine are the major inhibitory neurotransmitters in the CNS. Glutamate decarboxylase (GAD) converts glutamate into GABA in the presynaptic terminal cytoplasm. GABA is packaged and released as other transmitters (Figure 7–5). There is a Na/ GABA cotransporter that removes GABA from the synaptic cleft. GABAA receptors and glycine receptors are pentameric heteromers in the nAChR superfamily; they are permeable to Cl– ions. GABAB receptors are GPCRs that activate Kir (or GIRK) channels. The CNS operates with a tonic level of inhibition that can be shifted with various drugs. Muscimol, from the mushroom Amanita muscaria, is a potent GABAAR agonist. Common tranquilizers such as diazepam (Valium) and barbiturates such as phenobarbital enhance the opening of GABAARs. Picrotoxin, a potent convulsant, blocks GABAAR. Strychnine, also a convulsant, blocks glyRs. Tetanus toxin produces a spastic paralysis by blocking the release mechanism for GABA and glycine.

BIOGENIC AMINES The catecholamines, serotonin, and histamine are all biogenic amines. The catecholamines are dopamine, norepinephrine (NE), and epinephrine (EPI). Most of the effects produced by these biogenic amines are via GPCRs, often without producing PSPs. All are concentrated into vesicles and released by similar mechanisms, but some are released by nerve swellings, which are in the vicinity of the receptors but not as closely apposed (see Figure 7–19). Non-nerve cells also release EPI and histamine.

CATECHOLAMINES Dopamine and NE are found in the CNS. NE is the principal final transmitter of the sympathetic nervous system and EPI is made and released by the adrenal medulla. All three are synthesized by the same pathway, starting with the hydroxylation of tyrosine to dihydroxyphenylalanine (DOPA), which is then decarboxylated to form dopamine. Adding a beta-hydroxyl group forms NE and, in the adrenal medullary cells, a subsequent transfer of an N-methyl group forms EPI. Tyrosine hydroxylase (TH) is the rate-limiting enzyme. TH and DOPA decarboxylase are in the presynaptic terminal cytoplasm. Dopamine is concentrated into vesicles, where dopamine beta-hydroxylase (DBH) converts it to NE. NE is taken back into the presynaptic terminal by a Na/Cl-coupled cotransporter; there, it is broken down by monoamine oxidase (MAO) in mitochondria and by catecholamine-O-methyl transferase (COMT) in the cytoplasm. Catecholamine receptors are GPCRs and are found in the CNS, smooth muscle, and heart. Adrenergic receptors respond

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to NE and/or EPI. There are two categories of adrenergic receptors: alpha-adrenergic receptors have a higher affinity for NE and beta-adrenergic receptors have a higher affinity for EPI. However, there is cross-reactivity, and both receptors will respond to higher concentrations of both agonists. In the cardiovascular system, the alpha receptors are primarily found on the smooth muscle cells that control the diameter of small blood vessels; NE acts to constrict these vessels. The beta receptors are primarily in the heart and can make it beat faster and harder. Muscle relaxation via adrenergic receptor activation occurs in smooth muscle cells in the gut and the lungs. Some of these functions are discussed at greater length in the next section. Parkinson’s disease is characterized by the loss of dopaminergic neurons; its treatment often includes DOPA, which can partially relieve the symptoms. Drugs that block dopamine receptors have been used to treat schizophrenia; sometimes they induce Parkinson-like tremors. Reserpine, an early tranquilizer, inhibits dopamine transport into vesicles. Cocaine blocks the reuptake of catecholamines, prolonging their actions. Many over-the-counter remedies for nasal congestion, such as neosynephrine, activate catecholamine receptors.

SEROTONIN Serotonin, or 5-hydroxytryptamine (5-HT), is made from tryptophan by hydroxylation and decarboxylation. 5-HT receptors function in the gut in secretion and peristalsis, mediate platelet aggregation and smooth muscle contraction, and are distributed throughout the limbic system of the brain. Serotonin was initially identified as a substance in blood serum that constricted blood vessels, hence the name. Tryptophan hydroxylase is the rate-limiting step of 5-HT synthesis; in the CNS tryptophan hydroxylase is present only in serotonergic neurons. 5-HT is deactivated by reuptake and then broken down by MAO in mitochondria. Most 5-HT receptors are GPCRs; 5-HT3 receptors are ion channels. Selective serotonin reuptake inhibitors such as fluoxetine hydrochloride (Prozac) are commonly prescribed as antidepressants. Lysergic acid diethylamide (LSD) and psilocin, the active metabolite of psilocybin, are hallucinogens that activate 5-HT receptors.

HISTAMINE Most histamine in the body is released from mast cells (part of the immune system) in response to antigens or tissue injury. Histamine also is a regulator of acid secretion in the gut and acts as a neurotransmitter in the central nervous system. Histamine release is associated with allergic reactions; it initiates inflammatory responses, dilates blood vessels and increases capillary permeability, decreases heart rate, and contracts smooth muscles in the lung. Enterochromaffin-like cells in the gastric mucosa also release histamine, which promotes acid production. Histamine is made from histidine, stored in vesicles, and released; it is then broken down by histamine

N-methyl transferase. There are four different histamine receptors, which are all GPCRs.

PURINES ATP is contained in synaptic vesicles and released with NE in sympathetic vasoconstrictor neurons. It induces constriction when applied directly to the smooth muscles. P2X ATP receptors are ion channels that permit the entry of Ca2+, and the cells also have P2Y GPCRs. These receptors are also in the brain, as well as P1 receptors for adenosine.

PEPTIDES Neuropeptides are small polypeptides that are synthesized as larger inactive precursors (propeptides) and then cleaved out by specific endopeptidases. As they are proteins, they are synthesized in the cell body and transported in vesicles to the terminals. There is no reuptake mechanism. Peptides are less concentrated than other neurotransmitters in vesicles but have higher affinity for their receptors, which are GPCRs. Neuropeptides are released from large dense-core vesicles, while other neurotransmitters are secreted from smaller, clearer vesicles. Neuropeptides often act in concert with classic neurotransmitters. Not much is known about the function of most neuropeptides in the CNS except the opiate peptides, endorphin, enkephalin, and dynorphin, which are involved in the regulation of pain perception. Three opiate receptors have been identified, initially as the sites that bind synthetic opiates such as morphine. There are many nonopiod peptides released from neurons. The calcitonin gene–related peptide (CGRP) and substance Y are involved in maintaining blood pressure. Antidiuretic hormone (ADH, also called vasopressin) helps control water reuptake in the kidney. Oxytocin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) are involved in reproduction. Cholecystokinin (CCK), gastrin, and vasoactive intestinal peptide (VIP) facilitate digestion. All of these and many more have been identified as potential neurotransmitters in the CNS.

SYNAPTIC RELEASE The details of the synaptic release process are currently under active investigation. It is clear that the process is triggered by an increase in cytoplasmic Ca2+ levels. At many synapses, when a presynaptic action potential arrives, the Ca2+ enters the terminal through CaV channels. In some small sensory cells there is no action potential and the sensory generator potential opens the CaV channels. Synaptic vesicles cycle through loading with transmitters, docking at an active zone or release site, fusion with the surface membrane and release of contents, endocytotic recovery,

CHAPTER 7 Synapses

65

Na Dock

Ca

Fuse and release

Recycle

FIGURE 7–6 The channels involved in synaptic release. NaV channels depolarize the ending and CaV channels permit Ca2+ influx to trigger release. There are also KV channels that repolarize the membrane and thereby limit Ca2+ influx. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

and then loading again. In Figure 7–6, each step in the vesicular cycle is illustrated by a shift in the position of the vesicle. In reality, however, there is little movement in the attached states. In many synapses, the release site is across from a postsynaptic area containing the channels that are sensitive to the transmitter. In the neuromuscular junction (see Figure 7–9), CaV channels are adjacent to the release site, so that internal Ca2+ need only be elevated locally to cause release.

Docking and fusion involves the SNARE or soluble Nethylmaleimide-sensitive factor attachment protein (SNAP)— receptor proteins that are present on both membranes before fusion and associate into tight core complexes during fusion. Figure 7–7 shows the vesicular v-SNARE synaptobrevin binding the target t-SNARE syntaxin and SNAP-25. Synaptobrevin is the substrate of the endopeptidases contained in botulinum and tetanus toxins.

Synaptotagmin Synaptobrevin v-SNARE Ca

Syntaxin t-SNARE

FIGURE 7–7

A possible mechanism of vesicle fusion. SNARE proteins dock the vesicle and Ca2+ binds to synaptotagmin to cause fusion.

(Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

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SECTION II Cell Physiology

Ca-stimulated fusion requires the Ca2+-binding protein synaptotagmin, which is in the vesicular membrane and binds Ca2+. A proposed model suggests that Ca2+ allows the synaptotagmin to bind the surface membrane and pull the two lipid layers together. The recycling process returns the lipids and proteins to the vesicle pool. The vesicle is reformed as a clathrin-coated pit. The clathrin molecules have the shape of a triskelion, or three bent legs. The clathrin forms a closed surface covered with pentagons and pinches the recovered vesicle off the surface.

AXOPLASMIC TRANSPORT All of the proteins in the presynaptic terminal are synthesized in the cell body and transported perhaps 1 m before they are useful. In addition, the neuron has mechanisms that transport some materials in the reverse or retrograde direction back to the cell body. Some of the mechanisms used for this transport are used in other cells to deliver material to the periphery of the cell and also for the movement of chromosomes during mitosis. Axoplasmic transport is distinguished by the direction into orthograde and retrograde. Orthograde transport can be further divided into fast (100–400 mm per day or 1–5 μm/s) and slow (0.5–4 mm per day). Fast transport is for vesicles and mitochondria; slow transport is for soluble enzymes and those that make up the cytoskeleton. Retrograde transport is only of the fast type. Fast axoplasmic transport involves molecular motors that hydrolyze ATP and walk along microtubules, long hollow cylinders 25 nm in diameter. Two different classes of motors are used, kinesins for orthograde transport and dyneins for retrograde. Microtubules are polarized, and these motors can sense the polarity and move by 8-nm steps in the appropriate direction. The motors have two “feet,” or sites of interaction with the microtubules, and exhibit processivity, or the ability to function repetitively without dissociating from their substrate, the microtubule. Accessory molecules are used to attach the payload to the motor (Figure 7–8). Fast orthograde transport delivers the membrane proteins needed in the terminal for both the vesicles and the terminal Orthograde

Kinesin Microtubule Dynein Retrograde

FIGURE 7–8

Axoplasmic transport. Kinesin motors carry vesicles toward the nerve terminals. Dynein motors carry different vesicles toward the cell body. (Modified with permission from Landowne

D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

membrane. During development, it can also deliver cell adhesion molecules that recognize or induce targets. Retrograde transport can return damaged proteins for the endolytic pathway and bring information about signaling events back to the cell body. Retrograde transport is part of the pathophysiology of several diseases including polio, rabies, tetanus, and herpes simplex. The herpesvirus enters peripheral nerve terminals and then travels back to the cell body, where it replicates or enters latency. It can later return to the nerve ending by orthograde transport and make itself available for contact transmission to another person. The tetanus toxin is transported retrogradely in motoneurons to the dendrites and then transsynaptically to GABA- and glycinereleasing terminals, where it inhibits synaptic release. Axoplasmic transport is important for the regeneration of nerves following injury in the peripheral nervous system. Under usual circumstances, nerves in the CNS do not regenerate, although current researchers are hopeful that this will change in the future. If a peripheral nerve axon is cut or crushed, the distal portion will die and go through a characteristic Wallerian degeneration as the axon is resorbed over a few weeks. Within a few days, the cell body undergoes the axon reaction, often called chromatolysis, because of a change in staining when it is studied histologically. The nucleolus enlarges, the rough endoplasmic reticulum, or ER (Nissl substance), disperses, and the nucleus is displaced. Genes have been activated, RNA transcribed, and proteins synthesized. The longer the distance from the injury to the cell body, the greater the latency, indicating that retrograde transport is involved in the signaling to initiate the axonal reaction. At the site of injury, the end that is coupled to the cell body will reseal in hours and buds or sprouts will appear in a day or two. The cut tip swells with mitochondria and smooth ER. The sprouts grow out as thin fibers. If the regeneration is successful, one of the new fibers finds its way down the sheath of the distal degenerating nerve and reinnervates a postsynaptic target. The fiber will then increase in diameter and become remyelinated. The rate of fiber growth is about 1 mm per day, in the range of slow axonal transport. This is the number to use in estimating recovery times. In addition to the microtubule-based systems, intracellular transport can also occur via myosin motors traveling along actin filaments. The interaction is similar to that described in the section Chapters 8 and 9 except that the actin stays fixed and individual myosin molecules process along it. There are adapter molecules that attach the payload to the myosin.

POSTSYNAPTIC PROCESSES There are several different postsynaptic receptors for each transmitter; they are distinguished by their amino acid sequences and, in some cases, pharmacology. Different regions of the nervous system have characteristic receptors; sometimes an individual postsynaptic cell will have multiple receptor types. The ionotropic receptors are excitatory or inhibitory ac-

CHAPTER 7 Synapses cording to their ionic selectivity. The metabotropic receptors may indirectly cause channels to open or close and may also modulate the activity of the cells in other ways. The PSPs are called excitatory postsynaptic potentials (EPSPs), if their effect is to make the postsynaptic cell more likely to respond with an action potential, or inhibitory postsynaptic potentials (IPSPs), if they make the postsynaptic cell less likely to fire an action potential. Each channel has a selectivity pattern and allows different ions to flow through with differing ease. This means that each channel will have a reversal potential: a potential at which there will be no net flow of ions through the channel. If the membrane potential is more positive than the reversal potential, net current will flow out of the cell, tending to hyperpolarize it. If the membrane is less positive or more negative, current will flow in and tend to depolarize the cell. The current that flows through channels drives the membrane potential toward the reversal potential for that channel. Most neurons in the CNS receive a constantly fluctuating input from a variety of synapses and their membrane potential is always changing. If a synapse opens channels having a reversal potential more positive than the threshold for action potentials, they will produce an EPSP. If the reversal potential is more negative than the threshold, an IPSP will result. If a channel is permeable to a single ion, its reversal potential is the Nernst potential

67

for that ion (equation (4) in Chapter 4). If the channel is permeable to multiple ions, its reversal potential is the weighted average of the Nernst potentials for its ions (equation (6) in Chapter 4). nAChR channels and GluR channels are approximately equally permeable to Na+ and K+, and their reversal potential is about –10 mV; when activated, they make EPSPs. GABAAR and glyR are Cl channels; their reversal potential is about –80 mV. The cardiac mAChR, through a G protein, activates a Kir channel (KACh) that has a reversal potential about –90 mV. Both Cl− channels and K+ channels make IPSPs. If for some reason the cell happens to be more negative than –80 mV, opening Cl channels will depolarize the cell but still work to keep other channels from further depolarizing the cell to threshold.

THE NEUROMUSCULAR JUNCTION—A SPECIALIZED SYNAPSE Because of its easy accessibility, the neuromuscular (or myoneural) junction (Figure 7–9) is the best-studied synapse; it is the source of much of what is known about synapses. This section describes the functioning of this synapse, bringing together

Myelin Axon

Schwann cell

Mitochondria

Synaptic vesicles Synaptic cleft

Presynaptic membrane Postsynaptic membrane

Muscle nucleus

Synaptic fold

Myofibrils

FIGURE 7–9

The neuromuscular junction. A myelinated nerve (gray) ends on a specialized region of a skeletal muscle (colored). (Modified

with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

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SECTION II Cell Physiology

and illustrating many of the ideas introduced more abstractly above. The neuromuscular junction is of considerable clinical interest. Myasthenia gravis is a disease that incapacitates the neuromuscular junction; there are other diseases and several drugs and toxins that target the junction. The neuromuscular junction provides a convenient assay for the anesthesiologist gauging recovery from muscle immobilization after surgery. A single motoneuron controls between 3 and 1,000 muscle cells. Each muscle cell receives input from one motoneuron. The motoneuron and all of its muscle cells function together as a motor unit. In healthy people, an action potential in the motoneuron will produce a large EPSP in all of its muscle cells, large enough to greatly exceed the threshold of the muscle cells and produce action potentials and contraction. The CNS regulates movement by choosing which motor units to activate. Smaller motor units produce finer movements. At the nerve ending, the axon loses its myelin and spreads out to form the motor endplate, named for its anatomic appearance. The nerve terminals contain many mitochondria and many 40-nm-diameter synaptic vesicles that contain ACh. The nerve terminal is separated from the muscle by a 50-nm gap, the synaptic cleft, which contains a basal lamina. The muscle membrane contains AChRs and also AChE. In transmission electron micrographs, both presynaptic and postsynaptic membranes appear thickened, indicating the presence of channels and other proteins. Neuromuscular transmission can be described as a 10-step process: (1) an action potential enters the presynaptic terminal; (2) the nerve terminal is depolarized; (3) depolarization opens CaV channels; (4) Ca2+ enters the cell, moving with its electrochemical gradient; (5) Ca2+ acts on a release site, probably synaptotagmin, causing synaptic vesicles to fuse with the presynaptic membrane; (6) about 200 vesicles release their ACh into the synaptic cleft; (7) the ACh in the cleft either (a) diffuses away out of the cleft, (b) is hydrolyzed by AChE into acetate and choline, or (c) interacts with AChRs on the postsynaptic membrane; (8) the activated AChRs are very permeable to Na+ and K+ and slightly permeable to Ca2+; hence, a net influx of positive charge into the muscle cell depolarizes the muscle membrane in the endplate region; (9) when the muscle membrane is depolarized to threshold, an action potential is elicited, which propagates in both directions to the ends of the muscle cell (the link between muscle excitation and contraction is discussed in the next section); and finally (10) choline is recycled into the nerve terminal, Ca2+ is pumped out of the nerve terminal, and vesicles are recycled and refilled.

RECORDING THE ENDPLATE POTENTIAL If a microelectrode is inserted into a muscle fiber near the neuromuscular junction, a resting potential of about –90 mV will be measured. If the nerve is stimulated and the muscle is prevented from contracting by extreme stretching the membrane potential will be seen to change, as shown in the solid trace on the left in Figure 7–10. If, instead, the electrode is placed sev-

FIGURE 7–10 An endplate potential and action potential at the neuromuscular junction (left) and 2 cm away (right). Dashed lines indicate responses in low Ca2+ (see text). (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/ McGraw-Hill, 2006.)

eral centimeters away from the neuromuscular junction, the potential shown in the right trace will be seen. If the concentration of Ca2+ in the bath is decreased or the concentration of Mg2+ is increased and the nerve is stimulated again, the potential at the neuromuscular junction will change as shown in the dashed trace. Under these conditions there will be no change in the membrane potential several centimeters away from the junction. The solid trace on the left shows an action potential superimposed on an endplate potential (EPP). There is an initial depolarization due to a net entry of positive charge through AChRs that were activated by the released ACh. When the potential reached about –50 mV, an action potential was initiated. In normal Ca2+ the EPP is two or three times larger than necessary to depolarize the muscle membrane to threshold. The pure action potential is seen in the trace on the right; it can be recorded by stimulating one end of the muscle electrically or by placing the recording electrode a few centimeters away from the endplate. The dashed trace on the left shows an EPP with reduced amplitude. The EPP is not visible a few centimeters away from the endplate (right). A reduction in extracellular Ca2+ reduces the release of ACh and thus reduces the EPP. An increase in Mg2+ reduces transmitter release by reducing Ca2+ entry through CaV channels. These opposing effects of Ca2+ and Mg2+ have been seen on all chemical synapses that have been examined; this is now considered one of the tests for identifying a chemical synapse. Ca2+ and Mg2+ concentrations have different effects on the excitability or the threshold for action potentials on the nerve and muscle cells. The reduction of Ca2+ makes the cells more excitable or have a more negative threshold, or requires a smaller depolarization to reach threshold for an action potential. This is an effect on the NaV channels; in low Ca2+, NaV channels will open at more negative potentials. Ca2+ and Mg2+ have a synergistic action on NaV channels; they have opposing actions on neuromuscular transmission. Clinically, the effects of hypocalcemia are hyperexcitability and spontaneous action potentials in nerve and muscle. These effects are seen when there is still enough Ca2+ to support sufficient ACh release, so that every nerve action potential leads to a muscle action potential.

1 mV

CHAPTER 7 Synapses

10 ms

69

200,000 vesicles are released, which is equal to the number seen by the electron microscope in an unstimulated neuromuscular junction. After BWSV treatment, no vesicles are visible. BWSV paralyzes by depleting the nerve terminals of synaptic vesicles. It can be deadly if the nerve endings controlling breathing are compromised.

TRANSMITTER–RECEPTOR INTERACTION FIGURE 7–11 Some miniature endplate potentials (MEPPs) seen by stimulating a neuromuscular junction bathed in low Ca2+ four times. The second MEPP on the bottom trace was spontaneous. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

In this low-Ca2+ and high-Mg2+ case, the EPP is not large enough to reach threshold and elicit an action potential. Action potentials are actively propagated; the EPP spreads passively and will not be visible a few centimeters from the neuromuscular junction. These two potentials are produced by the activity of different channels that have differing pharmacology. Curare will block AChRs and the EPP without affecting the action potential seen following direct electrical stimulation of the muscle. A toxin from a cone snail (μ-conotoxin) will block the muscle action potential but not the EPP. The μ-conotoxin blocks muscle NaV channels but not nerve NaV channels, which are a different gene product. If the Ca2+/Mg2+ ratio is sufficiently low, the response to stimulation will appear as in Figure 7–11. Each trace represents the response to a stimulation that is repeated every 5 seconds. Three of the traces show a small EPP; in the third trial there was no response. The first response is about 1 mV high; the second and fourth responses are about 0.5 mV. When this experiment was repeated many times, the responses were found to be quantized with a unit response of about 0.5 mV. That is, there were many 0.5-, 1-, and 1.5-mV responses but very few with amplitudes in between. In addition, there are sometimes spontaneous 0.5-mV responses without any stimulation; one of these was caught on the fourth trace. These miniature endplate potentials (MEPPs) represent the postsynaptic response to the release of one, two, or three quanta of ACh. Each quantum is the contents of a single vesicle. The exact number of vesicles released on any particular stimulation cannot be known; only the average number or the mean quantal content can be predicted. The EPP in normal Ca2+/Mg2+ conditions is the response to about 200 quanta. The average rate of spontaneous MEPPs is about 1 vesicle/s. In a normal EPP, the 200 vesicles are released within 1 millisecond, which means that stimulation increased the rate of release by 200,000-fold. If BWSV is applied to a neuromuscular junction, the MEPP frequency increases to a few hundred per second for about 30 minutes and then stops. In total about

The nicotinic AChR at the neuromuscular junction has five subunits, each with four TM segments. Two of the subunits are called alpha subunits and bind ACh at the α–γ and α–δ interfaces near the top of the molecule, about 5 nm from the center of the membrane. The channel then undergoes a conformational change that is transmitted through the molecule to open the pore, most likely by causing the M2 TM segments to move out away from the axis of the pore, making it larger. The open pore allows Na+ and K+ and, to a lesser extent, Ca2+ to pass. The pore stays open about 1 millisecond and about 20,000 ions pass at a rate of 2 × 107/s, which is equivalent to about 3 pA. If a single AChR is captured in a patch of membrane and maintained with a –90 mV potential, application of ACh will cause the channel to open and close several times, each opening appearing as a 3-pA current pulse of varying duration averaging about 1 millisecond. A single quantum opens about 2,000 channels; 200 quanta open about 400,000. A neuromuscular junction has many more channels, about 20 million; thus, only a small fraction is used at any one time. The number of open channels is proportional to the concentration of ACh squared and the effective number of receptors. A kinetic scheme for the reaction is shown in Figure 7–12. The receptor can open with one or two ACh molecules bound; it stays open about 10 times longer with two bound. It is the concentration of R • 2ACh that is proportional to the concentration of ACh squared: Number of open channels = k[R][ACh]2

(1)

DESENSITIZATION If a single AChR is exposed to continuous ACh for several minutes, its response will slow and openings will become less frequent. If ACh is added to the bath containing a neuromuscular junction, the muscle membrane potential will

R

R • ACh

R • 2ACh

Closed

R∗ • ACh

R∗ • 2ACh

Open

FIGURE 7–12

A kinetic scheme of the reaction between acetylcholine and the nicotinic acetylcholine receptor. The receptor (R) can bind two ACh molecules. Once ACh is bound the receptors can open (R*) and allow the passage of ions. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

70

SECTION II Cell Physiology The Bungarus snake paralyzes its prey with α-bungarotoxin, which binds AChRs irreversibly and prevents their opening. Bungarotoxin has been fluorescently labeled and used experimentally to identify and locate nAChRs.

10 μM ACh

10 mV 1 min

MYASTHENIA GRAVIS FIGURE 7–13 Desensitization of acetylcholine receptors (AChRs). With prolonged ACh exposure the AChRs first open and then enter a desensitized and closed state where they no longer respond to ACh. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

depolarize but the response will reach a peak and then decline, as shown in Figure 7–13. This decline is called desensitization; the AChR molecule has entered an inactivated state from which it does not open. This is functionally somewhat similar to the inactivation of NaV channels except that the time course, the agent that causes the inactivation, and the molecular basis in the channels are completely different. Desensitization probably does not occur with normal use of neuromuscular junctions but may become a problem when drugs are used that block AChE. A patient with desensitized AChRs may be paralyzed and unable to breathe due to a lack of functional AChRs.

SOME DRUGS THAT ACT AT THE NEUROMUSCULAR JUNCTION d-Tubocurare is a classic neuromuscular blocking agent, originally discovered as an arrow poison from South America. Curare binds AChRs reversibly and prevents ACh from opening the channels. After application of curare, the EPP becomes smaller; if there is sufficient curare, the EPP becomes so small that it no longer elicits an action potential, similar to the dashed response in Figure 7–10, and the junction is effectively blocked. Higher doses of curare can eliminate the EPP. Curare reduces the EPP by reducing the number of receptors available to respond to ACh. Curare or a related drug is often used during surgery to immobilize muscles; it can also facilitate tracheal intubation and mechanical ventilation. Anticholinesterases such as neostigmine and physostigmine combine with AChE and prevent hydrolysis of ACh, which leads to a larger EPP. Neostigmine is used to speed recovery from the effects of curare and to reduce the symptoms of myasthenia gravis. There are dangers associated with neostigmine; an excess of ACh can lead to desensitization of the remaining receptors. Also, the body uses ACh to slow the heart and release saliva; both of these effects may be enhanced by physostigmine. Botulism is a potentially fatal food poisoning caused by the anaerobic bacterium Clostridium botulinum. Some of the toxins released by this organism are endopeptidases, which are taken up by nerve cells and cleave synaptobrevin, thus preventing transmitter release. The purified toxins are used clinically to prevent unwanted neuromuscular transmission.

Myasthenia gravis is a disease associated with muscle weakness and fatigability on exertion. It is an autoimmune disease that leads to the destruction of AChRs. Patients may have only 10–30% of the number of AChRs found in healthy individuals. Treatment with anticholinesterases increases the amount of available ACh, which makes it more likely that the remaining AChRs will be activated (equation (1)). There is a danger of giving too much anticholinesterase, which can lead to desensitization of the AChRs and further weakness. If this weakness is misinterpreted as insufficient anticholinesterase therapy, a tragic positive feedback loop leading to myasthenic crisis can ensue.

LAMBERT–EATON SYNDROME The Lambert–Eaton syndrome is seen with an autoimmune disease that reduces the number of CaV channels in the presynaptic terminal. With prolonged effort, these patients gain strength, the opposite of myasthenic patients. Prolonging the presynaptic action potentials with drugs that block KV channels, such as diaminopyridine, may alleviate some of the symptoms. The prolonged depolarization opens the remaining CaV channels for a longer time, allowing more Ca2+ entry and therefore more release. If the experiment shown in Figure 7–11 is performed on these neuromuscular junctions, they will be found to have a lower quantal content, that is, they release a lower number of vesicles per stimulus. This is in contrast to myasthenia gravis, which will show the normal quantal content but a smaller MEPP, the depolarization for each quantum.

REPETITIVE STIMULATION The amount of transmitter released by a synapse is not constant from impulse to impulse but depends on the past history of activity. If the nerve leading to a neuromuscular junction is stimulated once every 10 seconds or slower, it will consistently release about 200 vesicles. If the stimulation rate is abruptly changed to 50/s, which is roughly the rate used by the CNS to cause normal muscle contraction, the amount released per impulse will increase in the first half second and then decrease (Figure 7–14). The increase, called facilitation, is related to a buildup in residual calcium in the nerve terminal. The decrease, called depression, is thought to reflect a depletion of vesicles at the release sites. This variation does not affect the functioning of the neuromuscular junction in a healthy individual. Each of those nerve impulses releases sufficient ACh to produce an EPP large enough to fire a muscle action potential. However, the

CHAPTER 7 Synapses

Facilitation X Normal

1

Depression

40

80 Impulses

120

FIGURE 7–14 Facilitation and depression of synaptic transmission at the neuromuscular junction. With repetitive stimulation the amount of transmitter released by each stimulus changes, first increasing and later decreasing. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/ McGraw-Hill, 2006.)

myasthenic person may have functional neuromuscular transmission only early in the task and experience weakness as the depression occurs with a prolonged effort and the amount of ACh released falls below what is necessary to trigger a muscle action potential. An anticholinesterase with a short duration of action, edrophonium chloride (Tensilon), is often used as a test for myasthenia gravis in patients who show rapid weakening when asked to perform a sustained contraction.

POSTTETANIC POTENTIATION When the 50/s stimulus is stopped, there is an increase in the amount of transmitter that can be released by a single nerve impulse (Figure 7–15). The nerve was stimulated once every 30 seconds before and after the tetanic stimulation. During the

PTP

x Normal

1

1

2

3

4

Minutes

FIGURE 7–15 Posttetanic potentiation (PTP) of synaptic transmission at the neuromuscular junction. After the end of a period of repetitive stimulation the amount of transmitter released by subsequent infrequent stimuli is increased for several minutes. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

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tetanus, the release increased and decreased, as in Figure 7–14. After the tetanus, as the synapse recovered from depression, a posttetanic potentiation (PTP) was seen that lasted for several minutes. PTP is also related to an increase in residual Ca2+ concentration in the nerve terminal, but it has a slower onset and slower decline than facilitation. PTP is used as a diagnostic procedure following surgical procedures when curare or other neuromuscular blocking agents have been used to prevent unwanted motion. The anesthesiologist will give the patient cholinesterase inhibitors, but she or he wants to know when just enough inhibitor has been given to avoid giving too much and desensitizing the AChRs. The anesthesiologist will repeat the experiment shown in Figure 7–15, stimulating the thenar branch of the patient’s median nerve and feeling the strength of contraction of the thenar muscles. Two shocks are given before the tetanus and then one 30 seconds later. Under deep curare, none of these will produce a palpable contraction. As more ACh is made available by blocking the esterase, the stimulus following the tetanus will give a larger response than the two before the tetanus because it will be the first one with an EPP large enough to excite the muscle. The endpoint is when enough esterase has been given that all three responses are the same because all three EPPs are above threshold for muscle activation.

AUTONOMIC SYNAPSES The autonomic nervous system (ANS) has two divisions, both with two synapses outside the CNS (Figure 7–16). The synapse closer to the CNS is referred to as the ganglionic synapse; the nerves leading into and out of the ganglia are called preganglionic and postganglionic. The sympathetic ganglia lie in a chain adjacent to the spinal column; the parasympathetic ganglia are close to the end organs where the second synapse occurs. The second synapses are onto smooth muscles or cardiac cells or gland cells. Many tissues receive both sympathetic and parasympathetic innervations. The primary transmitter in the ganglionic synapse of both divisions is ACh; the receptors are nicotinic nAChRs that are heteromeric pentamers of related but different gene products than the nAChR of the skeletal muscle. The ganglionic receptors are less sensitive to curare and more easily blocked by hexamethonium. The primary postganglionic transmitter in the sympathetic nervous system is NE, and there are two categories of GPCRs on the postsynaptic cells called alpha- and beta-adrenergic receptors. The primary postganglionic receptor in the parasympathetic division is ACh and the receptors are muscarinic mAChRs, which are also GPCRs but generally with different G proteins than the NE receptors. The ganglionic synapses are usually described as behaving more or less like the neuromuscular junction. However, the situation is more complicated; the postsynaptic neurons have dendrites with more than one presynaptic nerve ending on them. Different subpopulations of presynaptic and postsynaptic cells have been distinguished by looking at the peptide

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SECTION II Cell Physiology

CNS Parasympathetic

ACh

ACh

Preganglionic

ACh

Sympathetic Postganglionic

Target

NE Target

ACh Epinephrine

Motor

ACh

Muscle

FIGURE 7–16

A schematic view of the efferent fibers of the autonomic nervous system and the motoneurons. From top to bottom: parasympathetic, sympathetic, adrenal medulla, motoneuron. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/

McGraw-Hill, 2006.)

transmitters that are in these cells along with their classic transmitters. Postganglionic cells also have mAChRs that produce a slow EPSP by closing a K channel. There are also small, intensely fluorescent cells in the ganglia that are innervated by preganglionic fibers and release NE or dopamine. All in all, it seems that some computation must be carried out in the ganglia, more than the simple passthrough circuit seen at the neuromuscular junction. The synapses between the postganglionic cells and the end organs are different from those in the neuromuscular junction. The presynaptic processes are similar, but postganglionic cells make “en passant” synapses on tissue targets over a length of axon. Synaptic vesicles are stored in varicosities of the nerve, which continues on to other varicosities before reaching its terminal. Activation of mAChRs by the ANS increases GI tone and motility, increases urinary bladder tone and motility, increases salivation and sweating, constricts bronchioles, and decreases heart rate and blood pressure. The ANS activates α-, β1-, and β2-adrenergic receptors, and α-adrenergic receptors raise blood pressure. β1-Adrenergic receptors increase heart rate and strength of contraction and blood pressure. β2-Adrenergic receptors dilate bronchioles in the lungs. The mechanism of the effects on cardiac and smooth muscle is discussed in the next section. Many agonist and antagonist drugs have been used to control these processes, some with more specificity than others. Thus, there are specific α agonists and β blockers. Amphetamines and cocaine have an indirect adrenergic effect by stimulating NE release. Some compounds, such as ephedrine, have both direct and indirect adrenergic effects. Atropine is the archetypical mAChR antagonist; its effects are the opposite of those attributed to ACh above. At many sites there is a tonic release of both

ACh and NE from the ANS, so the blocking of one set of receptors may produce effects similar to activating the other.

CENTRAL NERVOUS SYSTEM SYNAPSES The human CNS has billions of neurons with trillions of synapses between them. A single neuron may have thousands of both excitatory and inhibitory inputs; some larger neurons may have over 100,000 endings on them. In order to accommodate this convergence of synaptic inputs, most neurons have a dendritic tree that greatly expands the area available for synaptic contact. The cell body (soma) and the initial region of the axon (axon hillock) integrate the incoming synaptic signals and determine when and how often the neuron will fire action potentials (Figure 7–17). The axon carries the output of the neuron to the next group of neurons or to skeletal muscle cells if it is a motoneuron. Usually only a single axon leaves the cell body, but it later branches to allow the neuron to synapse with many other cells. This divergence of information combined with the convergence of many inputs onto a neuron gives the CNS much of its computational power. Each neuron in the CNS acts as one or more small computers. While each cell performs its computations in milliseconds, millions of times slower than the central processing unit of a modern computer, the billions of neurons operating in parallel make the CNS shine in comparison. The CNS is capable of creating every thought in recorded history while simultaneously regulating both walking and chewing gum. The synapses make this possible. Learning and memory are accomplished by the modification of synapses.

CHAPTER 7 Synapses

73

Axons converge on neuron

Dendrites

Synaptic inputs cover most of the surface of the soma and dendrites

Soma

Axon hillock or initial segment Axon

Synapses diverge

FIGURE 7–17 The convergence and divergence of synapses in the CNS. (Modified with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

There are two general types of synapses in the CNS, electrical and chemical. Electrical synapses operate by direct electrical current flow from the presynaptic neuron into the postsynaptic neuron through gap-junction channels between the membranes of the two cells (Figure 7–18). Neurotransmitters are not involved and electrical synapses can have less synaptic delay than chemical synapses. However, unlike chemical synapses, electrical synapses cannot amplify the signal, nor can they reverse the direction of current flow. Gap junctions, which work as electrical synapses and allow action potentials to flow selectively from one cell to another, also connect cells in the heart and some types of smooth muscle.

There are two general types of chemical synapses in the CNS, excitatory and inhibitory. Excitatory synapses generate EPSPs that depolarize the membrane toward threshold. Inhibitory synapses generate IPSPs that either hyperpolarize the membrane or resist depolarization to threshold. Each of these types can be further divided into chemosensitive ion channels (or ionotropic receptors) and G protein–linked ion channels (or metabotropic receptors). Chemosensitive ion channels typically give rise to fast synaptic events that last a few milliseconds; G protein–linked ion channels may produce effects for hundreds of milliseconds.

INTEGRATION OF SYNAPTIC CURRENTS

FIGURE 7–18

An electrical synapse. Current passes directly from the presynaptic cell to the postsynaptic cell through specialized cell–cell channels. (Modified with permission from Landowne D: Cell Physiology.

New York: Lange Medical Books/McGraw-Hill, 2006.)

Excitatory and inhibitory synapses inject current (positive or negative) into cells. These currents flow into the cell body and are summed. The PSPs passively spread to the spike initiation site or the part of the cell with the lowest threshold because of the cable properties of the cell. More distal synapses will be decremented compared to those near the site. The cell produces the spike initiation site by controlling the local density of NaV channels. Often the spike initiation site is the axon hillock near the start of the axon (see Figure 7–17) or at the first node of Ranvier. Because the PSPs last for several to many milliseconds, they can add together even though they do not occur synchronously; this is called temporal summation. The effects of synapses at different locations on the same postsynaptic cell can also add up; this is called spatial summation. Spatial summation is weighted inversely by the distance from the synapse to the initiation site of the action potential.

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Synaptic cleft Postsynaptic spine on dendrite

Axon

Presynaptic nerve terminal Synaptic vesicles

Postsynaptic density

FIGURE 7–19

A CNS synapse. These are less elaborate than the synapse at the neuromuscular junction (Figure 6–9). (Modified with

permission from Landowne D: Cell Physiology. New York: Lange Medical Books/ McGraw-Hill, 2006.)

Figure 7–19 is a schematic drawing of a chemical synapse in the CNS. The presynaptic terminal is about 1 μm in diameter and contains mitochondria and synaptic vesicles filled with neurotransmitter. Depolarization of the terminal opens CaV channels, and Ca2+ flows with its electrochemical gradient to act on synaptotagmin and trigger the fusion of a few vesicles with the presynaptic membrane in order to exocytose the neurotransmitter. The membrane is then recycled and the vesicles are refilled. The postsynaptic receptors are often on protrusions from dendrites, called spines, although synapses are also found on the dendritic shaft, the neuronal cell body, and other synaptic endings. CNS synapses share many features with the neuromuscular junction but differ in several important respects. CNS synapses are much smaller and release far fewer vesicles, typically less than 5 per impulse, compared to about 200 at the motor endplate. In the CNS, synaptic clefts are narrower, about 20 nm, and cadherins and other cell adhesion molecules span the gap. ACh is the transmitter at the neuromuscular junction; there is a wide variety of transmitters in the CNS. The EPP is always excitatory and large enough to bring the muscle membrane to threshold; synapses in the CNS are excitatory or inhibitory and threshold is reached by the combination of hundreds of EPSPs. There are some exceptional CNS synapses. In the cerebellum, a climbing fiber axon may make dozens of synapses on a Purkinje cell. In the calyx of Held, in the auditory pathway, the presynaptic ending forms a cap with fingerlike stalks that envelop the postsynaptic neuron, covering about 40% of its soma. At both of these synapses a single presynaptic impulse releases hundreds of quanta, and the resulting EPSP is large enough to trigger a postsynaptic action potential. Glutamate is the principal excitatory neurotransmitter in the CNS. There are several postsynaptic glutamate receptors, both channels and GPCRs. The channels can be grouped into two major types, NMDA and non-NMDA channels, according to their sensitivity to the synthetic agonist N-methyl-daspartate. Both types respond to glutamate. The non-NMDA

channels may be called AMPA, quisqualate, or kainate channels, according to which of these nonphysiologic agonists opens them. Non-NMDA channels typically generate fast EPSPs lasting about 5 milliseconds. When they are activated by glutamate, non-NMDA channels allow Na+ and K+ to flow through their pores. Each ion moves in the direction that will tend to bring the membrane potential to its Nernst equilibrium potential. Because both are moving, the membrane potential tends to approach the average of the two equilibrium potentials, which is about –10 mV. This potential, where the two ionic currents are equal, is called the reversal potential for the channel. When these channels open at potentials more negative than the reversal potential, the tendency for Na+ to enter the cell will dominate and the membrane will depolarize toward the reversal potential. If the starting potential were more positive than the reversal potential, the K+ ions would dominate and the cell would hyperpolarize toward the reversal potential. NMDA receptor channels generate EPSPs lasting hundreds of milliseconds. Open NMDA channels allow Na+ and K+ and also Ca2+ to pass through their pores. In the presence of glutamate, NMDA channels open only if the postsynaptic cell is also depolarized by some other means. This dual control of Ca2+ entry has a key role in learning, as discussed below. GABA is the major inhibitory transmitter in the brain. Glycine is an inhibitory transmitter in the brainstem and spinal cord. GABA opens GABAA channels directly, which allows Cl− ions to pass through their pores. GABA can also cause inhibition through GABAB receptors, which are GPCRs that lead to the opening of K channels. The reversal potential for GABAA channels is at the Nernst potential for Cl−, about –80 mV. If the membrane is more positive than ECl, Cl− will enter the cell and make the membrane potential more negative, which will make it less likely to initiate an action potential. Benzodiazepines such as diazepam (Valium) and barbiturates enhance the open probability of activated GABAARs. Both have been used as sedatives and anticonvulsants. General anesthetics such as ether, chloroform, and halothane increase the duration of IPSPs and decrease the amplitude and duration of EPSPs.

CNS—MODULATORY NEUROTRANSMITTERS In the CNS, ACh, NE, dopamine, and serotonin primarily act as diffuse modulators of activity, acting over timeframes that are long compared to action potentials, as opposed to being involved in specific discrete tasks. Each of these neurotransmitters has its own set of neurons and targets; some of these neurons may influence more than 100,000 postsynaptic neurons. The postsynaptic receptors are metabotropic and alter the responsiveness of the postsynaptic neurons through second messenger pathways. There are also ionotropic nAChRs in the CNS, but there are 10–100 times more mAChRs. The ACh and NE modulatory systems are part of the ascending

CHAPTER 7 Synapses

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Axon

B A

Neuron C

FIGURE 7–20

Presynaptic inhibition can occur by a synapse (A and B) on another synaptic ending. (Modified with permission from Landowne

D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

reticular activating system that arouses the forebrain in response to stimuli. In some general ways, the modulatory systems play a role in the CNS similar to the role played by the ANS in the rest of the body.

cellular space by a nonvesicular process. It binds to presynaptic cannabinoid receptors (CB1), which are GPCRs, and can alter the subsequent release of traditional neurotransmitters.

PRESYNAPTIC INHIBITION

REPETITIVE FIRING OF NERVE CELLS

Some CNS synapses act directly on other synaptic endings rather than on dendrites or cell bodies (Figure 7–20). Terminal A releases GABA on to terminal B, activating Cl channels that tend to hyperpolarize terminal B. If an action potential arrives in B while the Cl channels are open, the action potential’s amplitude will be reduced, so that it will open fewer CaV channels and therefore fewer vesicles will be released by terminal B, and it will have a smaller effect on neuron C.

If an axon or a muscle cell is subjected to a maintained depolarization, it will respond with one or perhaps two action potentials and then stop firing because the NaV channels enter the inactivated state and require a brief period near the resting potential to recover. Many CNS cells and the slowly adapting sensory nerve endings will respond to a sustained depolarization with a train of action potentials at about 50/s. This is made possible by CaV channels and Ca-activated K channels. The action potential depolarization opens the CaV channels and the Ca2+ that enters opens the Ca-activated K channels by binding to the intracellular portion of the molecule. The Ca-activated K channel then allows K+ to leave and the membrane potential to approach EK for a long-lasting hyperpolarization, long enough for the NaV channels to recover from inactivation (Figure 7–21). The balance between the sustained stimulus and the rate that Ca2+ is removed from the Ca-activated K channels determines the firing rate.

RETROGRADE FREELY DIFFUSIBLE CHEMICAL TRANSMITTERS In addition to the classic transmitters that are released from vesicles and bind to receptors, there are chemical messengers in the CNS with a different mode of operation. Nitric oxide (NO) is not stored but rather produced when needed. It can freely diffuse across cell membranes from the inside of one cell (typically a postsynaptic cell body) to the inside of other cells (typically presynaptic endings), where it alters some chemical reactions. NO may spread to several presynaptic endings in the vicinity. It is removed from the tissue by binding to hemoglobin. Anandamide, an endogenous cannabinoid, is also produced as needed in postsynaptic cells and reaches the extra-

LEARNING, MEMORY, AND SYNAPTIC PLASTICITY The cellular basis of learning and memory is a functional remodeling of synaptic connections, often called synaptic plasticity. This includes both explicit or declarative memory when

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+40

mV

0

−60 −70 0

200

400

ms

Sustained excitatory synaptic input

FIGURE 7–21

Repetitive firing of a motoneuron. Unlike axons, many nerve cells respond repetitively to a sustained input. (Modified

with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/ McGraw-Hill, 2006.)

the person can recall and describe some fact or past event and implicit or procedural memory, as in a learned motor skill. Memory is often subdivided into short-term, minutes to hours, and long-term, days to a lifetime. Short-term memory formation involves the modification of existing proteins, often by phosphorylation. Long-term changes involve gene activation, protein synthesis, and membrane rearrangement, including the formation and/or resorption of presynaptic terminals and postsynaptic spines. In a few studies, the volume of cerebral cortex dedicated to a task has been shown to increase with specific training. The most intensively studied cellular learning phenomenon is long-term potentiation (LTP) in hippocampal synapses. The hippocampus is required for the formation of new longterm memories. If both hippocampi are compromised, the person will live continuously in the present with no recollection of events after the damage. In the hippocampus, LTP occurs at glutamate synapses between presynaptic CA3 cells and postsynaptic CA1 cells. LTP and the related long-term depression (LTD) also occur in other locations in the CNS. The classic

experiment is similar to the PTP demonstration shown in Figure 7–15; the synapse is tested infrequently, subjected to high-frequency stimulation, and then tested infrequently again. Unlike PTP, which disappears in a few minutes, with LTP, the potentiation remains for many hours or days (Figure 7–22). Also unlike PTP, LTP is primarily a postsynaptic event. It is not necessary to provide the high-frequency stimulation to the presynaptic terminals; simple depolarization of the postsynaptic cell paired with the presynaptic stimulation will induce LTP. This response to pairs of inputs made LTP a candidate basis for associative learning. There are two types of glutamate receptors on the postsynaptic membranes: AMPA (non-NMDA) and NMDA receptors. During low-frequency unpaired stimulation, only the AMPA receptors are activated; the NMDA receptors are plugged by external Mg2+ ions. The AMPA receptor channels are permeable to Na+ and K+; near the resting potential, Na+ movement into the cell is favored. When the postsynaptic membrane is depolarized, either by high-frequency synaptic input or by injecting current into the postsynaptic cell, the Mg2+ is driven off the NMDA receptors and they respond to glutamate and allow Na+ and Ca2+ to enter the cell. The elevated Ca2+ activates a series of biochemical events that lead to the insertion of more AMPA receptors into the postsynaptic membrane. LTP has been associated with learning in rats using a water maze. Rats with surgically removed hippocampi do not learn the maze, neither do rats that have been treated with a specific antagonist for NMDA receptor channels. There are other examples of synaptic plasticity in other regions of the brain and there may well be additional mechanisms, including retrograde action of NO or anandamide.

CLINICAL CORRELATION About a month before coming to the hospital, a 56-yearold woman noticed she was unable to hold her shopping bag and that her head fell forward when she knelt to tie her shoes. Two weeks later she had to remain in bed and had difficulty sitting up. Her jaw began to droop, she had

5 4

mV

3 2 1 0 10

FIGURE 7–22

20

30 Minutes

40

50

60

Long-term potentiation. A brief conditioning stimulus (blue bar) causes a long-term increase in synaptic efficacy. (Modified

with permission from Landowne D: Cell Physiology. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 7 Synapses ■

to hold it up with her hand, and her left eyelid began to droop. Her speech became indistinct when she was excited, swallowing was difficult and fluid sometimes regurgitated through her nose. A few days after admission to the hospital, she developed weakness in the middle and ring fingers of both hands that was increased by excitement and lessened by rest. There was no muscle wasting and tendon reflexes were all present. Her masseter muscles showed a decremental response to tetanic electrical stimulation. In the hospital, she was injected with 1 mg of physostigmine. About 1 hour later, her left eyelid elevated, her arm movements were stronger, her jaw drooped less, swallowing was improved, and she reported feeling “less heavy.” The effect wore off gradually in 2–4 hours. With 1.3 mg the improvement was greater and lasted 4–5 hours. Still greater improvements, lasting 6–7 hours, followed an injection of 1.5 mg but the patient felt faint as if “something were going to happen.” The diagnosis is myasthenia gravis. It is an autoimmune disease that affects about 1 in 5,000 people. The immune system produces antibodies to the nicotinic AChR of the neuromuscular junction and neuromuscular transmission is impaired. With fewer receptors the effects of depression of synaptic transmission lead to a failure of neuromuscular transmission during sustained effort. This fatigability is a characteristic of the disease. Physostigmine is an inhibitor of AChE. In its presence more of the released ACh can interact with the receptor and transmission is more reliable. AChE inhibitors are used to relieve the symptoms of myasthenia gravis. Immunosuppressants, for example, the synthetic corticosteroid prednisone, are used to reduce antibody production. In some cases thymectomy (surgical removal of the thymus) is performed to suppress the immune system. Edrophonium chloride (Tensilon) is a short-acting AChE inhibitor that has been used to assist in diagnosis. Electrical stimulation and testing for circulating antibodies are also used diagnostically.

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GABA and glycine are the major inhibitory neurotransmitters in the CNS. Several biogenic amines are important neurotransmitters. NE is released by sympathetic nerves to control the heart and vascular smooth muscle. Neuropeptides are small proteins released as neurotransmitters. Synaptic release involves many proteins and is controlled by CaV channels, which are opened when an action potential invades the presynaptic terminal. Axons have a microtubule-based transport system to move materials from the cell body to the presynaptic terminal (orthograde transport) and in the other direction (retrograde transport). PSPs are excitatory (EPSPs) if they make the postsynaptic cell more likely to initiate an action potential and inhibitory (IPSPs) if they make it less likely. Neuromuscular transmission is a well-studied example of synaptic transmission. Hypocalcemia reduces the number of vesicles released when an action potential invades the presynaptic terminal. At the neuromuscular junction, the number of open channels is proportional to the concentration of ACh squared times the effective number of AChR channels. Several clinically important drugs act at the neuromuscular junction. The number of vesicles released per action potential depends on the rate and pattern of arrival of the action potentials. The ANS has two synapses outside the central nervous system. The first is cholinergic; the second is either adrenergic or cholinergic. In general, CNS synapses are similar to the neuromuscular junction, but they differ in many important ways. In the CNS, several transmitters act through G protein–coupled receptors to modulate the activity of the brain. In order to fire repetitively, nerve cells use Ca-activated K channels to hyperpolarize the cell and allow the NaV channels to recover from their inactivation. Learning and memory involve changes in synaptic efficacy.

STUDY QUESTIONS CHAPTER SUMMARY ■ ■

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Synapses may be chemical or electrical. Chemical synapses may be excitatory or inhibitory. In chemical synapses, the presynaptic terminal packages a neurotransmitter into vesicles. When the synapse is activated, the vesicle’s contents are released and then a recycling process recovers some of the released transmitter and vesicular components. ACh is the neurotransmitter at the neuromuscular junction. It is also an important component of the autonomic and central nervous system synapses. Glutamate is the major excitatory neurotransmitter in the CNS.

1. Ca2+ ions are needed in the extracellular solution for synaptic transmission because A) Ca2+ ions enter the presynaptic nerve terminal with depolarization and trigger synaptic vesicles to release their contents into the synaptic cleft. B) Ca2+ ions are required to activate glycogen metabolism in the presynaptic cell. C) Ca2+ ions must enter the postsynaptic cell to depolarize it. D) Ca2+ ions prevent Mg2+ ions from releasing the transmitter in the absence of nerve impulses. E) Ca2+ ions inhibit the acetylcholine esterase, enabling the released acetylcholine to reach the postsynaptic membrane.

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2. Inhibitory postsynaptic potentials can arise from all of the following except A) increased permeability of the nerve membrane to Cl− ion. B) direct application of GABA to neurons. C) increased permeability of the nerve membrane to K+ ion. D) increased permeability of the cell membrane to Na+ ion. 3. Electrical and chemical synapses differ in that A) electrical synapses have a longer synaptic delay than chemical synapses. B) chemical synapses can amplify a signal while electrical synapses cannot. C) chemical synapses do not have a synaptic cleft while electrical synapses do have a synaptic cleft. D) electrical synapses use agonist-activated channels and chemical synapses do not. E) electrical synapses are found only in invertebrate animals while chemical synapses are found in all animals. 4. Which one of the following does not contribute to the integration of synaptic potentials by neurons? A) convergence of many synaptic inputs on one neuron, allowing spatial summation B) the presence of EPSPs having amplitudes that exceed the threshold for generation of an action potential in the neuron C) temporal summation of synaptic potentials in neurons due to the time constant of the neurons D) the flow of currents from the distal regions of the dendrites to the soma due to the length constants of the dendrites E) inhibitory synaptic inputs

5. Which of the following ions is countertransported to energize neurotransmitter transport into presynaptic vesicles? A) Na+ B) K+ C) H+ D) Cl− E) Ca2+ 6. A branch of a 26-year-old man’s ulnar nerve was crushed in his left forearm, severing axons at a point about about 6 in (15 cm) from the skin on the medial part of the palm, where cutaneous sensation was lost. About how long will it likely take before the patient begins to feel stimuli in that part of the palm? A) 1 day B) 10 days C) 100 days D) 1,000 days E) never, since peripheral axons do not regenerate 7. Treatments for nerve gas poisoning target which of the following proteins? A) acetylcholinesterase (AChE) and choline acetyltransferase (CAT) B) AChE and nicotinic acetylcholine receptors C) muscarinic and nicotinic acetylcholine receptors D) muscarinic acetylcholine receptors and AChE E) CAT and synaptic choline transporters

SECTION III MUSCLE PHYSIOLOGY

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Overview of Muscle Function Kathleen H. McDonough

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Explain the differences in skeletal, cardiac, and smooth muscle with reference to appearance, contractile proteins, calcium-binding proteins, and neural input. Describe how the sarcolemma and the sarcoplasmic reticulum are involved in muscle contraction. Explain the energy source for contraction. Describe the role of the following proteins: actin, myosin, dihydropyridine receptors, ryanodine receptors, calmodulin, and troponin.

GENERAL COMPARISON Muscle is the largest organ system of the body. It consists of three different types based on factors such as morphology, cellular signaling pathways, ways to alter strength of contraction, contraction pattern (cyclic vs. graded), and the role of the nervous system in muscle function. The three types of muscle are skeletal, cardiac, and smooth muscle. Skeletal muscle is, for the most part, attached to bone and represents approximately 40% of the body mass of a typical healthy person. Cardiac muscle is the main component of the heart and contracts in a cyclic fashion for the lifetime of the individual. Smooth muscle is the major component of the organs of the gastrointestinal tract, bladder, uterus, airways, and blood vessels—in general, smooth muscle makes up the walls of hollow structures in the body except the heart. The requirement for calcium to initiate contraction is uniform in all muscle. Mechanisms for increasing calcium for contraction may vary from muscle type to muscle type and removal of calcium for relaxation also varies. However,

Ch08_079-082.indd 79

the overriding unifier is that cytosolic calcium concentrations must increase in order for contraction to occur and cytosolic calcium concentrations must decrease for relaxation to occur. Since, in smooth muscle, there is usually some moderate level of contraction, cytosolic calcium must increase for the strength of the contraction to increase and must decrease for the strength of the contraction to decrease. Thus, the organelles such as the sarcolemma (SL) and the sarcoplasmic reticulum (SR) that contain proteins that effect calcium fluxes are highly organized and efficient in muscle. Calcium levels in resting cardiac muscle, for example, are only 0.1 μM and can increase 100-fold during excitation. Removal of calcium for relaxation to occur is therefore critical. Processes involved in calcium movement are important in the understanding of muscle contraction in all three types of muscle. Muscle contraction is supported by hydrolysis of adenosine triphosphate (ATP). ATP is produced mainly by mitochondrial oxidative phosphorylation from substrates supplied by glycogen or triacylglycerol stores in the tissue or by

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blood-borne substrates such as glucose and fatty acids. Glycolysis also produces ATP but not as efficiently as oxidative phosphorylation. In some types of skeletal muscle, glycogen supplies glucose for glycolysis that provides energy for rapid, short-term contraction. Energy is additionally provided by creatine phosphate (CP), which can rapidly supply a source of high-energy phosphate bonds for resynthesis of ATP from ADP. The ADP is produced by ATPase enzymes located in the muscle cell. CP is not used directly by the ATPase but is used for rapid regeneration of ATP at the site of ATP use. ATP is used for both contraction and relaxation of muscle. The myosin ATPase hydrolyzes ATP to provide the energy for the sliding of the actin filament over the myosin filament; ATP also provides the energy for removal of calcium from the cytosol by calcium ATPases so that relaxation can take place.

DIFFERENCES IN SKELETAL, CARDIAC, AND SMOOTH MUSCLE Skeletal and cardiac muscle are both striated in appearance due to the orderly arrangement of the contractile proteins actin and myosin. In smooth muscle, the contractile proteins actin and myosin are responsible for contraction but they are not arranged in such an organized pattern; therefore, striations do not appear. Skeletal muscle is the only muscle type that is voluntary—you decide when to contract skeletal muscle for the most part and the muscle has to be activated by neurons regulated by the central nervous system. Cardiac muscle is involuntary; it contracts spontaneously. Action potentials are generated by specialized cells within the heart itself; thus, hearts can be transplanted from one person to another and the heart functions adequately even without neural input in the transplanted heart of the recipient. The beating rate of the heart as well as the strength of contraction of the cardiac muscle cells can, however, be modulated by the autonomic nervous system (ANS; see Chapter 19). The sympathetic nervous system (SNS) component of the ANS will increase the heart rate, whereas the parasympathetic nervous system (PNS) will decrease the heart rate. Smooth muscle is also involuntary. It has the potential to contract from many different types of stimuli but does not require neural input for contraction to occur. Even changes in the resting membrane potential and stretch of the muscle can change the strength of contraction. Smooth muscle does not usually exhibit contractions followed by complete relaxation as do skeletal and cardiac muscle but rather demonstrates increased or decreased strength of contraction. For example, if all of the vascular smooth muscle making up the blood vessels to the systemic organs were to relax completely, the individual would go into shock; blood pressure would decrease to dangerously low levels. This occurs under pathological conditions such as severe brain injury causing withdrawal of all neural control of vascular smooth muscle and resulting in neurogenic shock. Blood pressure cannot be maintained if all of the vascu-

lar smooth muscle in the blood vessels is completely relaxed. In smooth muscle, gradations of contraction are regulated and affected by many different influences, depending on the location and function of the smooth muscle.

CALCIUM Although calcium is uniformly required for muscle to contract or increase strength of contraction, the calcium-binding proteins in the three types of muscle differ, as do the sources of calcium. Troponin is the calcium-binding protein that initiates contraction in skeletal and cardiac muscle. Calmodulin binds calcium in smooth muscle and initiates increases in strength of contraction. Actin and myosin form the crossbridges in all three types of muscle. The source of the calcium that initiates contraction is different in the three muscle types. Calcium released from the SR through ryanodine receptors or channels raises the cytosolic calcium concentration and contraction begins in skeletal muscle (see Chapter 9). In cardiac muscle, the calcium that binds to troponin comes from both the SR and the extracellular space through SL voltage-gated calcium channels (dihydropyridine receptors). In addition, it is the calcium entering the cell through the calcium channels that activates the release of calcium from the SR through the ryanodine receptors or channels (see Chapter 10). In smooth muscle, calcium can enter the cytosol from extracellular fluid via the voltage-gated calcium channels in the SL and from the SR via receptors activated by signaling molecules from SL receptor pathways. Smooth muscle also has other receptors on the SL and SR for calcium mobilization that will be discussed in Chapter 11. In all three muscle types, increases in cytosolic calcium initiate cycling of crossbridge attachments between actin and myosin.

CONTRACTION PERIOD The time course of muscle contraction is different in skeletal, cardiac, and smooth muscle. Skeletal muscle contractions take several milliseconds to occur, cardiac muscle contractions take hundreds of milliseconds, while smooth muscle is much slower and can take up to minutes for contractions to occur. This difference in contraction time is mainly due to the rate of ATP hydrolysis occurring in the myosin head. Fast rates of ATP hydrolysis by the myosin ATPase result in more rapid contractions such as in skeletal muscle. Muscles with slower rates of ATP hydrolysis exhibit slower contractions such as in smooth muscle. Signaling pathways that cause increases in calcium in the cytosol can contribute to the delay between the signal and the contraction.

CHANGES IN STRENGTH OF CONTRACTION The strength of muscle contraction can be altered in all three muscle types but by different means. Phosphorylation of

CHAPTER 8 Overview of Muscle Function proteins results in stronger contractions in both cardiac muscle (Chapter 10) and smooth muscle (Chapter 11), whereas skeletal muscle achieves stronger contractions by recruiting more muscle cells or activating muscle cells with a higher frequency of nerve firing (Chapter 9).

SIMILARITIES IN SKELETAL, CARDIAC, AND SMOOTH MUSCLE As stated above, actin and myosin are the contractile proteins involved in crossbridge cycling in all three types of muscle although the anatomic distribution of the actin and myosin is different in smooth muscle compared to skeletal and cardiac muscle (nonstriated vs. striated, respectively). The myosin head contains a binding site for actin. This site is blocked when calcium levels are low but open when calcium binds to troponin (skeletal and cardiac muscle) or calmodulin (smooth muscle). With binding of actin and myosin, the ATPase site located on the myosin head can release energy from the ATP to allow cycling of the crossbridges, that is, actin sliding across myosin. All three types of muscle demonstrate the property of increasing strength of contraction by increasing the precontraction (resting) length of the muscle. This phenomenon is termed the length–tension relationship. Since skeletal muscle is attached to bones by tendons, variations in resting cell length are very limited and the muscle is usually operating at the peak of the length–tension relationship. In the heart, resting muscle cell length is usually not at the optimum length, so there is reserve, that is, stronger contractions can be elicited when the resting length is increased prior to the contraction. Smooth muscle also demonstrates the length–tension relationship but other influences on the muscle can override the effects of increased cell length. For example, in certain types of vascular smooth muscle, when the cell is stretched, the cell responds with an increased level of contraction. This phenomenon is called the myogenic response. In the gastrointestinal tract, this occurs with the presence of food in the stomach and small intestines. Hollow organs with specialized functions such as the bladder and uterus can be “stretched” but contraction is not stimulated due to other influences on muscle function. A comparison of skeletal, cardiac, and smooth muscle is given in Table 8–1. More details on the individual muscle types will be given in the next three chapters.

CHAPTER SUMMARY ■

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There are three types of muscle in the body classified by morphology, function, and cellular mechanisms of contraction—skeletal, cardiac, and smooth. All types of muscle require calcium to initiate contraction. SL and SR have specialized functions that increase cytosolic calcium for contraction and remove calcium for relaxation.

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TABLE 8–1 Comparison of skeletal, cardiac, and smooth muscle. Skeletal

Cardiac

Smooth

Appearance

Striated

Striated

Nonstriated

Sarcoplasmic reticulum

Most

Less

Least

Voluntary

Yes

No

No

Calciumbinding protein

Troponin

Troponin

Calmodulin

Source of calcium

SR

SR and SL

SL and SR

Innervation

Motor neuron

SNS; PNS

SNS; PNS

Contraction length

Milliseconds

100 ms

100 ms – minutes

Strength of contraction

Recruitment

Phosphorylation; length–tension

Phosphorylation; length–tension

Metabolism

Oxidative, glycolytic

Oxidative

Oxidative

Velocity of ATPase reaction

Rapid

Less rapid

Slow

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Muscle can increase strength of contraction by increasing the length of the muscle prior to the contraction—length–tension relationship. The energy for contraction is released from ATP by the myosin ATPase. Skeletal muscle requires neural input from a motor neuron to initiate contraction (voluntary muscle). Cardiac and smooth muscle can contract without neural input but the strength of contraction can be altered by input from the ANS—sympathetic and parasympathetic branches of the ANS (involuntary muscle).

STUDY QUESTIONS 1. Which of the following statements about muscle is true? A) The calcium source for skeletal muscle contraction is solely calcium entering the cell through the dihydropryidine receptors. B) The calcium source for smooth muscle contraction is solely calcium entering the cell through the dihydropyridine receptors. C) The calcium source for cardiac muscle contraction is solely calcium entering the cell through the dihydropryidine receptors. D) The calcium source for skeletal muscle contraction is solely calcium entering the cytosol through the ryanodine receptors. E) The calcium source for cardiac muscle contraction is solely calcium entering the cytosol through the ryanodine receptors.

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2. Which of the following statements about muscle is true? A) Both smooth and cardiac muscle remain partially contracted at all times. B) Both cardiac and skeletal muscle contraction is initiated by calcium binding to troponin. C) Both cardiac and smooth muscle must have action potentials to initiate contraction. D) Both cardiac and smooth muscle initiate contraction by calcium binding to troponin. 3. Which of the following statements about muscle is true? A) Skeletal muscle can increase strength of contraction by recruiting more motor units. B) Cardiac muscle can increase strength of contraction by recruiting more muscle cells. C) Smooth muscle cannot change strength of contraction. D) Cardiac muscle cannot change strength of contraction.

4. Which of the following statements about muscle is true? A) In all three muscle types (cardiac, skeletal, and smooth) all cells contract as a unit. B) All three muscle types are innervated by the autonomic nervous system. C) In all three muscle types, calcium is involved in contraction. D) In all three muscle types, dihydropryidine antagonists or blockers increase strength of contraction.

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Skeletal Muscle Structure and Function Kathleen H. McDonough

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Describe the processes that take place at the neuromuscular junction. Explain excitation–contraction coupling in skeletal muscle. Describe the role of the proteins that are involved in contraction. Describe what happens during an isometric contraction. Describe what happens during an isotonic contraction. How does the load affect shortening and velocity of shortening? Explain how muscle fiber strength of contraction can be increased by summation and tetanus. Explain the length–tension relationship in skeletal muscle. Explain the motor unit. Explain how whole muscle strength of contraction can be increased by recruitment of motor units. Explain the force–velocity relationship in skeletal muscle; explain the basis for the Vmax. Describe the three different types of skeletal muscle fibers and the bases for their differences. State when these fibers are recruited.

STRUCTURE Skeletal muscle is distinctive because of its anatomic structure—striations due to the regular pattern of sarcomeres that are composed of the orderly positioning of the actin and myosin proteins. Figure 9–1 shows sarcomeres composed of parallel alignments of thick filaments (i.e., myosin) and thin filaments (i.e., actin, tropomyosin, and troponin). Myosin makes up the A band. Actin, along with the two other proteins, tropomyosin and troponin, makes up the I band (portion of the sarcomere where actin does not overlap with myosin). Part of the actin filament overlaps with the myosin filament, thus allowing interaction of these two proteins to initiate contraction. The degree of overlap of thick and thin filaments is important in determining the amount of force that skeletal muscle, and cardiac muscle, can generate. The Z lines represent the borders of the sarcomere and, during shortening, the Z lines come closer to each other as the actin filament is pulled

Ch09_083-092.indd 83

over the myosin filament. The A band remains the same length (myosin does not shorten) but the I band becomes smaller as actin is pulled over the myosin. The sliding of the actin over the myosin, with energy provided by the myosin ATPase that is located on the myosin head, is the molecular basis of skeletal muscle contraction (Figure 9–2). Activation of the complex occurs when the calcium concentration in the cytosol increases and binds to the calcium-binding site on the troponin. Troponin has three components designated as TnT that attaches it to tropomyosin, TnI that inhibits interactions between actin and myosin, and TnC that binds the calcium. When calcium binds to TnC, there is a conformational change in the troponin/ tropomyosin position, removing the hindrance by TnI and tropomyosin and allowing the actin and myosin head to interact, thereby hydrolyzing ATP to supply the energy for the contraction—sliding of the actin over the myosin or crossbridge cycling. The cross-bridges will continue to cycle, that is, myosin heads will continue to bind to adjacent sites on actin

83

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SECTION III Muscle Physiology

Sarcomere

(a)

I band

A band H zone

(b)

Z line

Z line Titin

Thin filament

M line

Thick filament

FIGURE 9–1 (a) Magnified section of a sarcomere within a skeletal muscle cell showing the pattern of striation due to the orientation of the actin and myosin filaments. (b) Drawing of the components of the sarcomeres from Z band to Z band showing the structural protein titin and the thick filaments (myosin) and the thin filaments (actin, tropomyosin, and troponin). (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

Thick filament

Cross-bridge

Thin filament (a) Actin binding sites ATP binding sites

Troponin

Tropomyosin

Light chains Heavy chains

Actin

Myosin

Cross-bridge

(b)

FIGURE 9–2 (a) Drawing of the thick filament with the myosin heads or cross-bridges extending from the thick filament. Also shown is the twisted structure of the thin filaments. (b) Magnification of the myosin and actin showing the three components of the thin filament— actin, tropomyosin, and troponin—and the heavy and light chains of the myosin. Note the actin- and ATP-binding sites on the myosin. The actin-binding sites are blocked by tropomyosin when calcium levels in the cytosol are low. With calcium binding to troponin, tropomyosin is moved away and the binding site for actin is available. The energy for sliding the actin filament across the myosin filament is provided by the ATP hydrolyzed by the myosin ATPase that is located on the myosin head. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

CHAPTER 9 Skeletal Muscle Structure and Function and slide the actin further over the myosin, until the contraction is terminated by removal of calcium. Cross-bridge cycling results in either tension development or shortening or a combination of the two, depending on the load on the muscle. If the load is too great, there will be an isometric contraction in which there is tension development but no shortening of the muscle. If the load is less, there will be an isotonic contraction in which the muscle shortens after developing tension (discussed in more detail in Chapter 10). Other proteins are involved in maintaining the precise structure of the sarcomeres. Titin, a large structural protein in the skeletal muscle cell, extends from the Z line to the center of the sarcomere, stabilizing the structure. Another large protein complex consists of dystrophin and several glycoproteins. This complex is instrumental in attaching the sarcomere, in particular, actin, to the sarcolemma (SL) and the extracellular matrix, again for maintaining structure and stability of the sarcomeres. The gene that codes for the dystrophin complex is large and subject to mutations resulting in disorders of skeletal muscle termed muscular dystrophy. One symptom of this disease is progressive muscle weakness due to the loss of the proper structural integrity of the muscle

1

2

+ –

fibers. Duchenne muscular dystrophy is one type of dystrophy in which there is a complete absence of the dystrophin protein resulting in rapid decline in skeletal muscle function and early death.

NEUROMUSCULAR JUNCTION Skeletal muscle cells or fibers generally extend from one tendon to the other tendon that attaches the muscle to the bones. Skeletal muscle is classified as voluntary muscle since its contraction is mandated by the central nervous system—we can contract muscles at will. Thus, the innervation of skeletal muscle is essential for activation of contraction. Each fiber is activated by one motor neuron, whereas one motor neuron can innervate a number of muscle fibers forming a motor unit. When one motor neuron is activated, all of the fibers innervated by that motor neuron will contract. The motor neurons from the spinal cord or brainstem, in response to action potentials traveling down the axon toward the skeletal muscle cell, release the neurotransmitter acetylcholine as shown in Figure 9–3 at the neuromuscular junction.

Motor neuron action potential

Acetylcholine vesicle

Ca2+ enters voltage-gated channels

8

Propagated action potential in muscle plasma membrane Voltage-gated Na+ channels

Acetylcholine release

3

+ –

+ –

+ +

–

+ – –

9

85

Acetylcholine degradation

4

+

+ –

Acetylcholine binding opens ion channels + + + + – – – –

+ 5

–

Na+ entry + +

+

–

–

–

+

+

+

–

–

–

–

+

7

Acetylcholine receptor Acetylcholinesterase Motor end plate

+

6

Muscle fiber action potential initiation

Local current between depolarized end plate and adjacent muscle plasma membrane

FIGURE 9–3 The neuromuscular junction is the specialized part of the muscle cell—motor end plate—at which the motor neuron releases the neurotransmitter acetylcholine to activate the muscle cell or fiber. Events at the junction are listed in chronological order. Note that each muscle fiber receives impulses from only one motor neuron and all of the fibers receiving input from that motor neuron make up the motor unit and will contract in synchrony. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

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The amount of acetylcholine released is proportional to the frequency of action potentials. Acetylcholine diffuses across the synaptic cleft and binds to a cholinergic receptor—the nicotinic receptor—on the muscle cell membrane (SL). The part of the muscle SL that is associated with the neuromuscular junction is called the motor end plate. Within the cleft is the enzyme acetylcholine esterase that can hydrolyze unbound acetylcholine and thereby limit the activation of the muscle cell membrane nicotinic receptors. This receptor is a channel that allows sodium and potassium flux. The predominant ion movement is sodium entering the muscle cell causing partial depolarization of the cell membrane in the synaptic cleft—an end plate potential (see Chapter 7). Since motor neurons cause only depolarization of the postsynaptic membrane and not necessarily an action potential, the change is similar to an excitatory postsynaptic potential (EPSP) occurring in neurons.

EXCITATION–CONTRACTION COUPLING This depolarization is conducted to the SL outside of the neuromuscular junction and if strong enough will induce an action potential. The action potential is transmitted along the SL, into the T-tubules, which are invaginations of the SL that allow the cell membrane to come in close contact with an intracellular membrane system called the sarcoplasmic reticulum (SR; Figure 9–4). In skeletal muscle, the T-tubule makes contact with two components (cisternae or lateral sacs) of the SR forming a triad. Calcium is released from ryanodine receptors located on the cisternae when the T-tubule is depolarized during an action potential. Dihydropyridine (DHP) receptors, also known as calcium channels, on the SL cause a conformational change in the ryanodine receptors causing them to open and allowing calcium to diffuse from the SR into the cytosol. Contraction is initiated when calcium levels in the cytosol reach a critical level and bind to TnC. In skeletal muscle, all of the calcium used for contraction is released from the SR. For relaxation to occur, calcium must be returned to the SR. As seen in Figure 9–4, the SR consists of longitudinal components as well as the cisternal component. The longitudinal portion of the SR contains the calcium ATPase enzyme, referred to as SERCA. SERCA has a high Vmax and, using the energy from ATP, pumps calcium against its concentration gradient into the SR. Proteins such as calsequestrin within the SR bind calcium, providing a storage function in the SR but also maintaining an optimal free calcium concentration so that the calcium gradient for pumping calcium out of cytosol and back into the SR is not excessive. This process in which an action potential leads to increased calcium leading to contraction is termed excitation–contraction coupling. Due to the complexity of the neuromuscular junction, many disease states can occur when there is dysfunction. For example, nerve gases inhibit the acetylcholine esterase, thereby resulting in continuous activation of the nicotinic receptors

Sarcolemma

T tubule

Ca ATPase

Sarcoplasmic reticulum cisterna

Ryanodine receptor, channel

Dihydropyridine receptor

FIGURE 9–4 The connection between the sarcolemmal (SL) T-tubules and the cisternae of the sarcoplasmic reticulum (SR) is the mechanism for the coupling of the action potential traveling along the SL to the release of calcium from the SR. The connection between the calcium channels (dihydropyridine receptors) on the SL and the ryanodine receptors on the SR is altered by the action potential allowing opening of the SR calcium channels and release of calcium into the cytosol. and continuous activation of the skeletal muscle. Eventually the cells can no longer generate action potentials because the cells remain depolarized and sodium ion channels that would normally open and initiate depolarization are inactivated. Muscle weakness ensues and since the diaphragm contains skeletal muscle, respiratory failure leads to death. Autoimmune diseases such as myasthenia gravis can result in production of antibodies to the nicotinic cholinergic receptor. Binding of antibodies to the receptors results in impaired signaling or communication between the motor neuron and the skeletal muscle fibers. Contractions are impaired and with time the entire structure of the motor end plate deteriorates. Degeneration of the motor neuron, which is required to initiate contraction, results in diseases such as amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease). The motor neuron shrinks and degenerates, leading to denervation of the muscle cells and resulting in impaired ability of skeletal muscle to contract. Eventually the muscle cells atrophy. An early symptom of ALS is muscle weakness.

FUNCTION TYPES OF CONTRACTIONS Contraction can occur in two modalities: isometric and isotonic and combinations thereof. Isometric, as its name implies, refers to contractions in which the length (metric) of the muscle stays the same (iso) but tension or force increases. Figure 9–5 shows the schematic of the apparatus for measuring the output of isometric contractions. A thin skeletal muscle strip is suspended between a force transducer and an immovable bar. Since the muscle is tethered at both ends,

CHAPTER 9 Skeletal Muscle Structure and Function

87

Force transducer

Isometric contractions

Isotonic contractions Muscle

100 75 Stimulator

Muscle length

Stimulator

50 25 0

Force transducer

when the muscle is stimulated, cross-bridge cycling results only in tension (dyne/cm) or force (dyne) development. The length of the muscle does not change during contraction. Isotonic refers to contractions in which the tension (tonic) stays the same but the length changes. Prior to the shortening, however, the muscle must increase tension or force to exceed the load it is lifting or contracting against; thus, the contraction consists of tension development followed by shortening. Figure 9–6 shows the apparatus for measuring isotonic contractions. The change in muscle length (shortening) can be measured after the muscle is stimulated. There are two loads on the muscle: (1) the preload that sets the resting muscle length and (2) the afterload that the muscle does not sense until after the contraction begins. In the protocol, the preload is added to the muscle strip, the passive or resting length is established, and then the horizontal bar is placed under the muscle such that addition of the more weight, the afterload, does not allow the muscle to lengthen anymore. When the stimulator excites the muscle, the bar is removed and the muscle contraction results in the muscle generating force to equal the afterload and then shortening. Figure 9–7 shows a model for skeletal muscle contraction. Muscle consists of the contractile element (CE; the contractile proteins actin and myosin) and a series elastic component. The load can be considered the weight the muscle must lift in an isotonic contraction. Note that prior to shortening, the CE is getting smaller, that is, the cross-bridges are cycling and pulling actin across myosin, but the entire muscle is not shortening— the cross-bridge cycling is generating tension (Figure 9–7, B). When the tension or force matches the load (afterload), the remainder of the cross-bridge cycling (contraction) results in shortening of the muscle (Figure 9–7, C). Note that the afterload determines how much tension the muscle will have to generate

Afterload

FIGURE 9–6 Isolated muscle preparation to study isotonic contractions. The passive tension is set by the preload, and the muscle length is measured. A bar is place under the muscle so that when the afterload is added, the muscle does not lengthen (does not sense the afterload). On stimulation, the bar is removed and the muscle develops tension to just match the afterload. During the remainder of the contraction, the tension remains constant and the muscle shortens. The length of the muscle and the rate of shortening are measured.

B

A

C

Shortening

Isolated muscle preparation to study isometric muscle contractions. The muscle is not allowed to shorten. The passive tension on the muscle as a function of resting muscle length is measured with a force transducer and then the muscle is stimulated to contract.

Tension

FIGURE 9–5

Load (preload)

C CE

CE

CE

SE

Load

SE

SE

L

Time Stimulation

B

L

L L = Load

FIGURE 9–7 A model of skeletal muscle consists of the contractile element (CE) made up of the thick and thin filaments, and the series elastic (SE) component that consists of noncontractile components of the muscle. Phase A is the muscle at rest. Using the model to represent an isotonic contraction, after stimulation, the muscle develops tension (phase B) and stretches the series elastic component, that is, tension is developed (to match the load) but the whole muscle does not shorten. Note the contractile element is shortening, that is, cross-bridges are cycling and actin filament is being pulled over the myosin, but the whole muscle is not shortening. At point C, the tension developed by the contractile element stretching the series elastic component just exceeds the afterload and during the remainder of the contraction, the crossbridge cycling is actually shortening the whole muscle. The load on the muscle determines how much tension the muscle will have to develop in order to shorten and lift the load. (Reproduced with permission from Sonnenblick EH: The Myocardial Cell: Structure, Function and Modification. Briller SA, Conn HL (editors). University of Pennsylvania Press, 1966.)

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prior to shortening. A heavier load will require more tension development, and a lighter load will require less tension development. With a heavier load and more tension to develop, the muscle will exhibit less shortening. With a lighter load, and less tension to develop, the muscle will exhibit more shortening. When afterload is plotted on the x-axis and shortening velocity is plotted on the y-axis, an inverse relationship is demonstrated—the force–velocity curve (Figure 9–8). Where the curve intersects with the x-axis, there is no shortening (zero velocity of shortening)—this is an isometric contraction— maximum force is developed but there is no shortening. If afterload is decreased—red circle—less force must be developed and some shortening occurs and therefore the velocity of shortening can be depicted. If the afterload is decreased again, still less force is developed and even more shortening occurs and velocity of shortening increases. At the y-axis intercept, there is the maximum velocity of shortening—Vmax. Note the dashed line connecting the curve to the y-axis—this denotes that the intercept is an extrapolation of the curve—one cannot study a contraction in a muscle with zero load; therefore, Vmax is an estimate of the maximum velocity of shortening. One other fact to note is that shortening and velocity of shortening are changing in the same direction—increases in shortening occur with increases in shortening velocity. The force–velocity

Vmax

Velocity

relationship will also be discussed in Chapter 10 with reference to cardiac muscle contraction.

REGULATION OF CONTRACTION— LENGTH–TENSION The type of contraction, isometric versus isotonic, is determined by the loading conditions on the muscle. If the muscle is not allowed to shorten, tension development is the total outcome of cross-bridge cycling resulting in an isometric contraction. For example, pulling on an immoveable object results in an isometric contraction—the muscle is developing tension but cannot shorten. The amount of force generated during that contraction (twitch) is determined by the amount of calcium released from the SR. Under normal circumstances, the amount of calcium released in response to an action potential is maximal in skeletal muscle fibers. The length (preload) of the muscle prior to the contraction also affects the strength of the contraction. The length of the muscle fibers prior to contraction determines how much overlap there will be between actin and myosin and, thus, how many cross-bridges can be formed. Since the energy for the contraction is released by the myosin ATPase activity, altering the number of cross-bridges that interact alters the amount of myosin ATPase that is activated and thus the amount of ATP that will be hydrolyzed to provide the energy for contraction and relaxation. This has a significant effect on the strength of the contraction. As seen in Figure 9–9, length of the muscle (preload) affects developed tension, passive tension, and total tension. In skeletal muscle, passive tension is low until the Po point at which it begins to increase substantially. Total tension increases as a function of muscle length as does active or developed tension. Active tension is the tension that is developed during contraction by

Total

Po Force or load

FIGURE 9–8 The force–velocity curve is generated from the study of isolated muscle during isotonic contractions. To generate a typical curve, the preload on the muscle is held constant, that is, the resting length is the same for each contraction studied, but the afterload is varied. At the intercept of the x-axis, the greatest afterload, there is no shortening—this represents a maximal isometric contraction (Po). As the load decreases—the red point, less tension must be developed to match the afterload and therefore some shortening can occur. With more shortening there is a greater initial velocity of shortening that is plotted on the y-axis. With a further decrease in afterload to the light red point, there is even less tension developed and even more shortening can occur, so a greater velocity of shortening occurs. The green point represents an even lighter afterload and therefore an even greater velocity of shortening. The curve is extrapolated to the intercept of the y-axis that yields the maximum velocity of shortening (Vmax). This is a theoretical point because the muscle cannot be studied under conditions of zero load.

Active or developed Tension, dynes/cm Passive

Po Length, mm

FIGURE 9–9 The relationship between the length of muscle (set by the preload on the isolated muscle) and the tension that can be measured is shown. The active or developed tension is the difference between the total tension and the passive tension. It is the tension that the muscle produces during the contraction. At Po the muscle is at the optimum length to give the greatest tension— maximum isometric tension.

CHAPTER 9 Skeletal Muscle Structure and Function cross-bridge cycling and is therefore the difference between total tension and passive tension. Passive tension is due to the structural properties of skeletal muscle. Skeletal muscle demonstrates the length–tension relationship but in the body, since most of the skeletal muscle is attached to the bone by tendons, the optimum length is generally set by anatomy.

89

Tetanic contraction Summation A

B

C

D E

REGULATION OF STRENGTH OF CONTRACTION IN SKELETAL MUSCLE— RECRUITMENT, SUMMATION, AND TETANUS The physiological way for intact skeletal muscle to increase tension is via changes in the stimulation pattern by the motor neurons. Spatial recruitment refers to increased numbers of motor neurons firing, and, therefore, more motor units contracting. Temporal recruitment refers to increased number of action potentials in a motor neuron thereby affecting the contraction of the muscle fibers within that motor unit. Within a muscle, usually only a small percent of the muscle cells or fibers will contract at any one time but the contraction of each fiber will be maximal. All of the muscle fibers innervated by the same motor neuron will contract at the same time. The strength of the contraction of the entire muscle increases if more motor neurons are activated and therefore more muscle fibers are stimulated to contract—spatial recruitment. The order of recruitment of motor units will be discussed below with the presentation of muscle fiber types. Temporal recruitment results from increasing the number of action potentials in the motor neuron. In Figure 9–10, curve A shows the contraction or twitch in response to one stimulus. More rapid firing (more action potentials per second) repetitively releases acetylcholine to activate nicotinic receptors giving more action potentials in the muscle membrane. If two stimuli are far enough apart (e.g., 300-millisecond delay as shown for B in Figure 9–10), two separate identical contractions occur. When the two stimuli are approximately 40–50 milliseconds apart, the muscle contraction appears to be one twitch but the strength of the contraction is greater than that generated by a single stimulus (curve D, Figure 9–10). This response is called summation. The mechanism for summation is that the second contraction begins prior to the beginning of relaxation of the first contraction. Therefore, the total contraction is measurable tension development with no energy spent in overcoming the series elastic component or the resistance to contraction by all of the “noncontractile elements” present in the muscle. If the stimuli are more than 40–50 milliseconds apart (curve C), the first contraction begins to wane prior to initiation of the second contraction giving a biphasic appearance to the contractions. The optimum delay between two stimuli may vary in different types of skeletal muscle but the capacity to increase force by summation is present in all skeletal muscle. As the delay between the stimuli becomes smaller and smaller, the contraction becomes weaker and weaker until eventually the “summated” contraction will

Tension Twitch

Single 300 msec stimulus delay

120 msec delay

40–50 60 stimuli 1 msec per sec msec delay delay

FIGURE 9–10 Muscle tension developed during contractions performed under different patterns of stimulation is shown. (A) With a single stimulus, one twitch occurs. (B) With two stimuli that are 300 milliseconds apart, two identical twitches occur. (C) When the second stimulus occurs prior to complete relaxation from the first twitch, the second contraction shows greater tension development. (D) When the two stimuli are approximately 40–50 milliseconds apart, there appears to be only one contraction but the tension is 2–3-fold greater than that with one stimulus. When the muscle is stimulated with a rapid burst of stimuli (60 stimuli/s), tetanus occurs—the greatest amount of tension is developed and there is no relaxation. During this stimulation pattern, the release of calcium with each stimulus outstrips the calcium uptake mechanisms, so cytosolic calcium remains elevated and relaxation does not occur. Depending on the muscle type, tension will remain elevated until the stimulation ends or until fatigue develops and the muscle can no longer maintain tension. (E) When the two stimuli are approximately 1 millisecond apart, the contraction looks identical to the contraction given after one stimulus—the muscle cannot respond to the second stimulus because it is in the refractory period—the muscle cell membrane is not responsive to a normal stimulus. become identical to the single stimulus–initiated contraction—all fibers will have become refractory to the second stimulus—responding only to the first stimulus. This generally occurs with stimuli that are 1–2 milliseconds apart (E). The maximum tension that can be developed occurs during tetanic contractions (Figure 9–10). The basis for this increase in tension is that there are so many action potentials (e.g., 60/s) that the calcium release mechanisms occurring with every action potential outstrip the calcium uptake mechanisms; thus, cytosolic calcium levels remain elevated continuously and the muscle does not relax in between stimuli. The cross-bridges continue to cycle either until stimulation stops and cytosolic calcium concentrations decrease or until the cells fatigue. Both summation and tetanus (tetanic contractions) are examples of temporal recruitment—the same fibers are stimulated to contract by the same motor neurons but the frequency of stimulation by the neuron alters the muscle response. In summary, strength of contraction of an intact

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muscle made up of many different motor units can be increased by: (1) increasing the number of motor neurons activated, thereby increasing the number of motor units contracting; and (2) increasing the frequency of action potentials of the motor neuron, thereby eliciting summation or tetanus of those muscle fibers in the motor unit.

FIBER TYPES As mentioned above, the strength of contraction of skeletal muscle can be increased by spatial recruitment. Spatial recruitment occurs when more motor neurons participate in a contraction, thus “recruiting” more motor units, that is, more muscle fibers to contract. There are three basic types of muscle fibers in skeletal muscle—type I, type IIa, and type IIb (Table 9–1). These were formerly called red and white muscle for the color imbued by the presence of myoglobin and many mitochondria in red muscle and little myoglobin in white muscle. Since the red muscle has many mitochondria, it has the capacity, by oxidative phosphorylation production of ATP, to sustain contractions over long periods of time. The fiber types have different diameters as do the motor neurons that innervate them. The pattern of spatial recruitment is governed by the size of the muscle fibers with smallest fibers being most easily recruited (earliest recruitment), and largest fibers recruited last. The type I fibers have the smallest diameter and are innervated by motor

neurons that are also the smallest in diameter. This makes both the neurons and the fibers easy to activate. These small fibers that are recruited earliest have a high oxidative capacity and can perform work for long periods of time without fatiguing. Adequate blood flow and high concentrations of mitochondria for oxidative metabolism allow these fibers to contract for hours. These fibers have been called slow twitch because their myosin ATPase activity is low. These fibers also contain myoglobin, a heme-containing protein that binds oxygen and can therefore serve as an oxygen store that can be used when oxidative phosphorylation is occurring at elevated rates to support elevated rates of contraction. These type I fibers were classified as “red” fibers in the past because the high concentration of myoglobin gives color to the muscle fibers. Type II fibers have a higher myosin ATPase activity and therefore a faster rate of contraction. There are two subtypes in this group—type IIa are fibers with a fast twitch and both oxidative and glycolytic capacity, and type IIb are fibers with a fast twitch but rely almost entirely on glycolysis for ATP production. The type IIb fibers have high concentrations of the enzymes involved in glycolysis. These fibers have the largest diameter and are recruited last. They are innervated by motor neurons with large diameters that require a greater stimulus in order to generate an action potential, thereby making them the last to be recruited. They are more likely to fatigue than the other types of fibers due to the dependence on glycogen as a substrate for ATP to provide the energy for contraction. The supply of glycogen is limited and since they have a relatively sparse blood supply, glucose may not be as readily available. If

TABLE 9–1 Comparison of skeletal muscle fiber (cell) types. Type I

Type IIa

Type IIb

Metabolism

Oxidative

Oxidative/glycolytic

Glycolytic

Twitch

Slow

Intermediate

Fast

Mitochondria

Abundant

Intermediate

Few

Myoglobin

Abundant

Abundant

Few

Color

Red

Red

White

Glycogen

Little

Intermediate

Abundant

Myosin ATPase rate of hydrolysis of ATP

Lowest

Fastest

Fastest

Speed of contraction

Slowest

Intermediate

Fastest

Blood flow

Great

Intermediate

Low

Fatigue

Not readily

Intermediate

Rapid onset

Force

Least

Intermediate

Greatest

Size of motor neuron

Smallest

Intermediate

Largest

Size of fiber

Smallest

Intermediate

Largest

Recruitment

First

Second

Last

Total tension

Least

Intermediate

Greatest

CHAPTER 9 Skeletal Muscle Structure and Function glycolysis results in lactic acid production because oxygen is not readily available, the cells will fatigue in a matter of minutes and decrease tension development in spite of repeated motor neuron firing. These fibers were formerly classified as “white” fibers because they had lower levels of mitochondria, myoglobin, and blood flow—all of which lend the red color to the type I fibers. The type IIa fibers are of intermediate size and therefore are recruited after the type I slow fibers are activated. Type IIa fibers can use both glycolysis and oxidative phosphorylation for their energy supply and therefore also exhibit an intermediate time course for fatigue to occur. The ATPase activity and therefore speed of contraction is fast as in the type IIb fibers and the time for fatigue to occur is intermediate. The capacity for oxidative phosphorylation to provide some of the ATP for contraction prolongs the time of sustained contraction before fatigue occurs. In general, the diameter of the muscle fiber is indicative of the amount of actin and myosin in the fiber. Therefore, largerdiameter fibers have more actin and myosin, more crossbridges that can form, and can develop more tension. Smaller fibers develop less tension due to lower amounts of actin and myosin but again can contract for prolonged period due to their abundant blood supply and oxidative capacity. Most muscles in the body are made up of combinations of the three muscle fiber types with a predominance of either fast or slow fibers. Muscles involved in maintaining posture must have long-lasting capacity to contract and not to fatigue, so these have more of the type I, slow-twitch fibers. Of course, in maintaining posture, not all muscle fibers will be contracted at any one time but different motor units will take over contraction cyclically. Muscles that are involved in rapid changes such as eye movements are predominantly type IIb fibers—fast contractions that are not sustained for long periods of time. Many muscles have intermediate amounts of the different fiber types. For example, people who do prolonged activities such as endurance running have slower-twitch, oxidative fibers in their muscle responsible for running. Sprinters have more fast-twitch, glycolytic fibers that are best for bursts of activity but not for sustained activity.

(eyelid drooping) occurred with repeated, rapid eye movements. The physician suspects myasthenia gravis and orders tests to confirm the diagnosis. Myasthenia gravis is an autoimmune disease in which the immune system produces antibodies to the nicotinic receptor. Initially small motor units, especially in ocular muscles for eye movement, demonstrate the defect. Rapid motor neuron firing for rapid muscle contractions for eye movement eventually leads to release of less acetylcholine (production lags behind release). In normal individuals, there are adequate receptors to compensate for the decreased amount of acetylcholine released. With myasthenia gravis, antibodies bound to the receptors prevent the acetylcholine binding, thus leading to impaired muscle contractions. Rest can replenish the acetylcholine stores. Antibodies bound to the nicotinic receptor seem to trigger an immune response and degeneration of the muscle motor end plate. Eventually, with more antibody production, more muscle units become involved and can eventually lead to large muscle weakness including impaired respiratory muscle function. Treatments to decrease antibody production, often exacerbated by the thymus gland, include removal of the thymus and treatment with immunosuppressive drugs such as corticosteroids. Cholinesterase inhibitors are also used since they inhibit the enzyme that hydrolyzes acetylcholine at the neuromuscular junction, thereby maintaining higher concentrations of acetylcholine and greater stimulation of the motor end plate.

CHAPTER SUMMARY ■ ■

■

CLINICAL CORRELATION A 45-year-old woman notices that she has been feeling unusually tired after work for the past month. She also notices that her left eyelid begins to droop at the end of the day. Gradually she is noticing that the eyelid begins to droop even by the end of the work day if it has been a particularly stressful day. She is also experiencing more and more severe fatigue but both of these problems are gone after a good night’s sleep. She is concerned and makes an appointment with her physician. On physical examination, her physician notes that all measured variables were in the normal range except for movement of the left eye. Lateral movement was impaired and ptosis

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Skeletal muscle cells are also called fibers. Skeletal muscle cells have a specialized section of SL called the motor end plate where the motor neuron forms a synapse with the muscle. Acetylcholine is the neurotransmitter and nicotinic receptors on the SL bind the acetylcholine and increase sodium influx, causing partial depolarization, and eventually an action potential in the adjacent SL. The action potential travels down the invaginations of the SL (T-tubules) and, via the dihydropyridine receptors, causes the ryanodine receptors to open and release calcium. Troponin binds calcium and begins the contraction process. The motor neuron can innervate more than one skeletal muscle fiber—the motor neuron and the fibers it innervates are called a motor unit. All of these muscle cells contract at the same time. Contraction can be either isometric or isotonic. In isotonic contractions, the load determines how much tension or force the muscle must develop before the shortening phase of the contraction can occur. Skeletal muscle can increase strength of contraction by recruiting more motor units (spatial recruitment). The motor units with the smallest diameter of the neurons and fibers are recruited most readily (first). These are the

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SECTION III Muscle Physiology type I fibers that are highly oxidative and have a low myosin ATPase rate and therefore exhibit a slower contraction time. Type II fibers have a high myosin ATPase rate and therefore a faster contraction time. Type IIa are both glycolytic and oxidative and are recruited second. Type IIb are mainly glycolytic and recruited last (fibers and neurons have the greatest diameter). Type II fibers fatigue more quickly than do type I fibers, with type IIb fibers fatiguing most rapidly—in a few minutes after repeated stimulation. Skeletal muscle can also increase strength of contraction by more rapid firing of the motor neuron—summation and tetanus.

STUDY QUESTIONS 1. Which of the following statements about skeletal muscle contraction is correct? A) Acetylcholine release at the neuromuscular junction initiates an action potential in the motor end plate. B) Acetylcholine binds to a nicotinic receptor on the postsynaptic membrane. C) The depolarization in skeletal muscle results from influx of calcium through voltage-gated calcium channels (dihydropyridine receptors). D) Depolarization of the muscle fiber is not essential for skeletal muscle contraction. E) Norepinephrine activating adrenergic receptors causes increased strength of contraction.

2. Which of the following statements about muscle contraction is true for skeletal muscle? A) All cells have pacemaker potential. B) The strength of contraction is correlated with the degree of phosphorylation of the myosin light chains. C) The strength of contraction is increased by recruiting more motor units. D) All muscle cells have a high oxidative capacity due to the abundant presence of mitochondria and myoglobin. 3. Which of the following statements about muscle contraction is true for skeletal muscle? A) In the body, strength of contraction is altered physiologically by changing the resting cell length from 25% up to 100% of the maximum length. B) Strength of contraction is altered physiologically by altering the frequency of motor neuron firing. C) Tetanus cannot occur because the muscle action potential keeps the cell refractory to stimuli that are closer than 1 second apart. D) Muscle contraction consists only of tension development.

10 C

Cardiac Muscle Structure and Function Kathleen H. McDonough

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Explain the process of excitation–contraction coupling in cardiac muscle and how it differs from that of skeletal muscle. Explain the effects of changes in resting cell length on muscle tension development, that is, the length–tension relationship. Describe the sequence of events in isotonic contractions—tension development and shortening. Describe the effects of afterload on isotonic contractions in cardiac muscle. Explain the effects of changes in resting cell length on isotonic contractions at different afterloads, that is, explain the force–velocity curve. Describe the effects of increased contractility on the force–velocity curve. Explain the terms preload, afterload, contractility, force, and tension.

INTRODUCTION Cardiac muscle, like skeletal muscle, is striated due to the orderly structure of the actin and myosin filaments and the accessory proteins that stabilize the sarcomere. Like type I skeletal muscle, cardiac muscle appears to be red in color due to the high content of mitochondria and myoglobin and its blood supply. The heart uses large amounts of ATP in beating 60–100 times/min (during normal resting conditions) for the lifetime of the normal adult and oxidative phosphorylation is the main source of that ATP, thus the high myoglobin concentration and large mitochondrial content. There are estimates that the myocardial ATP pool turns over every 10 seconds. The heart is able to use any substrate provided to it in the blood and uptake is dependent on the concentration of those substrates such as glucose, pyruvate, lactate, free fatty acids, and ketone bodies. Normally fatty acid oxidation provides 60–90% of the ATP used by the adult heart. Like skeletal muscle, calcium is essential for contraction and is provided by excitation–contraction coupling. Although cardiac muscle can contract spontaneously due to pacemaker activity in the sinoatrial (SA) node, the individual muscle cells (myocytes) normally contract only when an action potential is initiated by the conduction system present in the heart and transmitted through cells specialized to conduct action poten-

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tials rapidly. Cardiac muscle cells have gap junctions through which cells communicate information about membrane potential—that is, if one cell depolarizes, the adjacent cells will also depolarize due to communication through the gap junctions. Thus, all cardiac myocytes in the atria contract together and then all of the myocytes in the ventricle contract together (Chapter 23). Because of this unified contraction of the ventricles (or the atria), the heart is said to be a functional syncytium. Since all ventricular muscle cells contract together, there is no type of spatial recruitment in the heart. The heart relies on other mechanisms to increase strength of contraction.

EXCITATION–CONTRACTION COUPLING Cardiac muscle cells contract when calcium levels in the cells increase from approximately 10−7 M (0.1 μM) to 10−6 to 10−5 M (1–10 μM). The level of calcium present in the cytosol to initiate contraction has a profound effect on the strength of the contraction (contractility). Excitation–contraction coupling in cardiac muscle varies somewhat from the process in skeletal muscle. The anatomy of the sarcolemma (SL)–sarcoplasmic reticulum (SR) interaction is different—diads are formed

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rather than triads as in skeletal muscle. There is less SR in cardiac muscle, so the calcium release process relies on entry of calcium into the cardiac cell through the voltage-gated channels (dihydropyridine receptors). These open when the membrane potential reaches approximately −40 mV. These calcium channels are also called “slow” or L-type calcium channels because they open more slowly than sodium channels and remain open longer, generally about 200–300 milliseconds. Therefore, the action potential in cardiac ventricular cells is much longer than the action potential in skeletal muscle in which the calcium channels do not actually open (see Chapter 9). Calcium entry through SL calcium channels is essential for contraction to occur. Absence of calcium in the extracellular fluid would prevent the heart from contracting. The process of excitation–contraction coupling is initiated by the pacemaker cells in the SA node that spontaneously generate action potentials (termed slow action potentials because they lack fast sodium channels and depolarization is due to calcium entry through the slow calcium channels). Action potentials are transmitted through the atrial conduction fibers across the atrioventricular valves and finally to the conduction system in the ventricles. All ventricular muscle cells depolarize at the same time due to the rapid influx of sodium down its electrochemical gradient (higher concentration of sodium outside of the cell and negative membrane potential on the inside of the SL) through SL fast sodium channels. When the membrane potential reaches ~−40 mV, the slow calcium channels open, allowing calcium to diffuse down its concentration gradient into the cytosol. Some of this calcium causes opening of ryanodine channels (receptors) on the SR and calcium diffuses out of the SR down its concentration gradient. Some of the calcium from the SL binds to troponin as does all of the calcium released from the SR. Calcium binding to troponin results in a similar type of interaction of actin and myosin and cross-bridge cycling to that which occurs in skeletal muscle. Relaxation occurs when the calcium concentration in the cytosol is lowered by the calcium ATPase on the longitudinal part of the SR pumping calcium back into the SR. Calsequestrin is also present in cardiac muscle to serve as a “sink” for calcium. When calcium levels decrease, calcium diffuses from the troponin and the cells relax. Two other proteins are involved in removing calcium from the cardiac cell. Since calcium enters the cell with each action potential, there must be mechanisms to remove calcium or the cell calcium content would increase with each heartbeat. The SL contains a calcium ATPase that has a high affinity for calcium and can therefore pump calcium out of the cell probably even during diastole. The other protein is the sodium–calcium exchanger. The exchanger operates on the basis of the sodium ion gradient. The sodium ion concentration is greater outside of the cell than in the cell. Via the exchanger, sodium ion enters the cell and calcium ion is removed from the cell. Three sodium ions enter for every one calcium ion leaving the cell. Manipulation of the sodium gradient can have significant effects on calcium extrusion from the cell and thus affect contraction. Since calcium levels change during each action potential, there is some evidence that increases in heart rate (more action

potentials per minute) can increase calcium availability for contraction, thereby increasing the amount of tension that can be generated. This phenomenon is called the staircase phenomenon or treppe. Physiologically heart rate is altered by autonomic nervous system (ANS) modulation of SA node firing rate and, as will be seen later, the sympathetic nervous system (SNS) component of the ANS not only increases heart rate, but also increases contractility. Therefore, the physiologic role of treppe is difficult to assess independent of SNS modulation of heart rate and contractility. There are two additional variations in contraction that occur in cardiac muscle that do not occur in skeletal muscle. Phosphorylation of contractile proteins alters the strength of contraction in the heart. The heart is very responsive to the SNS— the “fight or flight” component of the ANS. With activation of the SNS, beta-adrenergic receptors on the cardiac muscle cells are activated and an intracellular signaling scheme results in production of cAMP and activation of protein kinase A. Phosphorylation of proteins follows. Several proteins involved in contraction are phosphorylated and their activity is altered. SL calcium channels are phosphorylated and allow more calcium to enter the cell and the strength of contraction is increased (contractility is enhanced). A protein called phospholamban normally inhibits the SR calcium ATPase; when phospholamban is phosphorylated, it exerts less inhibition of the ATPase, so calcium uptake is enhanced. Phosphorylation of the calcium channels does not seem to occur in skeletal muscle in which the maximum amount of calcium is released during each action potential and therefore cannot be increased. Remember that skeletal muscle has two SR cisternae in conjunction with the T-tubule, whereas cardiac muscle has only one cisterna associated with the T-tubule. Skeletal muscle does not seem to have a functional phospholamban, so the calcium ATPase activity is always operating at its maximal capacity. Increasing the amount of calcium entering the cytosol is an important mechanism for increasing strength of contraction (contractility); removing calcium faster for relaxation is an important mechanism when the heart rate increases with SNS stimulation and there is less time during the contraction-relaxation cycle.

CONTRACTION—LENGTH– TENSION, ISOMETRIC CONTRACTIONS The strength of contraction in cardiac muscle can be altered by changes in the initial or resting length of the muscle cells (preload) similar to the phenomenon in skeletal muscle. Cardiac muscle, unlike skeletal muscle, can have physiologic changes in the length of the muscle cells. For example, when the volume in the ventricle at the end of diastole (the relaxation phase of the cardiac cycle) is changed, the muscle cell length is changed in the same direction. Increased ventricular end-diastolic volume results in increased ventricular muscle cell length prior to the

Tension, dynes/cm

CHAPTER 10 Cardiac Muscle Structure and Function

Active or developed

Passive – cardiac muscle Passive – skeletal muscle

Po Length, mm

FIGURE 10–1 The length–tension relationship in cardiac muscle is slightly different from that in skeletal muscle— primarily due to the presence of passive tension at shorter lengths. This is in part due to the anatomic differences in structure of skeletal muscle (all of the fibers in parallel) and cardiac muscle (fibers exist in a basket weave-type pattern) as well as the properties of the noncontractile components in skeletal muscle versus cardiac muscle. Note that in skeletal muscle, the fibers are usually operating at the blue point—resting length is optimum because most skeletal muscle is held in place by the bones and resting length cannot vary greatly. Cardiac muscle normally operates at lower (red point) than optimum length and therefore has reserve capacity to increase tension development, that is, have stronger contractions, when resting length is increased. In the intact heart, cardiac cell resting length is set by the volume in the ventricle at the end of diastole (the relaxed state of cardiac muscle).

onset of contraction. The heart normally operates at lower than maximal cell length or preload (Figure 10–1, red circle), whereas skeletal muscle usually works at maximal preloads (blue circle). Note also that the passive tension properties of the heart differ from those of skeletal muscle. Skeletal muscle does not increase passive tension until the muscle cell length is close to the length that gives the maximum active tension. Cardiac muscle has passive tension even at low cell lengths. These differences are due to the anatomic arrangement of the muscle cells with the noncontractile components in the muscle. Skeletal muscle is more distensible than cardiac muscle. In Figure 10–1, the effects of increases in preload are shown through isometric contractions—that is, greater tension is developed from greater resting cell length. The principle for the length–tension relationship, as in skeletal muscle, is that the change in cell and sarcomere length alters the degree of overlap of the actin and myosin filaments and therefore increases the potential for cross-bridges to form. Changes in the resting length of the whole muscle are associated with proportional changes in the individual sarcomere length. Maximum tension development occurs at sarcomere lengths of 2.2–2.3 μm. At shorter sarcom-

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ere lengths, the opposing thin filaments may overlap with each other and interfere with interaction with myosin. At long sarcomere lengths, overlap may be insufficient for optimal crossbridge formation. More cross-bridge interaction leads to a stronger contraction. Two other factors may contribute to the length–tension phenomenon in cardiac muscle. The second mechanism may result from a length-dependent change in calcium sensitivity of the myofilaments. For a similar cytosolic calcium concentration, a less stretched muscle develops less force than does a more stretched (longer) cardiac muscle preparation. This change in calcium sensitivity occurs immediately after a change in length with no delay. The sensitivity of the contractile proteins, specifically troponin C, seems to increase at greater resting lengths. Finally, there is some evidence that the amount of calcium released from the SR is greater at longer resting lengths. How much these two factors contribute to the greater tension development is open to speculation since studies to demonstrate these two effects of length on calcium dynamics are generally performed in isolated cells or organelles. In summary, the heart usually operates at lower than maximal preloads and therefore has reserve—increasing muscle length can have a profound effect on strength of contraction that allows the heart to meet the demands of increased work such as occurs during exercise.

CONTRACTION— FORCE–VELOCITY, ISOTONIC CONTRACTIONS The effects of altered preload on heart function can also be observed with isotonic contractions that represent a better match to physiologic contractions of the heart as a pump. The left ventricle must develop tension (pressure) to match the afterload (aortic pressure) in order to open the aortic valve and then allow the shortening phase of the contraction to pump blood (stroke volume) into the aorta. Recall from the discussion of skeletal muscle that there is an inverse relationship between afterload and velocity of shortening and therefore between afterload and shortening. Greater afterload results in less shortening. Using isotonic contractions, the effects of increased preload, that is, more cross-bridge cycling, on the force–velocity curve can be analyzed. When shortening and velocity of shortening are measured as a function of afterload, higher afterloads result in less shortening (see Figures 9–8 and 10–2, black curve). If the preload is increased from length 1 (L1) to length 2 (L2) and the same afterloaded contractions are studied from the higher preload, velocity of shortening (and shortening) is greater for each afterload. If more cross-bridges can interact, there is more myosin ATPase activity and therefore more energy from ATP hydrolysis available for the contraction. The cross-bridges develop the greater tension needed to match the greater afterload and more energy is available for more shortening and a greater velocity of shortening to occur (blue curve, labeled L2). Note that the

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maximum isometric tension (x-axis intercept) is increased but the Vmax is not increased compared to the Vmax at L1. Preload shifts only the maximum tension, not the maximum velocity of shortening.

INCREASES IN STRENGTH OF CONTRACTION IN CARDIAC MUSCLE As stated above, cardiac muscle can increase strength of contraction when the preload is increased as demonstrated by the length–tension relationship. Another way that cardiac muscle can increase strength of contraction is by increases in cytosolic calcium resulting in increased contractility. Contractility increases the velocity of cross-bridge cycling; therefore, increasing contractility can alter shortening and the velocity of shortening. In comparing the force–velocity curve during enhanced contractility (red curve in Figure 10–2), one can notice that increasing contractility causes the entire force– velocity curve to shift to the right—both the maximum isometric tension (intercept on the x-axis) and the Vmax

(extrapolated intercept on the y-axis) increase. This increased contractility should be compared to the curve generated at the same preload (L1), the black curve. Generally, increases in contractility result in more rapid contractions such that indexes of speed of tension development or maximum velocity of shortening (Vmax) are used to indicate increases in contractility. The figure demonstrates that there are two ways to increase the velocity of shortening at the same afterload (the three points in the figure), one is by increasing preload (blue curve), and the other is by increasing contractility (red curve). The mechanisms by which the contractions are stronger are, however, different. More optimum overlap of the actin and myosin filaments mediates the preload effect, whereas more cytosolic calcium to induce more rapid cross-bridge cycling mediates the contractility effect. The effects of increasing contractility can also be demonstrated by looking at the length–tension relationship. In Figure 10–3, sympathetic nerve stimulation to the heart results in a shift of the length–tension relationship upward and to the left. This indicates that for any given resting length of cardiac muscle, the tension that can be developed is greater as a result of SNS stimulation. The mechanism is the increase in calcium that results from the activation of beta-adrenergic receptors with the

Vmax

↑Contractility

Velocity

L1

↑Preload or length - L2 L1

Po Force or load

FIGURE 10–2 The force–velocity curve in cardiac muscle can be altered by changes in resting cell length and by changes in contractility. L1 represents the shorter resting cell length and L2 represents a greater resting cell length. In comparing the muscle at the same afterload (black point vs. blue point), the muscle can shorten more if the contraction starts from a greater preload or resting cell length (L2). In both contractions, the tension developed is set by the afterload. Note that the curve for increased preload intercepts the x-axis further to the right—greater resting length allows for greater maximum isometric tension (the length–tension relationship). If the muscle is studied at L1, and a drug that increases contractility is given, the entire force–velocity curve shifts upward and to the right from the black curve to the red curve—both Po and Vmax are increased. More calcium results in stronger contractions and a greater velocity of contraction, that is, a greater velocity of cross-bridge cycling. In comparing the black point to the red point, when contractility is greater, the muscle can develop the same tension to match the load and there is more capacity to shorten and a greater velocity of shortening. Changes in Vmax therefore indicate changes in contractility. Changes in Po can result from changes in preload or from changes in contractility.

CHAPTER 10 Cardiac Muscle Structure and Function

Developed tension

↑SNS

Length

FIGURE 10–3 The effects of changes in contractility on the length–tension relationship are shown. With sympathetic stimulation (SNS) of cardiac muscle, contractility increases and developed tension is greater at each resting cell length. consequent production of cyclic AMP and activation of phosphorylation of the SL calcium channels by protein kinase A. The importance of these two mechanisms will become very obvious in discussions of the cardiovascular system in Section 5.

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Excitation–contraction coupling in cardiac muscle is similar to that in skeletal muscle except that calcium must enter the cardiac muscle cell through the voltage-gated calcium channels to cause release of calcium from the SR ryanodine channels. In cardiac muscle, strength of contraction can be altered by changes in resting cell length (length–tension) and by changes in contractility. Indices of contractility, such as the maximum velocity of shortening (Vmax), are increased by beta-adrenergic agonists. Since the heart has cells with pacemaker potential, innervation of the heart is not required for contraction to occur. Ventricular cells contract at the same time (a functional syncytium) due to the conduction system and gap junctions between the cardiac cells. Sympathetic and parasympathetic nerves modulate the intrinsic beating rate. Sympathetic nerves modulate the strength of contraction (contractility) of cardiac cells.

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STUDY QUESTIONS 1. Which of the following statements about cardiac muscle contraction is correct? A) Acetylcholine release at the neuromuscular junction initiates an action potential in the postsynaptic membrane. B) Acetylcholine binds to a nicotinic receptor on the postsynaptic membrane. C) Depolarization of the muscle fiber is not essential for cardiac muscle contraction. D) Norepinephrine activating adrenergic receptors causes increased strength of contraction. 2. Which of the following statements about muscle contraction is true for cardiac muscle? A) All cells in the heart contract at their own rate. B) The strength of contraction is independent of the degree of phosphorylation of cellular proteins. C) The strength of contraction is increased by recruiting more motor units. D) All muscle cells have a high oxidative capacity due to the abundant presence of mitochondria and myoglobin. 3. Which of the following statements about muscle contraction is true for cardiac muscle? A) Strength of contraction is altered physiologically by changing the resting cell length from approximately 25% up to 100% of the maximum length. B) Strength of contraction is altered physiologically by altering the frequency of motor neuron firing. C) Tetanus occurs because the muscle action potential keeps the cell refractory to stimuli that are closer than 1 second apart. D) Muscle contraction consists only of tension development. 4. Which of the following statements about muscle contraction is true for cardiac muscle? A) The Po (maximum isometric tension) is altered by both contractility and the length–tension relationship. B) On the force–velocity curve the Vmax is altered by both contractility and the length–tension relationship. C) Afterload determines how many cross-bridges can interact during a contraction. D) Preload determines the phosphorylation state of the myosin light chain.

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11 C

Smooth Muscle Structure and Function Kathleen H. McDonough

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Explain the contraction process in smooth muscle and compare it to those of skeletal and cardiac muscle. Describe how smooth muscle can be activated to induce a contraction or to change the strength of a contraction. Explain the relationship between vascular smooth muscle membrane potential, voltage-gated calcium channels, and strength of contraction. Describe the difference between multiunit and unitary smooth muscle. Explain the following terms and their role in smooth muscle function: calmodulin, myosin light chain kinase, and myosin light chain phosphatase.

INTRODUCTION

CONTRACTION

Smooth muscle makes up the walls of most of the hollow organs of the body except the heart. As such, the function and control of contraction of the smooth muscle will vary depending on the organ in which it is located and the function of that organ or organ system. For example, smooth muscle in the gastrointestinal tract will be activated not only by mechanical stimulation by the presence of food in the GI tract, but also by its neural and hormonal input. Smooth muscle in the uterus will respond differently during development of an embryo/ fetus than during the normal menstrual cycle. Hormones and neural input will even change the morphology of smooth muscle during pregnancy, making the uterus work as a unit rather than as independent muscle cells in the nonpregnant uterus. The myosin ATPase activity in smooth muscle has a much slower rate of hydrolysis of ATP (10–100 times lower than that of skeletal muscle); therefore, contractions are much slower and sometimes the mode of contraction results in increases and decreases in the strength of contraction rather than complete relaxation after a contraction as occurs in skeletal and cardiac muscle.

The general contractile process is uniform in all types of smooth muscle. An increase in calcium in the cytosol results in binding of calcium to a calcium-binding protein, calmodulin (Figure 11–1). This complex will bind to, and activate, myosin light chain kinase (MLCK) that, in turn, phosphorylates the myosin light chain located on the myosin head. In smooth muscle, the myosin light chain must be phosphorylated in order for the actin and myosin to form crossbridges and initiate the crossbridge cycling or contraction. Relaxation or decreased tension development requires dephosphorylation of the myosin light chain by myosin light chain phosphatase. The balance of phosphorylation and dephosphorylation is important in regulating tension development in smooth muscle since the kinase and the phosphatase are always active. Increasing cytosolic calcium tips the balance toward more kinase activity and therefore more tension development. Lower calcium levels tip the balance toward less kinase and therefore more phosphatase activity and less tension development. There are other mechanisms to increase and decrease the activity of the kinase and the phosphatase. For example,

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Smooth muscle cell Contractions

Inactive MLCK

↑Cytosolic Ca2+

Ca calmodulin

Myosin light chain phosphatase

ATP

Active MLCK

~P myosin light chain

Myosin light chain

Cross bridge cycling

Relaxation

FIGURE 11–1 Scheme of steps in smooth muscle contraction. As in other types of muscle, calcium initiates the contraction. Calcium binds to calmodulin that activates the myosin light chain kinase to phosphorylate the myosin light chain. On phosphorylation the myosin can interact with the actin resulting in crossbridge cycling. Phosphatases can dephosphorylate the myosin light chain leading to relaxation or less tension development. The balance of kinase and phosphatase activities determines the level of tension development in smooth muscle. Phosphorylation of both the kinase and the phosphatase leads to a decrease in their activity—one resulting in weaker contraction and one in stronger contraction. phosphorylation of the MLCK enzyme decreases its activity, thereby decreasing phosphorylation of myosin and resulting in more relaxation. This occurs when a specific receptor, the beta2-adrenergic receptor, on the vascular smooth muscle and bronchiolar smooth muscle sarcolemma (SL) is activated and increases intracellular cAMP levels. Subsequent activation of protein kinase A phosphorylates the MLCK and decreases its activity. Nitric oxide causes a similar relaxation of smooth muscle although the kinase that phosphorylates the MLCK is protein kinase G that is activated by cyclic GMP. Regulation of the phosphatase is also important. For example, phosphorylation of the myosin light chain phosphatase decreases its activity, resulting in less dephosphorylation and therefore more phosphorylation of the myosin light chains and more contraction. The Rho kinase pathway leads to phosphorylation of the phosphatase. There are several other types of regulation of the MLC kinase and phosphatase that alter the contraction properties of smooth muscle and are more specific for each organ’s particular function and therefore will be discussed in the organ-specific sections of this book.

would theoretically utilize large amounts of ATP. The latch state seems to occur because the crossbridges do not dissociate very rapidly in spite of the fact that the myosin light chain is dephosphorylated; thereby, energy expenditure is minimized. The exact mechanism by which the latch state occurs is unknown. The physiologic significance, however, is remarkable—maintenance of tension with very little energy expenditure.

ENERGY FOR CONTRACTION AND RELAXATION

TABLE 11-1 Comparison of smooth muscle cell types.

The ATP used in contraction and relaxation in smooth muscle is produced primarily by oxidative phosphorylation. The substrates such as glucose and fatty acids are provided in the blood and mitochondrial oxidative processes produce adequate energy for the slower contractions that occur in smooth muscle due to the lower rate of the myosin ATPase enzyme. An interesting adaptation of smooth muscle ensures that sustained contractions can occur at a lower-than-predicted ATP utilization. Smooth muscle can maintain tension by a phenomenon termed the latch state. This is thought to be important in sphincter muscles where tension development must occur for long periods of time that

VASCULAR VERSUS VISCERAL; MULTIUNIT VERSUS UNITARY Smooth muscle can be divided into visceral and vascular muscle—visceral muscle making up the walls of most of the hollow organs and vascular making up the walls of blood vessels. Vascular smooth muscle and to some extent, visceral smooth muscle, can also be divided into two cell types— multiunit and unitary (Table 11–1). These two types of muscle cells have unique features that contribute to the variety of functions of smooth muscle. Multiunit smooth muscle

Multiunit

Unitary

Functional

Individual units

Syncytium

Innervation

Yes

Little

Gap junctions

Few

Yes

Response to stretch

Little

Yes

Response to SNS

Yes

Little

Control of contraction

Central or neural factors

Local factors

Examples

Airway smooth muscle

Small blood vessels

CHAPTER 11 Smooth Muscle Structure and Function

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Autonomic nerve fiber Varicosity Sheet of cells

Mitochondrion Synaptic vesicles Varicosities

FIGURE 11–2 Pattern of innervation of smooth muscle. Note that the nerve has multiple branches and varicosities on each of the branches. Neurotransmitter is released at the varicosities and diffuses to the smooth muscle. Binding to the appropriate receptor will result in the neural modulation of smooth muscle contraction. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

consists of cells that act as independent units—they are innervated and can respond strongly to nerves of the sympathetic and parasympathetic nervous systems. These types of cells have very few gap junctions and therefore activation of one cell does not necessarily lead to activation of cells in juxtaposition to that activated cell. Other cells receiving the same neural input will respond but only because the nerve is releasing neurotransmitters from varicosities (Figure 11–2) that release neurotransmitter near the muscle cell membrane. Note that the same nerve will release neurotransmitter onto many cells. Released neurotransmitter diffuses to the muscle cell membrane and binds to appropriate receptors—there is no specialized motor end plate on the muscle cell membrane, just the presence of receptors. Both sympathetic and parasympathetic nerves can innervate the same smooth muscle causing opposite effects on the cells as described below. Unitary muscle, on the other hand, has many gap junctions (as described in Chapter 3), so activation of one cell leads rapidly to activation of cells juxtaposed to that cell. Thus, the cells contract as a “unit.” These cells generally have little innervation and exhibit a response to stretch, that is, cells will increase tension in response to stretch, a property that will be discussed in more detail in Sections 5 and 8. Table 11–1 presents a list of the properties of multiunit versus unitary smooth muscle.

METHODS OF STIMULATION Smooth muscle can be stimulated to contract or alter the strength of a contraction by many different stimuli—action potentials, changes in membrane potential that do not achieve

an action potential, activation of receptors that initiate an intracellular signaling network, activation of receptors that are ion channels, and stretch, by itself. The exact stimuli that alter smooth muscle contraction may differ in various organs and even in two different types of muscle—unitary and multiunit. In Figure 11–3, the effects of sympathetic and parasympathetic nerve stimulation on the membrane potential of visceral smooth muscle are shown. Acetylcholine, the neurotransmitter of the parasympathetic nervous system, generally causes the membrane potential to become less negative and for spikes (action potentials) to occur—generating more contractile activity. Sympathetic stimulation generally results in the opposite—more negative membrane potential and resultant decreased contractile activity and relaxation. Note that stretch is also conducive to more action potential spikes, and, subsequently, more contraction; food in the gut induces increased contractile activity of the gut. Many other stimuli lead to activation or relaxation of smooth muscle. Figure 11–4 shows a smooth muscle cell and some of the many mechanisms involved in eliciting contraction and relaxation. Calcium can be provided by both influx of calcium from the extracellular fluid through the L-type voltage-gated calcium channels on the SL and release of calcium from the sarcoplasmic reticulum (SR). The SR, which is less abundant than in skeletal and cardiac muscle, can, nevertheless, release calcium through activation of IP3 receptors. The IP3 receptors are channels similar to the ryanodine receptors in the other two muscle types and when the channel is open, calcium diffuses down its concentration gradient into the cytosol to initiate contraction. IP3 is a product of receptor-mediated activation of phospholipase C (PLC) that hydrolyzes phosphatidylinositol (PIP2). Diacyglycerol, the other product, activates protein

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Acetylcholine, parasympathetic stimulation, cold, stretch

mV

0

−50

Membrane potential

Epinephrine, sympathetic stimulation

FIGURE 11–3 Examples of stimuli such as the SNS and the PNS on smooth muscle membrane potential and action potential generation. At more negative membrane potentials, as with epinephrine or SNS stimulation, there are no action potentials and muscle becomes more relaxed. At less negative action potentials, action potentials occur and the muscle is more likely to have more tension or tone. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

kinase C. There are several different receptors on smooth muscle that are linked to the PLC pathway resulting in stronger contractions. Some of these include alpha-adrenergic receptors that bind norepinephrine, muscarinic receptors that

bind acetylcholine, and specific endothelin receptors that bind endothelin 1. Influx of calcium through the voltage-gated calcium channels can be modulated by the resting membrane potential that is primarily a function of K+ movement. Opening of K channels (by calcium) or closing of K channels (by ATP) alters the membrane potential. Hyperpolarization of the cell (by opening the K channels) results in closure of the voltagegated calcium channels and relaxation or dilation if the cell is a vascular smooth muscle cell. Depolarization of the cell (not necessarily enough to generate an action potential) causes opening of the voltage-gated calcium channels leading to contraction (constriction of smooth muscle if the cell is vascular smooth muscle). Notice also the presence of storageoperated channels (SOC) on the SL. These channels allow entry of calcium into smooth muscle in order to replenish SR calcium stores. The mechanisms sensing decreased SR calcium levels and the communication between the SR and the SL are not clear but do seem to be effective in maintaining adequate calcium stores in the smooth muscle cell. Finally, receptor-operated channels exist on smooth muscle cells. These receptors are literally channels that allow ion movements. Purinergic channels represent this type of control— ATP, which is a purine, opens this type of channel allowing calcium entry into the cell and promoting contraction. In the renal vascular smooth muscle, adenosine, which is normally considered a vasodilator, binds to ROC allowing calcium entry and contraction. Not shown in Figure 11–4 is the modulation of smooth muscle contraction that occurs by products from the other cells associated with smooth muscle. For example, endothelial

Smooth muscle cell

Receptor PLC PIP2

IP3 + DAG

IP3 receptor

SR Ca2+ release ROC

PKC

SOC ~P proteins

Voltage gated calcium channel

ATP (closes K channel)

Ca2+ (opens K channel) Channels

FIGURE 11–4 A smooth muscle cell with some of the many influences on contraction. Contractions can be initiated by action potentials, by receptors that couple to phospholipase C, and by alterations in the open state of the voltage-gated calcium channels that are sensitive to the membrane potential as controlled primarily by potassium movements across the membrane. SOC are the storage-operated channels that open when SR calcium stores are low. ROC are receptor-operated channels—primarily responsive to agents such as adenosine and ATP. Calcium release from the SR or calcium entry through voltage-gated calcium channel leads to the calmodulin binding and ultimately contraction.

CHAPTER 11 Smooth Muscle Structure and Function cells that line the blood vessels release several factors that modulate vascular smooth muscle force development. As stated above, acetylcholine, which activates muscarinic receptors on vascular smooth muscle, can cause contraction by a PLC mechanism. However, acetylcholine binding to muscarinic receptors on endothelial cells causes the production of nitric oxide that diffuses to the vascular smooth muscle cell, and activates guanylate cyclase to produce cGMP. The cGMP activates protein kinase G that phosphorylates MLCK and decreases contraction. Thus, the site at which acetylcholine binds to the receptor (smooth muscle vs. endothelial cell) determines the response. In the body, due to the anatomy of the endothelial cells and the vascular smooth muscle cells and the presence of acetylcholine esterase, acetylcholine from the parasympathetic varicosities would predominantly release acetylcholine that would bind to muscarinic receptors on endothelial cells resulting in relaxation or dilation. Other biological responses of smooth muscle to stimulation are also site specific. For example, visceral smooth muscle in the gastrointestinal tract becomes quiescent with sympathetic nerve stimulation (Figure 11–3), whereas vascular smooth muscle in the blood vessels of the gastrointestinal tract develops stronger contraction when stimulated by sympathetic nerves. This site-specific response is due to the type of receptors on the cells—beta-adrenergic receptors cause relaxation in response to sympathetic stimulation in visceral smooth muscle, whereas alpha-adrenergic receptors cause stronger contraction in response to sympathetic stimulation in vascular smooth muscle. In summary, smooth muscle is the most diverse muscle in the body. Its functions are dependent to a great extent on the tissue in which they are found. Therefore, more specific detail about smooth muscle function will be presented in Sections 5, 7–9.

CHAPTER SUMMARY ■ ■ ■

■ ■

In smooth muscle, the calcium-binding protein is calmodulin rather than troponin as in skeletal and cardiac muscle. The calcium–calmodulin complex activates MLCK. Contraction is dependent on MLCK phosphorylating the myosin light chain allowing for binding of the myosin to the actin. MLC phosphatase removes the phosphate from the myosin light chain resulting in decreased strength of contraction. Many different stimuli can induce contraction or increase the strength of contraction of smooth muscle—voltage-gated calcium channels, voltage-gated potassium channels, receptoroperated channels, SOC, and receptor-mediated pharmacomechanical coupling. Even stretch can activate smooth muscle contraction.

■

■ ■

103

The myosin ATPase activity is lowest in smooth muscle, resulting in the slowest contractions or changes in tension development. Multiunit smooth muscle cells are innervated, have few gap junctions, and contract individually. Unitary smooth muscle cells can respond to stretch and have gap junctions that enable them to contract as a “unit.”

STUDY QUESTIONS 1. Which of the following statements about smooth muscle is true? A) Phosphorylation of myosin light chains is required for contraction. B) Inhibition of myosin light chain kinase increases strength of contraction. C) Inhibition of myosin light chain phosphatase decreases contraction. D) Stimulation of the smooth muscle cells by nitric oxide will increase contraction. 2. Which of the following statements about smooth muscle contraction is correct? A) Acetylcholine release at the neuromuscular junction initiates an action potential in the postsynaptic membrane. B) Acetylcholine binds to a nicotinic receptor on the postsynaptic membrane. C) Depolarization of the muscle fiber is not essential for smooth muscle contraction. D) Norepinephrine activating adrenergic receptors always causes increased strength of contraction in all smooth muscle cells. 3. Which of the following statements about muscle contraction is true for smooth muscle? A) All cells have pacemaker potential. B) The strength of contraction is correlated with the degree of phosphorylation of the myosin light chains. C) The strength of contraction is increased by recruiting more motor units. D) All muscle cells have a high myosin ATPase velocity and therefore a rapid contraction. 4. Which of the following statements about muscle contraction is true for smooth muscle? A) Strength of contraction cannot be altered physiologically by changing the resting cell length from 25% up to 100% of the maximum length. B) Strength of contraction is altered physiologically by altering the frequency of motor neuron firing. C) Strength of contraction can be changed by changing the balance of the myosin light chain kinase and phosphatase activities. D) Muscle contraction occurs as contractions followed by complete relaxation of the cell.

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SECTION IV CNS/NEURAL PHYSIOLOGY

12 C

Introduction to the Nervous System Susan M. Barman

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■

Name the various types of glia and their functions. Name the parts of a neuron and their functions. Describe the role of myelin in nerve conduction. List the types of nerve fibers found in the mammalian nervous system. Describe the general organization of thalamic, cortical, and reticular formation neurons. Describe the function of neurotrophins. Compare peripheral and central nerve regeneration.

INTRODUCTION The nervous system can be divided into two parts: the central nervous system (CNS), which is composed of the brain and spinal cord, and the peripheral nervous system, which is composed of nerves that connect the CNS to muscles, glands, and sense organs. Neurons are the basic building blocks of the nervous system. The human brain contains about 1011 (100 billion) neurons. It also contains 10–50 times this number of glial cells or glia. The CNS is a complex organ; it has been calculated that 40% of the human genes participate, at least to a degree, in its formation.

CELLULAR ELEMENTS IN THE CNS GLIAL CELLS The word glia is Greek for glue; for many years, glia were thought to function merely as connective tissue. However,

Ch12_105-114.indd 105

these cells are now recognized for their role in communication within the CNS in partnership with neurons. Unlike neurons, glial cells continue to undergo cell division in adulthood and their ability to proliferate is particularly noticeable after brain injury. There are two major types of glia, microglia and macroglia. Microglia are scavenger cells that resemble tissue macrophages and remove debris resulting from injury, infection, and disease. Microglia arise from macrophages outside of the CNS and are physiologically and embryologically unrelated to other neural cell types. There are three types of macroglia: oligodendrocytes, Schwann cells, and astrocytes (Figure 12–1). Oligodendrocytes and Schwann cells are involved in myelin formation around axons in the CNS and peripheral nervous system, respectively. Astrocytes, which are found throughout the brain, are of two subtypes. Fibrous astrocytes, which contain many intermediate filaments, are found primarily in white matter. Protoplasmic astrocytes are found in gray

105

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106

SECTION IV CNS/Neural Physiology

A Oligodendrocyte Oligodendrocyte in white matter

C Astrocyte

B Schwann cell Perineural oligodendrocytes

Capillary

Nodes of Ranvier

End-foot Neuron

Layers of myelin

Axons Schwann cell

End-foot

Fibrous astrocyte

Nucleus Inner tongue

Axon Neuron

FIGURE 12–1 Principal types of glial cells in the nervous system. A) Oligodendrocytes are small with relatively few processes. Those in the white matter provide myelin, and those in the gray matter support neurons. B) Schwann cells provide myelin to the peripheral nervous system. Each cell forms a segment of myelin sheath about 1 mm long; the sheath assumes its form as the inner tongue of the Schwann cell turns around the axon several times, wrapping in concentric layers. Intervals between segments of myelin are the nodes of Ranvier. C) Astrocytes are the most common glia in the CNS and are characterized by their starlike shape. They contact both capillaries and neurons and are thought to have a nutritive function. They are also involved in forming the blood–brain barrier. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. McGraw-Hill, 2000.)

matter and have a granular cytoplasm. Both types of astrocytes send processes to blood vessels, where they induce capillaries to form the tight junctions making up the blood–brain barrier. The blood–brain barrier prevents the diffusion of large or hydrophilic molecules (e.g., proteins) into the cerebrospinal fluid and brain, while allowing diffusion of small molecules. The astrocytes also send processes that envelop synapses and the surface of nerve cells. Protoplasmic astrocytes have a membrane potential that varies with the external K+ concentration but do not generate propagated potentials. They help maintain the appropriate concentration of ions and neurotransmitters by taking up K+ and the neurotransmitters glutamate and γ-aminobutyrate (GABA).

NEURONS Neurons in the mammalian CNS come in many different shapes and sizes. Most have the same parts as the typical spinal motor neuron illustrated in Figure 12–2. The cell body (soma) contains the nucleus and is the metabolic center of the neuron. Dendrites extend outward from the cell body and arborize extensively. Particularly in the cerebral and cerebellar cortex, the dendrites have small knobby projections called dendritic spines. A typical neuron has a long fibrous axon that originates from a thickened area of the cell body, the axon hillock. The first portion of the axon is called the initial segment. The axon divides into presynaptic terminals, each

ending in a number of synaptic knobs that are also called terminal buttons or boutons. They contain granules or vesicles that store the synaptic transmitters secreted by the nerves. Based on the number of processes that emanate from the cell body, neurons can be classified as unipolar, bipolar, and multipolar (Figure 12–3). The axons of many neurons are myelinated, that is, they acquire a sheath of myelin, a protein–lipid complex that is wrapped around the axon (Figure 12–2). In the peripheral nervous system, myelin forms when a Schwann cell wraps its membrane around an axon. This can occur up to 100 times, resulting in many layers of myelin around an axon (Figure 12–1). The myelin is then compacted when the extracellular portions of a membrane protein called protein zero (P0) lock to the extracellular portions of P0 in the apposing membrane. Various mutations in the gene for P0 cause peripheral neuropathies. The myelin sheath envelops the axon except at its ending and at the nodes of Ranvier, periodic 1-μm constrictions that are about 1 mm apart (Figure 12–2). The insulating function of myelin is critical for saltatory conduction of action potentials (see Chapter 6). Some neurons have axons that are unmyelinated, that is, they are simply surrounded by Schwann cells without the wrapping of the Schwann cell membrane that produces myelin around the axon. Within the CNS, the cells that form the myelin are oligodendrocytes (Figure 12–1). Unlike the Schwann cell, which forms the myelin on a single neuron, oligodendrocytes emit multiple processes that form myelin on many neighboring axons. In

CHAPTER 12 Introduction to the Nervous System

107

Cell body (soma) Initial segment of axon

Node of Ranvier

Schwann cell

Axon hillock Nucleus

Terminal buttons

Dendrites

FIGURE 12–2 Motor neuron with a myelinated axon. A motor neuron is comprised of a cell body (soma) with a nucleus, several processes called dendrites, and a long fibrous axon that originates from the axon hillock. The first portion of the axon is called the initial segment. A myelin sheath forms from Schwann cells and surrounds the axon except at its ending and at the nodes of Ranvier. Terminal buttons (boutons) are located at the terminal endings. (Reproduced with permission from Barrett KE, Barman SM, Boitano S, Brooks H: Ganong’s Review of Medical Physiology, 23rd ed. McGraw-Hill Medical, 2009.)

multiple sclerosis (MS), a crippling autoimmune disease, patchy destruction of myelin occurs in the CNS. The loss of myelin is associated with delayed or blocked conduction in the demyelinated axons.

PERIPHERAL NERVOUS SYSTEM The peripheral nervous system transmits information from the CNS to the effector organs throughout the body. It contains 12 pairs of cranial nerves and 31 pairs of spinal nerves. The cranial nerves have rather well-defined sensory and motor functions (Table 12–1). Many of these functions are described individually in more detail in later chapters in this section. Spinal nerves are named on the basis of the vertebral level from which the nerve exits (cervical, thoracic, lumbar, sacral, and coccygeal). These nerves include motor and sensory fibers of muscles, skin, and glands throughout the body.

NERVE FIBER TYPES AND FUNCTION Axonal conduction velocity is the speed by which an action potential travels along the axon. In general, there is a direct relationship between the diameter of a given nerve fiber and its speed of conduction. Nerve conduction tests are often used by neurologists in the diagnosis of some diseases. Axonal conduction velocity and other characteristics have led to the classification of nerve fibers as shown in Table 12–2. Mammalian nerve fibers are divided into three major groups (A, B, and C); the A group is further subdivided into α, β, γ, and δ fibers. In Table 12–2, the various fiber types are listed with their diameters, electrical characteristics, and functions. Large axons are concerned primarily with proprioceptive sensation, somatic motor function, conscious touch,

and pressure, while smaller axons subserve pain and temperature sensations and autonomic function. Dorsal root C fibers conduct some impulses generated by touch and other cutaneous receptors in addition to impulses generated by pain and temperature receptors. A numerical system (Ia, Ib, II, III, IV) has also been used to classify sensory fibers. A comparison of the number system and the letter system is shown in Table 12–3. In addition to variations in speed of conduction and fiber diameter, the various classes of fibers in peripheral nerves differ in their sensitivity to hypoxia and anesthetics (Table 12–4). This fact has clinical as well as physiological significance. For example, local anesthetics depress transmission in group C fibers before they affect group A touch fibers. Conversely, pressure on a nerve can cause loss of conduction in large-diameter motor, touch, and pressure fibers while pain sensation remains relatively intact. This is sometimes seen in individuals who sleep with their arms under their heads for long periods, causing compression of the nerves in the arms. Because of the association of deep sleep with alcoholic intoxication, the syndrome is most common on weekends and has acquired the interesting name Saturday night or Sunday morning paralysis.

ORGANIZATION OF THE THALAMUS, CEREBRAL CORTEX, & RETICULAR FORMATION The thalamus is a large collection of neuronal groups within the diencephalon; it participates in sensory, motor, and limbic functions that will be described in later chapters in this section. Virtually all information that reaches the cerebral cortex is first processed by the thalamus, leading to its being called the “gateway” to the cortex.

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A Unipolar cell

B Bipolar cell

C Pseudo-unipolar cell

Dendrites

Peripheral axon to skin and muscle

Dendrite

Cell body Axon Cell body

Single bifurcated process

Axon

Central axon

Cell body

Axon terminals Invertebrate neuron

Bipolar cell of retina

Ganglion cell of dorsal root

D Three types of multipolar cells

Dendrites Apical dendrite Cell body Cell body Basal dendrite Axon

Dendrites

Axon

Motor neuron of spinal cord

Pyramidal cell of hippocampus

Cell body

Axon

Purkinje cell of cerebellum

FIGURE 12–3 Different types of neurons in the mammalian nervous system. A) Unipolar neurons have one process, with different segments serving as receptive surfaces and releasing terminals. B) Bipolar neurons have two specialized processes: a dendrite that carries information to the cell and an axon that transmits information from the cell. C) Some sensory neurons are in a subclass of bipolar cells called pseudounipolar cells. As the cell develops, a single process splits into two, both of which function as axons—one going to skin or muscle and another to the spinal cord. D) Multipolar cells have one axon and many dendrites. Examples include motor neurons, hippocampal pyramidal cells with dendrites in the apex and base, and cerebellar Purkinje cells with an extensive dendritic tree in a single plane. (Adapted from Ramon Y Cajal: Histology. 10th ed. Baltimore: Wood, 1933.)

The thalamus is divided into nuclei that project diffusely to wide regions of the neocortex and nuclei that project to specific portions of the neocortex and limbic system. The nuclei that project to wide regions of the neocortex are the midline and intralaminar nuclei. The nuclei that project to specific areas include the specific sensory relay nuclei and the nuclei concerned with efferent control mechanisms. The specific sensory relay nuclei include the medial and lateral geniculate bodies, which relay auditory and visual impulses to the auditory and visual cortices, and the ventral posterior lateral (VPL) and ventral posteromedial, which relay somatosensory information to the postcentral gyrus. The ventral anterior and ventral lateral nuclei are concerned with motor function; they receive input from the basal ganglia and cerebellum and

project to the motor cortex. The anterior nuclei receive afferents from the mamillary bodies and project to the limbic cortex (memory and emotion). Most thalamic neurons are excitatory and release glutamate. The thalamic reticular nucleus neurons are inhibitory and release GABA; they modulate the responses of other thalamic neurons to input coming from the cortex. The neocortex is arranged in six layers (Figure 12–4). The most common neuronal type is the pyramidal cell with an extensive vertical dendritic tree (Figure 12–5) that may extend to the cortical surface. Their cell bodies can be found in all cortical layers except layer I. The axons of these cells give off recurrent collaterals that turn back and synapse on the superficial portions of the dendritic trees. Afferents from the

CHAPTER 12 Introduction to the Nervous System

109

TABLE 12–1 Functions of cranial nerves. Cranial Nerve

Type

Function

I. Olfactory

Sensory

Smell

II. Optic

Sensory

Vision

III. Occulomotor

Motor

Upward, downward, and medial eye movements; pupil diameter; lens shape

IV. Trochlear

Motor

Downward and lateral eye movement

V. Trigeminal

Motor Sensory

Chewing Proprioception from skin and muscle of the face

VI. Abducens

Motor

Lateral eye movements

VII. Facial

Motor Sensory

Facial expression; salivary gland secretions Sensation from skin of external ear canal; taste from anterior two thirds of the tongue

VIII. Vestibulocochlear

Sensory

Hearing; sense of motion

IX. Glossopharyngeal

Motor Sensory

Swallowing; parotid salivary gland secretions Taste from posterior one third of the tongue; baroreceptor and chemoreceptors

X. Vagus

Motor Sensory

Skeletal muscles of larynx and pharynx; smooth muscle and glands in pharynx, larynx, thorax, and abdomen Receptors in thorax and abdomen; taste from posterior tongue and oral cavity

XI. Accessory

Motor

Skeletal muscles in the neck

XII. Hypoglossal

Motor

Skeletal muscle of tongue

specific nuclei of the thalamus terminate primarily in cortical layer IV, and the nonspecific afferents are distributed to layers I–IV. Pyramidal neurons are the only projection neurons of the cortex, and they are excitatory neurons that release glutamate. The other cortical cell types are local circuit neurons (interneurons) that are classified based on their shape, pattern of projection, and neurotransmitter. Inhibitory interneurons

(basket cells and chandelier cells) release GABA. Basket cells account for most inhibitory synapses on the pyramidal soma and dendrites. Chandelier cells are a powerful source of inhibition of pyramidal neurons because they terminate on the initial segment of the pyramidal cell axon. Their terminal boutons form short vertical rows that resemble candlesticks, thus accounting for their name. Spiny stellate cells, excitatory interneurons that release glutamate, are located primarily in

TABLE 12–2 Classification of mammalian nerve fibers.a Fiber Type

Function

Fiber Diameter (μm)

Conduction Velocity (m/s)

Spike Duration (milliseconds)

Absolute Refractory Period (milliseconds)

0.4–0.5

0.4–1

A α

Proprioception; somatic motor

12–20

70–120

β

Touch, pressure

5–12

30–70

γ

Motor to muscle spindles

3–6

15–30

δ

Pain, cold, touch

2–5

12–30

Preganglionic autonomic

+90 degrees

Left axis deviation < 0 degrees

0 degrees

+90 degrees

Range of normal 0 to +90 degrees

LL

FIGURE 25–5

Mean electrical axis and axis deviations.

(Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

the patient’s upper left-hand quadrant and may indicate any of the several conditions such as a physical displacement of the heart to the left, left ventricular hypertrophy, or loss of electrical activity in part of the right ventricle (e.g., after an infarct). A right axis deviation exists when the mean electrical axis falls in the patient’s lower right-hand quadrant and may indicate, among several conditions, a physical displacement of the heart to the right, right ventricular hypertrophy, or loss of electrical activity in part of the left ventricle. The mean electrical axis of the heart can be determined from the electrocardiogram. The process involves determining what single net dipole orientation will produce the R-wave amplitudes recorded on any two leads. For example, if the R waves on leads II and III are both positive (upright) and of equal magnitude, the mean electrical axis must be +90°. As should be obvious, in this case, the amplitude of the R wave on lead I will be zero. Alternatively, one can scan the electrocardiographic records for the lead tracing with the largest R waves and then deduce that the mean electrical axis must be nearly parallel to that lead. In Figure 25–4, for example, the largest R wave occurs on lead II. Lead II has an orientation of +60°, which is very close to the actual mean electrical axis in this example.

THE STANDARD 12-LEAD ELECTROCARDIOGRAM The standard clinical electrocardiogram involves voltage measurements recorded from 12 different leads. Three of these are the bipolar limb leads I, II, and III, which have already been discussed. The other nine leads are unipolar leads. Three of these leads are generated by using the limb electrodes. Two of the electrodes are electrically connected to form an indifferent electrode while the third limb electrode is made the positive pole of the pair. Recordings made from these electrodes are called augmented unipolar limb leads. The voltage record obtained between the electrode at the right arm and the indifferent electrode is called a lead aVR electrocardiogram. Similarly, lead aVL is recorded from the electrode on the left arm and lead aVF is recorded from the electrode on the left leg.

The standard limb leads (I, II, and III) and the augmented unipolar limb leads (aVR, aVL, and aVF) record the electrical activity of the heart as it appears from six different “perspectives.” As shown in Figure 25–6A, the axes for leads I, II, and III are those of the sides of Einthoven’s triangle, while those for aVR, aVL, and aVF are specified by lines drawn from the center of Einthoven’s triangle to each of its vertices. As indicated in Figure 25–6B, these six limb leads can be thought of as a hexaxial reference system for observing the cardiac vectors in the frontal plane. The other six leads of the standard 12-lead electrocardiogram are also unipolar leads that “look” at the electrical vector projections in the transverse plane (a horizontal plane that divides the body into superior and inferior segments). These potentials are obtained by placing an additional (exploring) electrode in six specified positions on the chest wall as shown in Figure 25–6C. The indifferent electrode in this case is formed by electrically connecting the limb electrodes. These leads are identified as precordial or chest leads and are designated as V1–V6. As shown in this figure, the wave of ventricular excitation sweeps away from V1, resulting in a downward deflection. The wave of ventricular excitation sweeps toward V6, resulting in an upward deflection. In summary, the electrocardiogram is a powerful tool for evaluating cardiac excitation characteristics. It must be recognized, however, that the ECG does not provide direct evidence of mechanical pumping effectiveness. For example, a leaky heart valve will usually have no direct electrocardiographic consequences but may adversely influence pumping ability of the heart.

ABNORMAL CARDIAC EXCITATION AND RHYTHMICITY The material presented here is an introduction to the more common abnormalities in cardiac rate and rhythm with an emphasis on the primary physiological consequences of these abnormal situations. Many cardiac excitation problems can be diagnosed from the information in a single lead of an electrocardiogram. The lead II electrocardiogram trace at the top of Figure 25–7 is identified as normal sinus rhythm based on the following characteristics: (1) the frequency of QRS complexes is ~1/s, indicating a normal beating rate of 60 beats/min; (2) the shape of the QRS complex is normal for lead II and its duration is less than 120 milliseconds, indicating rapid depolarization of the ventricles via normal conduction pathways; (3) each QRS complex is preceded by a P wave of proper configuration, indicating SA nodal origin of the excitation; (4) the PR interval is less than 200 milliseconds, indicating proper conduction delay of the impulse propagation through the AV node; (5) the QT interval is less than half of the R-to-R interval, indicating normal ventricular repolarization; and (6) there are no extra P waves, indicating that no AV nodal conduction block is present. The subsequent electrocardiographic tracings in Figures 25–7 and 25–9 represent irregularities commonly found in clinical practice. Examination of each of these traces with the above characteristics in mind will aid in the differential diagnosis.

CHAPTER 25 Cardiac Function Assessments

A

B RA

− −

I +

aV

R

− − −

aVF

II +

+ + LL

aV L +

+ LA −

aVR

−

−

C

−

+

241

+

−

aVL

+ I

III −

− + III

+ aVF

V6 V1

+ II

V2 V3

V4

V5

D

FIGURE 25–6. The standard 12-lead electrocardiogram. A and B) Leads in the frontal plane. C) Electrode positions for precordial leads in the transverse plane. D) A 12 lead ECG. The bottom line is a rhythm strip taken from lead V1 (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006. Fig. 25–6D courtesy of Dr. David Gutterman)

The physiological consequences of abnormal excitation and conduction in the heart depend on whether the electrical abnormality evokes a tachycardia, which will limit the time for cardiac filling between beats; evokes a bradycardia, which is inadequate to support sufficient cardiac output; or decreases the coordination of myocyte contraction, which will reduce stroke volume (SV).

SUPRAVENTRICULAR ABNORMALITIES Traces 2–6 below the normal trace in Figure 25–7 represent typical supraventricular arrhythmias (i.e., originating in the atria or AV node). Supraventricular tachycardia (shown in trace 2 of Figure 25–7 and sometimes called paroxysmal atrial tachycardia) occurs when the atria are abnormally excited and drive the ventricles at a very rapid rate. These paroxysms may begin abruptly, last for a few minutes to a few hours, and then, just as abruptly, disappear and heart rate reverts to normal. QRS complexes appear normal (albeit frequent) with simple paroxysmal atrial tachycardia because the ventricular conduction pathways operate normally. The P and T waves may be superimposed because of the high heart rate. Low blood pressure and dizziness may accompany bouts of this

arrhythmia because the extremely high heart rate does not allow sufficient diastolic time for ventricular filling. There are two mechanisms that may account for supraventricular tachycardia. First, an atrial region, usually outside the SA node, may become irritable (perhaps because of local interruption in blood flow) and begin to fire rapidly to take over the pacemaker function for the entire heart. Such an abnormal pacemaker region is called an ectopic focus. Alternatively, atrial conduction may become altered so that a single wave of excitation does not die out but continually travels around some abnormal atrial conduction loop. In this case, the continual activity in the conduction loop may drive the atria and AV node at a very high frequency. This self-sustaining process is called a reentry phenomenon and is diagrammed in Figure 25–8. This situation may develop as a result of abnormal repolarization and altered refractory periods in local areas of the myocardium. Atrial flutter is a special form of tachycardia of atrial origin in which a large reentrant pathway drives the atria at very fast rates (250–300 beats/min) and normal refractory periods of AV nodal tissue are overwhelmed. Thus, ventricular rate is often some fixed ratio of the atrial rate (2:1, 4:1) with frequencies often 150–220 beats/min.

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SECTION V Cardiovascular Physiology

1. Normal sinus rhythm 2. Supraventricular tachycardia 3. First-degree block 2:1

4:1

4. Second-degree block

5. Third-degree block

FIGURE 25–7 Supraventricular arrhythmias. (Reproduced with permission from

6. Atrial fibrillation

1 mV

Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed.

1s

New York: Lange Medical Books/McGraw-Hill, 2006.)

Conduction blocks occur at the AV node and generally represent impaired conduction through this tissue. In first-degree heart block (trace 3 of Figure 25–7), the only electrical abnormality is unusually slow conduction through the AV node. This condition is detected by an abnormally long PR interval (>0.2 second). Otherwise, the electrocardiogram may be normal. At normal heart rates, the physiological effects of a first-degree block are usually inconsequential. The danger, however, is that the slow conduction may deteriorate to an actual interruption of conduction. A second-degree heart block (trace 4 of Figure 25–7) is said to exist when some but not all atrial impulses are transmitted through the AV node to the ventricle. Impulses are blocked in the AV node if the cells of the region are still in a refractory period from a previous excitation. The situation is aggravated by high atrial rates and slower-than-normal conduction through the AV nodal region. In second-degree block, some but not all P waves are accompanied by corresponding QRS complexes and T waves. Atrial rate is often faster than ventricular rate by a certain ratio (e.g., 2:1, 3:1, 4:1). This condition may not represent a serious clinical problem as long as the ventricular rate is adequate to meet the pumping needs. In third-degree heart block (trace 5 of Figure 25–7), no impulses are transmitted through the AV node. In this event, some area in the ventricles—often in the common bundle or bundle branches near the exit of the AV node—assumes the pacemaker role for the ventricular tissue. Atrial rate and ventricular rate are completely independent, and P waves and QRS complexes are totally dissociated in the electrocardiogram. Ventricular rate is likely to be slower than normal (bradycardia) and sometimes is slow enough to impair cardiac output. Atrial fibrillation (trace 6 of Figure 25–8) is characterized by a complete loss of the normally close synchrony of the excitation and resting phases between individual atrial cells. Cells in different areas of the atria depolarize, repolarize, and are excited again randomly. Consequently, no P waves appear in the electrocardiogram although there may be rapid irregular small waves apparent throughout diastole. The ventricular rate is often very irregular in atrial fibrillation because impulses enter the AV

node from the atria at unpredictable times. Fibrillation is a selfsustaining process. The mechanisms behind it are not well understood, but impulses are thought to progress repeatedly around irregular conduction pathways (sometimes called circus pathways, which imply a reentry phenomenon as described earlier and in Figure 25–8). However, because atrial contraction usually plays a negligible role in ventricular filling, atrial fibrillation may be well tolerated by most patients as long as ventricular rate is sufficient to maintain the cardiac output. The real danger with atrial fibrillation lies in the tendency for blood to form clots in the atria in the absence of the normal vigorous, coordinated atrial contraction. These clots can fragment and move out of the heart to lodge in small arteries throughout the systemic or pulmonary circulation. These emboli can have devastating effects on function of critical organs. Consequently, anticoagulant therapy is used as prophylaxis for patients in atrial fibrillation.

VENTRICULAR ABNORMALITIES Traces 2–6 below the normal trace in Figure 25–9 show typical ventricular electrical abnormalities. Conduction blocks called bundle branch blocks or hemiblocks (trace 2 of Figure 25–9)

Normal pathway

Reentrant pathway

FIGURE 25–8 Normal and reentrant (circus) cardiac excitation pathways. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 25 Cardiac Function Assessments

243

1. Normal sinus rhythm

2. Bundle branch block 3. Premature ventricular contraction 4. Ventricular tachycardia

5. Long QT syndrome with torsades des pointes

FIGURE 25–9 1 mV 1s

can occur in either of the branches of the Purkinje system of the intraventricular septum often as a result of a myocardial infarction. Ventricular depolarization is less synchronous than normal in the half of the heart with the nonfunctional Purkinje system. This results in a widening of the QRS complex (>0.12 second) because a longer time is required for cell-to-cell ventricular depolarization of the blocked side to be completed. The direct physiological effects of bundle branch blocks are usually inconsequential. Premature ventricular contractions (PVCs; trace 3 of Figure 25–9) are caused by action potentials initiated by and propagated away from an ectopic focus in the ventricle. As a result, the ventricle depolarizes and contracts before it normally would. A PVC is often followed by a missed beat (called a compensatory pause) because the ventricular cells are still refractory when the next normal impulse emerges from the SA node. The highly abnormal ventricular depolarization pattern of a PVC produces the large-amplitude, long-duration deflections on the electrocardiogram. The shapes of the electrocardiographic records of these extra beats are highly variable and depend on the ectopic site of their origin and the depolarization pathways involved. The volume of blood ejected by the premature beat itself is smaller than normal (if a volume is ejected at all), whereas the stroke volume of the beat following the compensatory pause is larger than normal. This is partly due to the differences in filling times and partly to an inherent phenomenon of cardiac muscle called postextrasystolic potentiation. Single PVCs occur occasionally in most individuals and, although sometimes alarming to the individual experiencing them, are not dangerous. Frequent occurrence of PVCs, however, may be a signal of possible myocardial damage or perfusion problems and can lead to ventricular tachycardia and even ventricular fibrillation (discussed below). Ventricular tachycardia (trace 4 of Figure 25–9) occurs when the ventricles are driven at high rates, usually by impulses originating from a ventricular ectopic focus. Ventricular tachycardia is a very serious condition. Not only is diastolic

Ventricular arrhythmias.

(Modified with permission from Mohrman DE, Heller LJ:

6. Ventricular fibrillation

Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

filling time limited by the rapid rate, but also the abnormal excitation pathways make ventricular contraction less synchronous and therefore less effective than normal. In addition, ventricular tachycardia often precedes ventricular fibrillation. Prolonged QT intervals (left side of trace 5 in Figure 25–9) are a result of delayed ventricular myocyte repolarization, which may be due to inappropriate opening of sodium channels or prolonged closure of potassium channels during the action potential plateau phase. Although the normal QT interval varies with heart rate, it is normally less than 40% of the cardiac cycle length (except at very high heart rates). Long QT syndrome is identified when the QT interval is greater than 50% of the cycle duration. It may be genetic in origin (mutations influencing various ion channels involved with cardiac excitability), may be acquired from several electrolyte disturbances (low blood levels of Ca2+, Mg2+, or K+), or may be induced by several pharmacological agents (including some antiarrhythmic drugs). The prolongation of the myocyte refractory period, which accompanies the long QT syndrome, extends the vulnerable period during which extra stimuli can evoke tachycardia or fibrillation. Patients with long QT syndrome are predisposed to a particularly dangerous type of ventricular tachycardia called torsades de pointes (“twisting of points” as shown on the right side of trace 5 in Figure 25–9). This differs from the ordinary ventricular tachycardia in that the ventricular electrical complexes cyclically vary in amplitude around the baseline and can deteriorate rapidly into ventricular fibrillation. In ventricular fibrillation (trace 6 of Figure 25–9), various areas of the ventricle are excited and contract asynchronously. The mechanisms are similar to those in atrial fibrillation. The ventricle is especially susceptible to fibrillation whenever a premature excitation occurs at the end of the T wave of the previous excitation, that is, when most ventricular cells are in the “hyperexcitable” or “vulnerable” period of their electrical cycle. In addition, because some cells are repolarized and some are still refractory, circus pathways can be triggered easily at

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LV pressure (mm Hg)

A

Increased contractility

Normal contractility

120 Increased afterload 80

˙ X

Increased preload

40

60 LV volume (mL)

80

120

Cardiac failure patient d se es tility r p c De ntra co Untreated

co

120

No ntr rmal ac tilit y

Normal individual

B LV pressure (mm Hg)

niques. One of the most accurate methods of measuring cardiac output by invasive means makes use of the Fick principle, which is discussed in more detail in Chapter 26. Briefly, this principle states that the amount of a substance consumed by the tissues, Xtc, is equal to what goes in minus what goes out (which is the arterial–venous concentration difference in the ˙ ). This substance ([X]a – [X]v) times the blood flow rate, Q relationship can be algebraically arranged to solve for blood flow as follows:

Treated with afterload reducer

40

60

120

180

LV volume (mL)

FIGURE 25-10 Left ventricular end systolic pressurevolume relationships. A) The effect of increased contractility shifts the line upward and to the left. B) The effect of systolic cardiac failure shifts the line downward and to the right. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

this time. Since no pumping action occurs with ventricular fibrillation, the situation is fatal unless quickly corrected by cardiac conversion (commonly referred to as external electrical defibrillation or cardioversion). During this procedure, the artificial application of large currents to the entire heart (via paddle electrodes applied across the chest) may be effective in depolarizing all heart cells simultaneously and thus allowing a normal excitation pathway to be reestablished. Cardiopulmonary resuscitation (CPR) must be administered until a defibrillation is achieved.

MEASUREMENT OF CARDIAC OUTPUT Fick Principle: Measurement of cardiac output is not a simple task and usually involves either some invasive maneuver or some significant assumptions based on noninvasive tech-

tc ˙ = ________ Q [X] _ [X] a

(1)

v

A common method of determining cardiac output is to use the Fick principle to calculate the collective flow through the systemic organs from (1) the whole body oxygen consumption ˙ tc), (2) the oxygen content of the arterial blood ([X]a), rate (X and (3) the concentration of oxygen in mixed venous blood ([X]v). Of the values required for this calculation, the oxygen content of mixed venous blood is the most difficult to obtain. Generally, the sample for venous blood oxygen measurement must be taken from a venous catheter positioned in the pulmonary artery to ensure that it is a mixed sample of venous blood from all systemic organs. The calculation of cardiac output from the Fick principle is best illustrated by an example. Suppose a patient is consuming 250 mL of O2/min when systemic arterial blood contains 200 mL of O2/L and the right ventricular blood contains 150 mL of O2/L. This means that, on the average, each liter of blood loses 50 mL of O2 as it passes through the systemic organs. In order for 250 mL of O2 to be consumed per minute, 5 L of blood must pass through the systemic circulation each minute: 250[mL O /min]

2 ˙ = __________________ = 5[L blood/min] Q 200–150[mL O /L blood]

(2)

2

Although use of the Fick Principle as described above provides the gold standard for cardiac output determination, there are several other techniques that give good estimates of cardiac output. Indicator dilution techniques involve injection of a known quantity of indicator (dye or a thermal bolus) into blood entering the right heart and appropriate detectors are arranged to continuously record the concentration of the indicator in blood as it leaves the left heart. The dilution of the indicator is proportional to the cardiac output. Other techniques for imaging the heart (echocardiography, ventricular angiography, radionuclide ventriculography) can be used to estimate stroke volume, cardiac output and other indices of ventricular function as are described below. Cardiac index is the cardiac output corrected for the individual’s size. For example, the cardiac output of a 50-kg woman will be significantly lower than that of a 90-kg man. It has been found, however, that cardiac output correlates better with body surface area than with body weight. Therefore, it is common to express the cardiac output per square meter of surface area. Under resting conditions, the cardiac index is normally approximately 3 (L/min)/m2.

CHAPTER 25 Cardiac Function Assessments

CARDIAC CONTRACTILITY ESTIMATIONS It is often important to assess an individual’s cardiac function without using major invasive procedures. Advances in several techniques have made it possible to obtain two- and threedimensional images of the heart throughout the cardiac cycle. Visual or computer-aided analysis of such images provides information useful in clinically evaluating cardiac function. Echocardiography is the most widely used of the several imaging techniques currently available. This noninvasive technique is based on the fact that sound waves reflect back toward the source when encountering abrupt changes in the density of the medium through which they travel. A transducer, placed at specified locations on the chest, generates pulses of ultrasonic waves and detects waves reflected from the cardiac tissue interfaces. The longer the time between the transmission of the wave and the arrival of the reflection, the deeper the structure is in the thorax. Such information can be reconstructed by computer in various ways to produce a continuous image of the heart and its chambers throughout the cardiac cycle. Echocardiography is especially well suited for detecting abnormal operation of cardiac valves or contractile function in portions of the heart walls. It also can provide estimates of heart chamber volumes at different times in the cardiac cycle that are used in a number of ways to assess cardiac function. Ejection fraction (EF) is an extremely useful clinical measurement that can be calculated from an echocardiogram. It is defined as the ratio of stroke volume (SV) to end-diastolic volume (EDV): SV EF = ____ EDV

(3)

Estimates of end-diastolic and -systolic volumes can be made from the images and SV calculated. EF is commonly expressed as a percentage and normally ranges from 55% to 80% (mean 67%) under resting conditions. EFs of less than 55% indicate depressed myocardial contractility. The end-systolic pressure–volume relationship is another useful clinical technique to assess cardiac contractility. Endsystolic volume for a given cardiac cycle is estimated by one of the imaging techniques described above while end-systolic pressure for that cardiac cycle can obtained from the arterial pressure recorded at the point of the closure of the aortic valve (the incisura). Values for several different cardiac cycles may be obtained during infusion of a vasoconstrictor (which increases afterload), and the data plotted as in Figure 25–10 in the context of overall ventricular pressure–volume loops. As shown, increases in myocardial contractility are associated with a leftward rotation in the end-systolic pressure–volume relationship. This method of assessing cardiac function is particularly important because it provides an estimate of contractility that is independent of the EDV (preload). (Recall from Figure 24–4 that increases in preload cause increases in SV without changing the end-systolic volume. Thus, only altera-

245

tions in contractility will cause shifts in the end-systolic pressure–volume relationship.) Note in Figure 25–10A that both the “normal” and “increased contractility” end-systolic pressure–volume lines nearly project to the origin at zero pressure, zero volume. Thus, it is possible to get a reasonable clinical estimate of the slope of the end-systolic pressure–volume relationship (read “myocardial contractility”) from a single measurement of end-systolic pressure and volume. This avoids the need to do multiple expensive tests with vasodilator or vasoconstrictor infusions. A decrease in contractility (as may be caused by heart disease) is associated with a downward shift of the end-systolic pressure–volume relationship and is known as systolic heart failure. In this situation, increases in sympathetic drive have limited influence on cardiac output. Part of the compensatory process involves a significant increase in body fluid retention that results in an increase in circulating blood volume and ventricular EDV (see Chapter 29). A left ventricular pressure– volume loop describing the events of a cardiac cycle from a failing heart (shown in Figure 25–10B) is displaced far to the right of that of a normal heart. The untreated patient described in this figure is in serious trouble with a reduced SV and EF and high filling pressure with possible pulmonary vascular congestion. Furthermore, the slope of the line describing the end-systolic pressure–volume relationship is shifted downward and is less steep, indicating the reduced contractility of the cardiac muscle. However, because of this flatter relationship, small reductions in cardiac afterload (i.e., arterial blood pressure) will produce substantial increases in EF and SV that will significantly help this patient.

ABNORMAL CARDIAC VALVE FUNCTION Pumping action of the heart is impaired when the valves do not function properly. A number of techniques, ranging from simple auscultation (listening to the heart sounds) to echocardiography or cardiac catheterization, are used to obtain information about the nature and extent of these valve malfunctions. Often, abnormal heart sounds called murmurs accompany cardiac valve defects. These sounds are caused by abnormal pressure gradients and turbulent blood flow patterns that occur during the cardiac cycle. In general, when a valve does not open fully (i.e., is stenotic), the chamber upstream of the valve has to develop more pressure during its systolic phase to achieve a given flow through the valve. This increase in “pressure” work will induce hypertrophy of cardiac muscle cells and thickening of the walls of that chamber. (This is analogous to the hypertrophied skeletal muscles of the weightlifter doing isometric or high-tension work.) When a valve does not close completely (i.e., is insufficient, regurgitant, or incompetent), the regurgitant blood flow represents an additional volume that must be ejected in order to get sufficient forward flow out of the ventricle into the tissues. This increase in “volume” work often leads to chamber dilation but

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not to an increase in wall thickness. (This is analogous to the nonhypertrophied but well-toned skeletal muscles of the longdistance runner doing isotonic or shortening work.) A second generality about valve abnormalities is that whenever there is an increase in the atrial pressure as a result of AV valve stenosis or regurgitation, this will result in higher pressures in the upstream capillary beds. If capillary hydrostatic pressures are increased, tissue edema will ensue with substantial negative consequences on the function of those upstream organs. A brief overview of four of the common valve defects influencing left ventricular function is given in Figure 25–11. The reader should note that similar stenotic and regurgitant abnor-

malities can occur in right ventricular valves with similar consequences on right ventricular function.

AORTIC STENOSIS Some characteristics of aortic stenosis are shown in Figure 25–11A. Normally, the aortic valve opens widely and offers a pathway of very low resistance through which blood leaves the left ventricle. If this opening is narrowed (stenotic), resistance to flow through the valve increases. A significant pressure difference between the left ventricle and the aorta may be required to eject blood through a

A

B

150

Aortic pressure 100 Left ventricular pressure Left atrial pressure

50

0 ECG Phonocardiogram

C

D Aortic pressure

100

Left ventricular pressure Left atrial pressure

50

0 ECG

Phonocardiogram

FIGURE 25–11 Common valve abnormalities. A) Aortic stenosis. B) Mitral stenosis. C) Aortic regurgitation (insufficiency). D) Mitral insufficiency. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 25 Cardiac Function Assessments stenotic aortic valve. As shown in Figure 25–11A, intraventricular pressures may rise to very high levels during systole while aortic pressure rises more slowly than normal to a systolic value that is subnormal. Pulse pressure is usually low with aortic stenosis. High intraventricular pressure development is a strong stimulus for cardiac muscle cell hypertrophy, and an increase in left ventricular muscle mass invariably accompanies aortic stenosis. This tends to produce a leftward deviation of the electrical axis. (The mean electrical axis will fall in the upper right-hand quadrant of Figure 25–5.) Blood being ejected through the narrowed orifice may reach very high velocities, and turbulent flow may occur as blood enters the aorta. This abnormal turbulent flow can be heard as a systolic (or ejection) murmur with a properly placed stethoscope. The primary physiological consequence of aortic stenosis is a high ventricular afterload that is caused by restriction of the outflow tract. This imposes an increased pressure workload on the left ventricle.

MITRAL STENOSIS Some characteristics of mitral stenosis are shown in Figure 25–11B. A pressure difference of more than a few millimeters of mercury across the mitral valve during diastole is distinctly abnormal and indicates that this valve is stenotic. The high resistance mandates an increased pressure difference to achieve normal flow across the valve (Q ˙ = ΔP/R). Consequently, as shown in Figure 25–11B, left atrial pressure is increased with mitral stenosis. The high left atrial workload may induce hypertrophy of the left atrial muscle. Increased left atrial pressure is reflected back into the pulmonary bed and, if high enough, causes pulmonary edema and pulmonary vascular congestion. A diastolic murmur associated with turbulent flow through the stenotic mitral valve can often be heard. The primary physiological consequences of mitral stenosis are increases in left atrial pressure and pulmonary capillary pressure. The latter can cause interference with normal gas exchange in the lungs, leading to dyspnea (shortness of breath).

AORTIC INSUFFICIENCY Typical characteristics of aortic regurgitation (insufficiency, incompetence) are shown in Figure 25–11C. When the leaflets of the aortic valve do not provide an adequate seal, blood regurgitates from the aorta back into the left ventricle during the diastolic period. Aortic pressure falls faster and further than normal during diastole, which causes a low diastolic pressure and a large pulse pressure. In addition, ventricular EDV and pressure are higher than normal because of the extra blood that reenters the chamber through the incompetent aortic valve during diastole. Turbulent flow of the blood reentering the left ventricle during early diastole produces a characteristic diastolic murmur. Often the aortic valve is altered so that it is both stenotic and insufficient. In these instances, both a sys-

247

tolic and a diastolic murmur are present. The primary physiological consequences of aortic insufficiency are a reduction in forward flow out to the tissues (if the insufficiency is severe) and an increase in the volume workload of the left ventricle.

MITRAL REGURGITATION Typical characteristics of mitral regurgitation (insufficiency, incompetence) are shown in Figure 25–11D. When the mitral valve is insufficient, some blood regurgitates from the left ventricle into the left atrium during systole. A systolic murmur may accompany this abnormal flow pattern. Left atrial pressure is increased to abnormally high levels, and left ventricular EDV and pressure increase. Mitral valve prolapse is a common form of mitral insufficiency in which the valve leaflets evert into the left atrium during systole. The primary physiological consequences of mitral regurgitation are somewhat similar to aortic insufficiency in that forward flow out of the left ventricle into the aorta may be compromised (if the insufficiency is severe) and there is an increase in the volume workload of the left ventricle. In addition, the elevated left atrial pressure can also lead to pulmonary effects with shortness of breath.

CLINICAL CORRELATION A 72-year-old man comes to the doctor’s office with complaints of diminished exercise tolerance. He has had dyspnea (shortness of breath) on exertion for several years but it has gotten worse lately. He now experiences chest pain and some dizziness with only mild exertion and, the day before his appointment, he fainted when getting out of bed. His heart rate is 75 beats/min and his blood pressure is 113/90 mm Hg. A loud systolic murmur is heard using a stethoscope placed above the aorta, and a slowly rising pulse is detected in his radial artery. An ECG reveals normal rate and rhythm but significant left ventricular hypertrophy (positive R wave in lead I, negative R wave in lead AVF , and large R-wave amplitudes in leads aVl, V5, and V6). Echocardiography indicated significant left ventricular wall thickening and significant narrowing of the aortic valve opening during systole. This man’s symptoms can all be a result of an increasing severity of aortic valve stenosis. Because of the elevated resistance to outflow (essentially an increased afterload), the left ventricular muscles must develop more force to generate sufficient pressure to eject blood during systole. Left ventricular pressure during systole will be much higher than aortic pressure during systole, thereby producing a significant pressure gradient. Over time, this increased workload induces hypertrophy of the left ventricular muscle that accounts for the leftward shift in the mean electrical axis. The dyspnea on exertion is a result of an exercise-induced imbalance in SV from the normal

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right side and the abnormal left side of the heart and blood backing up into the pulmonary circulation. Fainting may be a common symptom in patients with aortic stenosis and, although it certainly reflects a decrease in brain blood flow, the specific causes are not entirely clear. A popular theory is that because the left ventricular SV (and therefore cardiac output) is nearly fixed and not able to adjust to the many cardiovascular challenges associated with even mild exertion, arterial pressure decreases as a result of the unopposed decrease in peripheral vascular resistance. Other possibilities include a hypertrophyinduced predisposition to arrhythmias or a vasodilator reflex evoked by high left ventricular pressures. The chest pain (angina pectoris) is a result of inadequate coronary blood flow to meet the myocardial metabolic demands. Ischemia can be a result of either an impediment to coronary flow (as might occur with coronary artery disease or atherosclerosis) or an increase in metabolic demands. In this case, the increase in myocardial work because of the aortic stenosis plus the accompanying hypertrophy outstrips the ability of the coronary bed to provide sufficient flow. (Eventually, there will be ischemia even at rest and ECG signs of ventricular strain and subendocardial ischemia will appear. These signs include ST-segment depression and T-wave inversion.) The treatment for aortic stenosis is surgical replacement of the aortic valve.

CHAPTER SUMMARY ■

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The electrocardiogram is a record of the voltage changes that occur on the surface of the body as a result of the propagation of the action potential through the heart during a cardiac cycle. There are standardized conventions used for recording electrocardiograms. The magnitude and direction of the net dipole formed by the wavefront of the action potential at any instant in time can be deduced from the magnitude and orientation of the electrocardiographic deflections. The mean electrical axis describes the orientation of the net dipole at the instant of maximum wavefront propagation during ventricular depolarization and normally falls between 0° and +90° on a polar coordinate system. The standard 12-lead electrocardiogram is widely used to evaluate cardiac electrical activity and consists of a combination of bipolar and unipolar records from limb electrodes and chest electrodes. Cardiac arrhythmias can often be detected and diagnosed from a single electrocardiographic lead. Physiological consequences of abnormal excitation and conduction in the heart depend on whether the electrical abnormality limits the time for adequate cardiac filling or

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decreases the coordination of myocyte contractions resulting in inadequate pressure development and ejection. Supraventricular arrhythmias are a result of abnormal action potential initiation at the SA node or altered propagation characteristics through the atrial tissue and the AV node. Tachycardias may originate either in the atria or ventricles and are a result of increased pacemaker automaticity or of continuously circling pathways setting up a reentrant circuit. Abnormal conduction through the AV node results in conduction blocks. Abnormal conduction pathways in the Purkinje system or in the ventricular tissue result in significant QRS alterations. Ventricular tachycardia and ventricular fibrillation represent severe abnormalities that are incompatible with effective cardiac pumping. A variety of methods are available for measuring various aspects of cardiac mechanical function. These methods are based on the Fick principle and various imaging techniques including echocardiography. The ejection fraction (which is the stroke volume divided by the end-diastolic volume) and the ventricular end-systolic pressure–volume relationship are very useful indices of cardiac contractility. Failure of cardiac valves to open fully (stenosis) can result in elevated upstream chamber pressure and abnormal pressure gradients, congestion in upstream vascular beds, chamber wall hypertrophy, turbulent forward flow across the valve, and murmurs during systole or diastole. Failure of cardiac valves to close completely (insufficiency, incompetence, regurgitation) can result in large stroke volumes, abnormal pressure pulses, congestion in upstream vascular beds, turbulent backward flow across the valve, and murmurs during systole or diastole.

STUDY QUESTIONS 1. Your 75-year-old male patient is alert with complaints of general fatigue. His heart rate = 90 beats/min and arterial pressure = 140/50 mm Hg. A diastolic murmur is present. There are no ECG abnormalities identified and mean electrical axis = 10°. Cardiac catheterization indicate that LV pressure = 140/20 mm Hg and left atrial pressure = 10/3 mm Hg (as peak systolic/end diastolic). Which of the following is most consistent with these findings? A) aortic stenosis B) aortic insufficiency C) mitral stenosis D) mitral insufficiency E) right ventricular hypertrophy 2. Evaluation of your patient’s electrocardiogram shows that P waves occur at a regular rate of 90/min and QRS complexes occur at a regular rate of 37/min. Which of the following is the most likely diagnosis? A) supraventricular tachycardia B) first-degree heart block C) second-degree heart block D) third-degree heart block E) bundle branch block

CHAPTER 25 Cardiac Function Assessments 3. Given the following information, calculate cardiac output and determine whether this would be a normal value for a healthy 70 kg young adult: systemic arterial blood oxygen concentration, [O2]SA = 200 mL/L; pulmonary arterial blood oxygen concentration, [O2]PA = 140 mL/L; total body oxygen consumption, VO2 = 600 mL/min. A) 10 L/min that is normal for mild exercise B) 10 L/min that is abnormally low at rest C) 6 L/min that is close to a normal resting value D) 0.6 L/min that is abnormally low at rest E) 60 L/min that is impossible for normal individuals 4. Your patient takes a drug that decreases AV nodal action potential conduction velocity. The direct effect of this drug will be seen on the ECG as A) a decrease in QRS-wave frequency. B) an increase in P-wave amplitude. C) an increase in the PR interval. D) a widening of the QRS interval. E) an increase in the ST-segment duration.

5. Your patient’s ECG shows that R-wave amplitude on leads I and aVF is upright and equally large. Which of the following statements is true? A) This indicates a significant left electrical axis deviation. B) The mean electrical axis is +90°. C) The R-wave amplitude will be smallest on lead aVL. D) The R-wave amplitude will be positive on lead aVR. E) The left ventricle is hypertrophied.

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26 C

Peripheral Vascular System David E. Mohrman and Lois Jane Heller

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Define convective transport and diffusion and list the factors that determine the rate of each. Given data, use the Fick principle to calculate the rate of removal of a solute from blood as it passes through an organ. Describe how capillary wall permeability to a solute is related to the size and lipid solubility of the solute. List the factors that influence transcapillary fluid movement and, given data, predict the direction of transcapillary fluid movement. Describe the lymphatic vessel system and its role in preventing fluid accumulation in the interstitial space. Given data, calculate the vascular resistances of networks of vessels arranged in parallel and in series. Describe differences in the blood flow velocity in the various segments and how these differences are related to their total cross-sectional area. Describe laminar and turbulent flow patterns and the origin of flow sounds in the cardiovascular system. Identify the approximate percentage of the total blood volume that is contained in the various vascular segments in the systemic circulation. Define peripheral venous pool and central venous pool. Describe the pressure changes that occur as blood flows through a vascular bed and relate them to the vascular resistance of the various vascular segments. State how the resistance of each consecutive vascular segment contributes to an organ’s overall vascular resistance and, given data, calculate the overall resistance. Define total peripheral resistance (systemic vascular resistance) and state the relationship between it and the vascular resistance of each systemic organ. Define vascular compliance and state how the volume–pressure curves for arteries and veins differ. Predict what will happen to venous volume when venous smooth muscle contracts or when venous transmural pressure increases. Describe the role of arterial compliance in storing energy for blood circulation.

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Describe the auscultation technique of determining arterial systolic and diastolic pressures. Identify the physical bases of the Korotkoff sounds. Indicate the relationship between arterial pressure, cardiac output, and total peripheral resistance and predict how arterial pressure will be altered when cardiac output and/or total peripheral resistance change. Given arterial systolic and diastolic pressures, estimate mean arterial pressure. Indicate the relationship between pulse pressure, stroke volume, and arterial compliance and predict how pulse pressure will be changed by changes in stroke volume, or arterial compliance. Describe how arterial compliance changes with age and how this affects arterial pulse pressure.

OVERVIEW OF THE PERIPHERAL VASCULAR SYSTEM Homeostasis implies that each and every cell in the body is continuously bathed in a local environment of constant composition that is optimal for cell function. In essence, the peripheral vascular system is a sophisticated irrigation system. Blood flow is continuously delivering nutrients to and removing waste products from the local interstitial environment throughout the body. The heart supplies the pumping power required to create flow through the system. Because of the heart’s action, pressure at the inlet (the aorta) of the vascular network is higher than that at its outlets (the vena cavae). Everywhere within the vascular system, blood always flows from higher pressure to lower pressure according to well-known physical rules. Like water flowing downhill, blood seeks to travel along the path of least resistance. Consequently, the peripheral vascular system changes the resistance of its various pathways to direct blood flow to where it is needed. This chapter begins with a description of the mechanisms responsible for the transport of dissolved substances through the vascular system and the movement of these substances and fluid from capillaries to and from the interstitial space. Next, the basic equation for flow though a single vessel (Q = ΔP/R, presented in Chapter 22) is applied to the complex network of branching vessels that actually exists in the cardiovascular system. Then, the consequences of the elastic properties of the large diameter arteries and veins on overall cardiovascular system operation are considered. Finally, the principles of the routine clinical measurement of arterial blood pressure are presented along with the conclusions about overall cardiovascular function that can be made from the information.

CARDIOVASCULAR TRANSPORT THE FICK PRINCIPLE Substances are carried between organs within the cardiovascular system by the process of convective transport, the simple process of being swept along with the flow of the blood in which they are contained. The rate at which a substance (X) is transported by this process depends solely on the concentration of the substance in the blood and the blood flow: Transport rate = Flow × Concentration or . . X = Q [X]

(1) . . where X is the rate of transport of X (mass/time), Q is the blood flow (volume/time), and [X] is the concentration of X in blood (mass/volume). It is evident from the preceding equation that only two methods are available for altering the rate at which a substance is carried to an organ: (1) a change in the blood flow through the organ or (2) a change in the arterial blood concentration of the substance. The preceding equation might be used, for example, to calculate how much oxygen is carried to a certain skeletal muscle each minute. Note, however, that this calculation would not indicate whether the muscle actually used the oxygen carried to it. One can extend the convective transport principle to determine a tissue’s rate of utilization (or production) of a substance by simultaneously considering the transport rate of the substance to and from the tissue. The relationship that results is referred to as the Fick principle and may be formally stated as follows: . . Xtc= Q ([X]a − [X]v) (2)

CHAPTER 26 Peripheral Vascular System . . where X tc is the transcapillary efflux rate of X (mass/time), Q the blood flow (volume/time), and [X]a,v the arterial and venous concentrations of X. The Fick principle demonstrates that the amount of a. substance that goes into an organ in a given . period of time (Q[X]a) minus the amount that comes out (Q [X]v) must equal the tissue utilization rate of that substance. (If the tissue is producing substance X, then the above equation will yield a negative utilization rate.) Recall that one method for determining cardiac output (CO) described in Chapter 25 used the Fick principle to calculate the blood flow through the systemic circulation. In that case, the known variables included the systemic tissue oxygen consumption rate and the concentrations of oxygen in arterial blood and mixed venous blood and the. above equation was rearranged to solve for the blood flow (Q ).

TRANSCAPILLARY SOLUTE DIFFUSION Capillaries act as efficient exchange sites where most substances cross the capillary walls by passively diffusing from regions of high concentration to regions of low concentration (see Chapter 1). There are four factors that determine the diffusion rate of a substance between the blood and the interstitial fluid: (1) the concentration difference, Δ[X], (2) the surface area for exchange, A, (3) the diffusion distance, ΔL, and (4) the permeability of the capillary wall to the diffusing substance represented as the diffusion coefficient, D. These factors are combined in an equation (Fick’s first law of diffusion) that . describes the diffusion (X d) of a substance X across a barrier: . Δ[X] Xd= DA ____ (3) ΔL

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Capillary beds allow huge amounts of materials to enter and leave blood because they maximize the area across which exchange can occur while minimizing the distance over which the diffusing substances must travel. Capillaries are extremely fine vessels with a lumen (inner) diameter of about 5 μm, a wall thickness of approximately 1 μm, and an average length of perhaps 0.5 mm. (For comparison, a human hair is roughly 100 μm in diameter.) Capillaries are distributed in incredible numbers in organs and communicate intimately with all regions of the interstitial space. It is estimated that there are about 1010 capillaries in the systemic organs with a collective surface area of about 100 m2. That is roughly the area of one player’s side of a singles tennis court. Recall from Chapter 22 that most cells are no more than about 10 μm (less than one tenth the thickness of paper) from a capillary. Diffusion is a tremendously powerful mechanism for material exchange when operating over such a short distance and through such a large area. We are far from being able to duplicate—in an artificial lung or kidney, for example—the favorable geometry for diffusional exchange that exists in our own tissues. As diagrammed in Figure 26–1, the capillary wall itself consists of only a single thickness of endothelial cells joined to form a tube. The ease with which a particular solute crosses the capillary wall is expressed in a parameter called its capillary permeability. Permeability takes into account all the factors (diffusion coefficient, diffusion distance, and surface area)—except concentration difference—that affect the rate at which a solute crosses the capillary wall. Two fundamentally distinct pathways exist for transcapillary exchange. Lipid-soluble substances, such as the gases oxygen and carbon dioxide, cross the capillary wall easily. Because the lipid endothelial cell plasma membranes are not a significant diffusion barrier for lipid-soluble substances, transcapillary

Interstitium

Water-filled channels

Endothelial cell 1 μ m thick Plasma

Cytoplasm Plasma membranes

40 Å

Na+, K+ Cl– , H2O, glucose

O2, CO2, ethanol

Proteins Small water-soluble substances

Lipid-soluble substances

FIGURE 26–1 Pathways for transcapillary solute diffusion. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

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SECTION V Cardiovascular Physiology

movement of these substances can occur through the entire capillary surface area. The capillary permeability to small polar particles such as sodium and potassium ions is about 10,000-fold less than that for oxygen. Nevertheless, the capillary permeability to small ions is several orders of magnitude higher than the permeability that would be expected if the ions were forced to move through the lipid plasma membranes. It is therefore postulated that capillaries are somehow perforated at intervals with waterfilled channels or pores (which may actually be clefts between the endothelial cells). Calculations from diffusion data indicate that the collective cross-sectional area of the pores relative to the total capillary surface area varies greatly between capillaries in different organs. Brain capillaries appear to be very tight (have few pores), whereas capillaries in the kidney and fluid-producing glands are much more leaky. On the average, however, pores constitute only a very small fraction of total capillary surface area—perhaps 0.01%. This area is, nevertheless, sufficient to allow very rapid equilibration of small watersoluble substances between the plasma and interstitial fluids of most organs. Thus, the concentrations of inorganic ions measured in a plasma sample can be taken to indicate their concentrations throughout the entire extracellular space. In general, albumin and other large plasma proteins cannot easily cross capillary walls. The precise mechanism for the low capillary permeability to proteins is in dispute. One hypothesis is that capillary pores are just physically smaller than the diameter of plasma protein molecules. Whatever the mechanism(s), the result is that much higher protein concentrations normally exist in blood plasma than in interstitial fluid.

ENDOTHELIAL CELLS In addition to forming capillaries, a layer of endothelial cells lines the entire cardiovascular system—including the heart chambers and valves. Because of their ubiquitous and intimate contact with blood, endothelial cells have evolved to serve many functions in addition to acting as a barrier to transcapillary solute and water exchange. For example, endothelial cell membranes contain specific enzymes that convert some circulating hormones from inactive to active forms. Endothelial cells are also intimately involved in producing substances that lead to blood clot formation and the stemming of bleeding in the event of tissue injury. Moreover, and as will be discussed in the next chapter, the endothelial cells lining muscular vessels such as arterioles can produce vasoactive substances that act on the smooth muscle cells that surround them to influence arteriolar diameter.

important for a host of physiological functions, including the maintenance of circulating blood volume, intestinal fluid absorption, tissue edema formation, and saliva, sweat, and urine production. Net fluid movement out of capillaries is referred to as filtration, and fluid movement into capillaries is called reabsorption. Fluid flows through transcapillary channels in response to pressure differences between the interstitial and intracapillary fluids according to the basic flow equation. However, both hydrostatic and osmotic pressures influence transcapillary fluid movement. How hydrostatic pressure provides the driving force for causing blood flow along vessels has been discussed previously. The hydrostatic pressure inside capillaries, Pc, is about 25 mm Hg and is the driving force that causes blood to return to the right heart from the capillaries of systemic organs. In addition, however, the 25-mm Hg hydrostatic intracapillary pressure tends to cause fluid to flow through the transcapillary pores into the interstitium where the hydrostatic pressure (Pi) is near 0 mm Hg. Thus, there is normally a large hydrostatic pressure difference favoring fluid filtration across the capillary wall. Our entire plasma volume would soon be in the interstitium if there were not some counteracting force tending to draw fluid into the capillaries. The balancing force is an osmotic pressure that arises from the fact that plasma has a higher protein concentration than interstitial fluid. Recall that water always tends to move from regions of low to regions of high total solute concentration in establishing osmotic equilibrium. Also recall that the driving force for osmotic water movement between one solution and another can be expressed as an osmotic pressure difference between the two. The osmotic pressure difference is directly related to the difference in total solute concentration in the two solutions in question. Because plasma and interstitial fluid are essentially identical except for their protein concentrations, plasma proteins are primarily responsible for the net osmotic pressure difference across capillary walls. The component of total osmotic pressure due to proteins has been given the special name, oncotic pressure (or colloid osmotic pressure). Because of plasma proteins, the oncotic pressure of plasma (πc) is about 25 mm Hg. Due to the absence of proteins, the oncotic pressure of the interstitial fluid (πi) is near 0 mm Hg. Thus, there is normally a large osmotic force for fluid reabsorption into capillaries. The forces that influence transcapillary fluid movement are summarized on the left side of Figure 26–2. The relationship among the factors that influence transcapillary fluid movement, known as the Starling hypothesis, can be expressed by the following equation: Net filtration rate = k[(Pc − Pi) − (πc − πi)]

TRANSCAPILLARY FLUID MOVEMENT In addition to providing a diffusion pathway for polar molecules, the water-filled channels that traverse capillary walls permit fluid flow through the capillary wall. Net shifts of fluid between the capillary and interstitial compartments are

(4)

where Pc is the hydrostatic pressure of intracapillary fluid, πc the oncotic pressure of intracapillary fluid, Pi and πi the hydrostatic and oncotic pressures for interstitial fluid, respectively, and k a constant expressing how readily fluid can move across capillaries (essentially the reciprocal of the resistance to fluid flow through the capillary wall).

CHAPTER 26 Peripheral Vascular System

Interstitium

Endothelial cell

Plasma Hydrostatic Pi

Pc

Osmotic πi

Net fluid filtration Pc – Pi > πc – πi

πc

No net movement Pc – Pi = πc – πi

Net fluid reabsorption Pc – Pi < πc – πi

FIGURE 26–2 Factors influencing transcapillary fluid movement. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

Fluid balance within a tissue (the absence of net transcapillary water movement) occurs when the bracketed term in this equation is zero. This equilibrium may be upset by alterations in any of the four pressure terms. The pressure imbalances that cause capillary filtration and reabsorption are indicated on the right side of Figure 26–2. In most tissues, rapid net filtration of fluid is abnormal and causes tissue swelling as a result of excess fluid in the interstitial space (edema). For example, a substance called histamine is often released in damaged tissue. One of the actions of histamine is to increase capillary permeability to the extent that proteins leak into the interstitium. Net filtration and edema accompany histamine release, in part because the oncotic pressure difference (πc – πi) is reduced below normal. Transcapillary fluid filtration is not always detrimental. Indeed, fluid-producing organs such as salivary glands and kidneys utilize high intracapillary hydrostatic pressure to produce continuous net filtration. Moreover, in certain abnormal situations, such as severe loss of blood volume through hemorrhage, the net fluid reabsorption accompanying diminished intracapillary hydrostatic pressure helps restore the volume of circulating fluid.

LYMPHATIC SYSTEM Despite the extremely low capillary permeability to proteins, these molecules as well as other large particles such as long-chain fatty acids and bacteria find their way into the interstitial space. If such particles are allowed to accumulate in the interstitial space, filtration forces will ultimately exceed reabsorption forces and edema will result. The lymphatic system represents a pathway by which large molecules reenter the circulating blood.

255

The lymphatic system begins in the tissues with blind-end lymphatic capillaries that are roughly equivalent in size to but less numerous than regular capillaries. These capillaries are very porous and easily collect large particles accompanied by interstitial fluid. This fluid, called lymph, moves through the converging lymphatic vessels, is filtered through lymph nodes where bacteria and particulate matter are removed, and reenters the circulatory system through the thoracic duct near the point where the blood enters the right heart. Flow of lymph from the tissues toward the entry point into the circulatory system is promoted by (1) increases in tissue interstitial pressure (due to fluid accumulation or to movement of surrounding tissue), (2) contractions of the lymphatic vessels, and (3) valves located in these vessels to prevent backward flow. Roughly 2.5 L of lymphatic fluid enters the cardiovascular system each day. In the steady state, this indicates a total body net transcapillary fluid filtration rate of 2.5 L per day. When compared with the total amount of blood that circulates each day (about 7,000 L), this may seem like an insignificant amount of net capillary fluid leakage. However, lymphatic blockage is a very serious problem and is accompanied by severe swelling (lymphedema). Thus, the lymphatics play a critical role in keeping the interstitial protein concentration low and in removing excess capillary filtrate from the tissues.

BASIC VASCULAR FUNCTION RESISTANCE AND FLOW IN NETWORKS OF VESSELS In. Chapter 22, it was asserted that the basic flow equation (Q =ΔP/R) may be applied to networks of tubes as well as to individual tubes. The reason is that any network of resistances, however complex, can always be reduced to a single “equivalent” resistor that relates the total flow through the network to the pressure difference across the network. To do so, one must make use of the two equations below for series (one after another) and parallel (side-by-side) networks of individual vessels. When vessels with individual resistances R1, R2, …, Rn are connected in series, the overall resistance of the network is given by the following formula: Rs = R1 + R2 + … + Rn

(5)

Figure 26–3A shows an example of three vessels connected in series between some region where the pressure is Pi and another region with a lower pressure Po, so that the total pressure difference across the network, ΔP, is equal to Pi – Po. By the series resistance equation, the total resistance across this network (Rs) is equal to R1 + R2 + R3. By . the basic flow equation, the flow through the network. (Q ) is equal to ΔP/Rs. It should be intuitively obvious that Q is also the flow (volume/ time) through each of the elements in the series as indicated in Figure 26–3B. (Fluid particles may move with different

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SECTION V Cardiovascular Physiology

velocities [distance/time] in different elements of a series network, but the volume that passes through each element in a minute must be identical.) As shown in Figure 26–3C, a portion of the total pressure decrease across the network occurs within each element of the series. The pressure decrease across any element in the series can be calculated by applying . the basic flow equation to that element, for example, ΔP1 = Q R1. Note that the largest portion of the overall pressure decrease will occur across the element in the series with the largest resistance to flow (R2 in Figure 26–3). As indicated in Figure 26–4, when several tubes with individual resistances R1, R2, …, Rn are brought together to form a parallel network of vessels, one can calculate a single overall resistance for the parallel network Rp according to the following formula: 1 __ 1 1 __ = 1 + __ + … + __ Rp R1 R2 Rn

A

R1

R3

R2

Pi

P0

Q

b

a

c

d

Rs = R1 + R2 + R3 ΔP• = Pi − P0 Q = ΔP/Rs B

•

Flow

Q

a

d 70

C

(6)

c b Position along network

Pi

•

ΔP1 =Q ·R1

The total flow through a parallel network is determined by ΔP/Rp. As the preceding equation implies, the overall resistance of any parallel network will always be less than that of any of the elements in the network. (In the special case where the individual elements that form the network have identical resistances Rx, the overall resistance of the network is equal to the resistance of an individual element divided by the number (n) of parallel elements in the network: Rp = Rx/n.) In general, the more parallel elements that occur in the network, the lower the overall resistance of the network. Thus, for example, a capillary bed that consists of many individual capillary vessels in parallel can have a very low overall resistance to flow even though the resistance of a single capillary is relatively high. As indicated in Figure 26–4, the basic flow equation may be applied to any single element in the network or to the network as a whole. For example, the flow through only the first element . . of the network (Q 1) is given by Q 1 = ΔP/R1 , whereas the flow . through the entire parallel network is given by Qp = ΔP/Rp .

•

ΔP

Pressure

ΔP2 =Q ·R2 •

ΔP3 =Q ·R3 P0

a

FIGURE 26–3

b c Position along network

d

A–C) Series resistance network. (Modified with

permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

PERIPHERAL BLOOD FLOW VELOCITIES It is important to make the distinction between blood flow (volume/time) and blood flow velocity (distance/time) in the peripheral vascular system. Linear velocity of flow at any point

•

Q1 = ΔP/R1

R1

Pi

•

Q2 = ΔP/R2

R2

P0

•

R3

Q3 = ΔP/R3 1 1 1 1 = + + Rp R1 R2 R3 ΔP = Pi − P0 •

•

•

•

Qtotal = Q1 + Q2 + Q3 •

Qtotal = ΔP/Rp

FIGURE 26–4

Parallel resistance network. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange

Medical Books/McGraw-Hill, 2006.)

CHAPTER 26 Peripheral Vascular System

across the tube as shown on the left side of Figure 26–6. Velocity is fastest along the central axis of the tube and falls to zero at the wall. The concentric layers of fluid with different velocities slip smoothly over one another. Little mixing occurs between fluid layers so that individual particles move in straight streamlines parallel to the axis of the flow. Laminar flow is very efficient because little energy is wasted on anything but producing forward fluid motion. Because blood is a viscous fluid, its movement through a vessel exerts a shear stress on the walls of the vessel. This is a force that wants to drag the inside surface (the endothelial cell layer) of the vessel along with the flow. The endothelial cells that line a vessel are able to sense (and possibly respond to) changes in the rate of blood flow through the vessel by detecting changes in the shear stress on them. Shear stress may also be an important factor in certain pathological situations. For example, atherosclerotic plaques tend to form preferentially near branches of large arteries where, for complex hemodynamic reasons beyond the scope of this text, high shear stresses exist. When blood is forced to move with too high a velocity through a narrow opening, the normal laminar flow pattern may break down into the turbulent flow pattern shown on the right side of Figure 26–6. With turbulent flow, there is much internal mixing and friction. When the flow within a vessel is

is equal to the flow divided by the cross-sectional area. Consider the analogy of a stream whose water moves with greater velocity through shallow rapids than it does through an adjacent deep pool. The volume of water passing through the pool in a day (volume/time = flow), however, must equal that passing through the rapids in the same day. In such a series arrangement, the flow is the same at all points along the channel but the flow velocity varies inversely with the local cross-sectional area. The situation is the same in the peripheral vasculature, where blood flows most rapidly in the region with the smallest total cross-sectional area (the aorta) and most slowly in the region with the largest total cross-sectional area (the capillary beds). Regardless of the differences in velocity, when the CO (flow into the aorta) is 5 L/min, the flow through the systemic capillaries (or arterioles, or venules) is also 5 L/min. The changes in flow velocity that occur as blood passes through the peripheral vascular system are shown in the top trace of Figure 26–5. The important consequence of this slow flow through the capillaries is that it allows sufficient time for adequate solute and fluid exchange between the vascular and interstitial compartments. Blood normally flows through all vessels in the cardiovascular system in an orderly streamlined manner called laminar flow. With laminar flow, there is a parabolic velocity profile

Arteries

Arterioles

257

Capillaries

Venules and veins

500 mm/s

Flow velocity 0.5 mm/s

Blood volume 60% 12%

5%

2%

Systolic Mean 100 mm Hg 25 mm Hg Diastolic blood pressure

Vascular resistance

FIGURE 26–5 Flow velocities, blood volumes, blood pressures, and vascular resistances in the peripheral vasculature from aorta to right atrium. Approximately 20% of the total volume is contained in the pulmonary system and the heart chambers and is not accounted for in this figure. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

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SECTION V Cardiovascular Physiology

Streamlines

FIGURE 26–6

Velocity profile

Laminar and turbulent flow patterns. Turbulent flow

(Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

Laminar flow

turbulent, the resistance to flow is significantly higher than that predicted from the Poiseuille equation given in Chapter 22. Turbulent flow also generates sound, which can be heard with the aid of a stethoscope. Cardiac murmurs, for example, are manifestations of turbulent flow patterns generated by cardiac valve abnormalities. Detection of sounds from peripheral arteries (bruits) is abnormal and usually indicates a pathological reduction of a large vessel’s cross-sectional area or an abnormally high blood flow through an organ.

waves (traveling back toward the heart) caused by discontinuities such as branching points in the arterial system. A large pressure drop occurs in the arterioles, where the pulsatile nature of the pressure also nearly disappears. The average capillary pressure is approximately 25 mm Hg. Pressure continues to decrease in the venules and veins as blood returns to the right heart. The central venous pressure (which is the filling pressure for the right heart) is normally very close to 0 mm Hg.

PERIPHERAL BLOOD VOLUMES

PERIPHERAL VASCULAR RESISTANCES

The second trace in Figure 26–5 shows the approximate percentage of the total circulating blood volume that is contained in the different vascular regions of the systemic organs at any instant. Note that most of the circulating blood is contained within the veins of the systemic organs. This diffuse but large blood reservoir is often referred to as the peripheral venous pool. A second but smaller reservoir of venous blood, called the central venous pool, is contained in the great veins of the thorax and the right atrium. When peripheral veins constrict, blood is displaced from the peripheral venous pool and enters the central pool. An increase in the central venous volume, and thus pressure, enhances cardiac filling, which in turn augments stroke volume (SV) according to the Starling law of the heart. This is an extremely important mechanism of cardiovascular regulation and will be discussed in greater detail in Chapter 28.

The bottom trace in Figure 26–5 indicates the relative resistance to flow that exists in each of the consecutive vascular regions. Because arterioles have such a large vascular resistance in comparison to the other vascular segments, the overall vascular resistance of any organ is determined to a very large extent by the resistance of its arterioles. Arteriolar resistance is strongly influenced by arteriolar radius (R is proportional to 1/r4). Thus, the blood flow through an organ is primarily regulated by adjustments in the internal diameter of arterioles caused by contraction or relaxation of their muscular arteriolar walls. When the arterioles of an organ change diameter, not only does the flow to the organ change, but the manner in which the pressures decrease within the organ is also modified. The effects of arteriolar dilation and constriction on the pressure profile within a vascular bed are illustrated in Figure 26–7. Arteriolar constriction causes a greater decrease in pressure across the arterioles, and this tends to increase the arterial pressure while it decreases the pressure in capillaries and veins. Conversely, increased organ blood flow caused by arteriolar dilation is accompanied by decreased arterial pressure and increased capillary pressure. Because of the changes in capillary hydrostatic pressure, arteriolar constriction tends to cause transcapillary fluid reabsorption, whereas arteriolar dilation tends to promote transcapillary fluid filtration.

PERIPHERAL BLOOD PRESSURES Blood pressure decreases in the consecutive segments with the pattern shown in the third trace of Figure 26–5. Recall from Figure 24–1 that aortic pressure fluctuates between a systolic and a diastolic value with each heartbeat, and the same is true throughout the arterial system. The average pressure in the arch of the aorta, however, is about 100 mm Hg, and this mean arterial pressure decreases by only a small amount within the arterial system. As indicated in Figure 26–5, arterial pulse pressure actually increases with distance from the heart, a phenomenon referred to as peripheral peaking of pulse pressure. The hemodynamic reasons for this are very complex but involve the positive addition of primary pressure waves produced by the heart (that travel much faster than blood flow does) and reflected pressure

TOTAL PERIPHERAL RESISTANCE The overall resistance to flow through the entire systemic circulation is called the total peripheral resistance (TPR; sometimes called the systemic vascular resistance [SVR]). Because the systemic organs are generally arranged in parallel (see Figure 22–2), the vascular resistance of each organ contributes to the TPR according to the parallel resistance equation (6).

Distending pressure (mm Hg)

Blood pressure

CHAPTER 26 Peripheral Vascular System

Arteriolar dilation Normal

Arterial compartment 100

Arterioles

ΔP ΔV

50

D

Arteriolar constriction Arteries

Cons

Capillaries

0

Veins

FIGURE 26–7 Effect of changes in arteriolar resistance on vascular pressures. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

ELASTIC PROPERTIES OF ARTERIES AND VEINS Arteries and veins contribute only a small portion to the overall resistance to flow through a vascular bed. Therefore, changes in their diameters have no significant effect on the blood flow through systemic organs. The elastic behavior of arteries and veins is, however, very important to overall cardiovascular function because they can act as reservoirs and substantial amounts of blood can be stored in them. Arteries or veins behave more like balloons with one pressure throughout rather than as resistive pipes with a flowrelated pressure difference from end-to-end. Thus, think of an “arterial compartment” and a “venous compartment,” each with an internal pressure that is related to the volume of blood within it at any instant and how easily its walls can be stretched. This is characterized by a parameter called compliance (C; see Chapter 1) given as follows that describes how much its volume changes (ΔV) in response to a given change in distending pressure (ΔP), which is the difference between the internal and external pressures on the vascular walls: ΔV C = ___ ΔP

(7)

Volume–pressure curves for the systemic arterial and venous compartments are shown in Figure 26–8. It is apparent from the disparate slopes of the curves in this figure that the elastic properties of arteries and veins are very different. For the arterial compartment, the ΔV/ΔP measured near a normal operating pressure of 100 mm Hg indicates a compliance of about 2 mL/mm Hg. By contrast, the venous pool has a compliance of over 100 mL/mm Hg near its normal operating pressure of 5–10 mm Hg. Because veins are so compliant, even small changes in peripheral venous pressure can cause a significant amount of the circulating blood volume to shift into or out of the peripheral venous pool. Standing upright, for example, increases venous pressure in the lower extremities and promotes blood accumulation

259

d tricte Norma Volume

l

Venous compartment C

B ΔP

A

ΔV

FIGURE 26–8 Volume–pressure curves of arterial and venous compartments. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

(pooling) in these vessels as might be represented by a shift from point A to point B in Figure 26–8. Fortunately, this process can be counteracted by active venous constriction. The dashed line in Figure 26–8 shows the venous volume–pressure relationship that exists when veins are constricted by activation of venous smooth muscle. In constricted veins, volume may be normal (point C) or even below normal (point D) despite greater-thannormal venous pressure. Peripheral venous constriction tends to increase peripheral venous pressure and shift blood out of the peripheral venous compartment. The elasticity of arteries allows them to act as a reservoir on a beat-to-beat basis. Arteries play an important role in converting the pulsatile flow output of the heart into a steady flow through the vascular beds of systemic organs. During the early rapid phase of cardiac ejection, the arterial volume increases because blood is entering the aorta more rapidly than it is passing into systemic arterioles. Thus, part of the work the heart does in ejecting blood goes to stretching the elastic walls of arteries. Toward the end of systole and throughout diastole, arterial volume decreases because the flow out of arteries exceeds flow into the aorta. Previously stretched arterial walls recoil to shorter lengths, and in the process give up their stored potential energy. This reconverted energy is what actually does the work of propelling blood through the peripheral vascular beds during diastole. If arteries were rigid tubes that could not store energy by expanding elastically, arterial pressure would fall immediately to zero with the termination of each cardiac ejection.

MEASUREMENT OF ARTERIAL PRESSURE Recall that the systemic arterial pressure fluctuates with each heart cycle between a diastolic value (PD) and a higher systolic value (PS). Obtaining estimates of an individual’s systolic and

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SECTION V Cardiovascular Physiology

diastolic pressures is one of the most routine diagnostic techniques available to the clinician. The basic principles of the auscultation technique used to measure blood pressure are described as follows with the aid of Figure 26–9: 1. An inflatable cuff is wrapped around the upper arm, with a recording device attached to monitor the pressure within the cuff. The cuff is initially inflated with air to a pressure (usually 175–200 mm Hg) that is well above normal systolic values. This pressure collapses all blood vessels under the cuff. 2. After initial inflation, air is gradually “bled” from the cuff so that the pressure within it decreases slowly and steadily through the range of arterial pressure fluctuations. 3. The moment cuff pressure decreases below peak systolic arterial pressure, some blood is able to pass beneath the cuff during the systolic phase of the cycle. Because the flow through these partially compressed vessels is intermittent and turbulent, tapping sounds can be detected with a stethoscope placed over the radial artery at the elbow. As indicated in Figure 26–9, sounds of varying character, known collectively as Korotkoff sounds, are heard whenever the cuff pressure is between the systolic and diastolic arterial pressures. The highest cuff pressure at which tapping sounds are heard is taken as the systolic arterial pressure. 4. When the cuff pressure decreases below the diastolic pressure, blood flows through the vessels beneath the cuff without periodic interruption and again no sound is detected over the radial artery. The cuff pressure at which the sounds become muffled or disappear is taken as the diastolic arterial pressure.

DETERMINANTS OF ARTERIAL PRESSURE MEAN ARTERIAL PRESSURE Mean arterial pressure is a critically important cardiovascular variable because it is the average effective pressure that drives

blood through the systemic organs. One of the most fundamental equations of cardiovascular physiology is that which indi– cates how mean arterial pressure (Pa) is related to CO and TPR: – Pa = CO × TPR (8) The above equation is simply a rearrangement of the basic . flow equation Q = ΔP /R applied to the entire systemic circulation with the single assumption that central venous pressure is – approximately zero so that ΔP = Pa . Note that mean arterial pressure is influenced both by the heart (via CO) and by the peripheral vasculature (via TPR). All changes in mean arterial pressure result from changes in either CO or TPR. Calculating the true value of mean arterial pressure requires mathematically averaging the arterial pressure waveform over one or more complete heart cycles. Most often, however, we know from auscultation only the systolic and diastolic pressures, yet wish to make some estimate of the mean arterial pressure. Mean arterial pressure necessarily falls between the systolic and diastolic pressures. A useful rule of thumb is that – mean arterial pressure (Pa) is approximately equal to diastolic pressure (PD) plus one third of the difference between systolic and diastolic pressures (PS – PD).

ARTERIAL PULSE PRESSURE The arterial pulse pressure (Pp) is defined simply as systolic pressure minus diastolic pressure (PS – PD). To be able to use pulse pressure to deduce something about how the cardiovascular system is operating, one must do more than just define it. It is important to understand what determines pulse pressure, that is, what causes it to be what it is and what can cause it to change. In a previous section of this chapter, there was a brief discussion about how, as a consequence of the compliance of the arterial vessels, arterial pressure increases as arterial blood volume is expanded during cardiac ejection. The magnitude of the pressure increase (ΔP) caused by an increase in arterial volume depends on how large the volume change (ΔV) is and on how compliant (Ca) the arterial compartment is: ΔP = ΔV/Ca. If, for the moment, the fact that some blood leaves the arterial com-

Cuff pressure Arterial pressure A mm Hg

120

80 B

FIGURE 26–9 Blood pressure measurement by auscultation. Point A indicates systolic pressure and point B indicates diastolic pressure. (Modified with

Lou

der

fter

So

permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

No sound

Korotkoff sounds

No sound

CHAPTER 26 Peripheral Vascular System partment during cardiac ejection is neglected, then the increase in arterial volume during each heartbeat is equal to the SV. Thus, pulse pressure is, to a first approximation, equal to SV divided by arterial compliance: SV ___ Pp ∼ − C

(9)

Arterial pulse pressure is about 40 mm Hg in a normal resting young adult because SV is about 80 mL and arterial compliance is about 2 mL/mm Hg. Pulse pressure tends to increase with age in adults because of a decrease in arterial compliance (and increase in arterial stiffness also referred to as “hardening of the arteries” or arteriosclerosis. This differs from atherosclerosis which involves deposition of fat in the vessel wall). Arterial volume–pressure curves for a 20- and a 70-year-old are shown in Figure 26–10. The increase in arterial stiffness with age is indicated by the steeper curve for the 70-year-old (more ΔP for a given ΔV) than for the 20-year-old. Thus, a 70-year-old will necessarily have a larger pulse pressure for a given SV than a 20-year-old. As indicated in Figure 26–10, the increase in arterial stiffness is sufficient to cause increased pulse pressure even though SV tends to decrease with age (Also see Figure 73–1). Figure 26–10 also illustrates the fact that arterial blood volume and mean arterial pressure tend to increase with age. The increase in mean arterial pressure is not caused by the decreased arterial compliance, however, because compliance changes do not directly influence either CO or TPR, which are the sole – determinants of Pa. Mean arterial pressure tends to increase with age because of an age-dependent increase in TPR that is controlled primarily by arterioles, not arteries. Arterial compliance also decreases with increasing mean arterial pressure as evidenced by the curvature of the volume– pressure relationships shown in Figure 26–10. Otherwise, arterial compliance is a relatively stable parameter. Thus, most acute changes in arterial pulse pressure are the result of changes

261

in SV. Changes in TPR, however, have little or no effect on pulse pressure, because a change in TPR causes parallel changes in both systolic and diastolic pressures. A common misconception in cardiovascular physiology is that the systolic pressure alone or the diastolic pressure alone indicates the status of a specific cardiovascular variable. The reader should not attempt to interpret systolic and diastolic pressure values independently. Interpretation is much more straightforward when the focus is on mean arterial pressure – (Pa = CO × TPR) and arterial pulse pressure (Pp ∼ − SV/Ca).

CLINICAL CORRELATION A 27-year-old woman comes to the clinic because of the overnight onset of a pain in her left leg and swelling in her left ankle and foot. She describes the pain as a cramping sort of deep ache. She had returned to the United States yesterday on a 12-hour flight from Brazil where she had spent several weeks on an expedition to the rain forests. She takes no drugs except birth control pills containing estrogen (see Chapter 68). She is 1.73-m tall and weighs 93 kg. Vital signs are all within normal ranges. On examination, it is noted that her left lower leg is sensitive to touch and her left foot feels warmer than her right. Furthermore, there is edema with her left ankle and foot significantly swollen compared to her right. The symptoms suggest that there is an imbalance between filtration and absorptive forces at work in the capillaries of the lower left leg. Because these symptoms are restricted to one leg and not both, overall circulatory abnormalities that might cause ankle edema can be eliminated (e.g., decreased

Arterial pressure (mm Hg)

200

20-year-old

ΔP

ΔP

100 ΔV

0

FIGURE 26–10

70-year-old

ΔV

Arterial volume

Effect of age on systemic arterial volumes and pressures and arterial stiffness. (Modified with permission from Mohrman DE,

Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

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plasma proteins which would decrease plasma oncotic pressure; or right-sided heart failure, liver or kidney disease which would increase fluid retention and peripheral venous pressure). Local factors that might cause fluid to accumulate in the interstitial space could include situations that either prevent lymphatic drainage of this space (i.e., lymphedema from tropical pathogenic filarial parasites) or increase hydrostatic pressure in the veins draining the tissue. Because of the rapid onset and symptoms, it is much more likely that a clot has formed in one of the large veins draining her left leg (deep vein thrombosis [DVT]) that has increased the upstream capillary hydrostatic pressure, and caused the pain, filtration of fluid out of the vascular space, and edema of the tissue. Being overweight and taking birth control pills containing estrogens are risk factors that predispose this woman toward the development of such a clot. In addition, a long period of time spent in a sitting position without moving her legs (as might have occurred on her long airplane ride) allows blood to pool in these lower extremities and is an added risk factor for DVT or inflammation of the more superficial veins (thrombophlebitis). In addition to the localized discomfort, there is the real danger that these clots can become dislodged from their anchorage in the leg vein, travel to the heart as an embolus, and become lodged in the lungs (pulmonary embolism). This can be a life-threatening event and requires immediate treatment. Doppler ultrasonic examination of the patient’s leg revealed the presence of DVT and she was treated with an anticoagulant (heparin at first and then warfarin) as well as drugs that can help dissolve clots. It is also possible that this patient has an increased tendency to form clots (i.e., she is hypercoagulable) in part due to being overweight. There are some inherited forms of hypercoagulability that she and her blood relatives can be tested for. It is possible that she will require lifelong treatment with anticlotting drugs. Finally, she will be encouraged to switch to a different birth control method, as estrogens can increase the tendency to form clots.

CHAPTER SUMMARY ■

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Within the cardiovascular system, convection is used to transport substances between capillary beds and diffusion is used to transport substances between blood and tissue. Water may move out of (filtration) or into (reabsorption) capillaries depending on the net balance of hydrostatic and osmotic forces across capillary walls. Plasma proteins are responsible for the major osmotic force across capillary walls. Lymphatic vessels serve to remove excess filtrate from tissues and keep interstitial protein concentration low. The velocity of blood flow is indirectly proportional to the total cross-sectional area of the vascular segment and is slowest in capillaries.

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Turbulent blood flow is usually abnormal and makes noise (murmurs and bruits). Veins contain most of the total blood volume. Arterioles contribute most to the resistance to flow through organs. Arteriolar constriction tends to reduce flow through an organ, reduce capillary hydrostatic pressure, and promote transcapillary fluid reabsorption within the organ. Venous constriction is important for cardiac filling and the ability to cope with blood loss. Because arteries and arterioles are elastic, the intermittent flow from the heart is converted to continuous flow through capillaries. Mean systemic arterial pressure is determined by the product of CO and TPR. Changes in arterial pulse pressure reflect changes in SV and/or the compliance of the arterial space.

STUDY QUESTIONS 1. Determine the rate of glucose uptake by an exercising skeletal muscle from the following data: arterial blood (glucose) = 50 mg per 100 mL blood; muscle venous blood (glucose) = 30 mg per 100 mL blood; muscle blood flow = 60 mL/min. A) 3,000 mg/min B) 1,200 mg/min C) 30 mg/min D) 20 mL/mg E) 12 mg/min 2. Which of the following conditions favor net absorption of fluid out of the interstitial space and into the capillary bed within an organ? A) increased interstitial protein concentration B) venous clot C) decreased plasma protein concentration D) increased capillary pore size E) arteriolar constriction 3. Which of the following is consistent with a normal mean arterial pressure but an abnormally high arterial pulse pressure? A) low stroke volume B) high heart rate C) decreased total peripheral resistance D) increased arterial stiffness E) aortic valve stenosis 4. Which of the following substances is likely to move most easily across a skeletal muscle capillary wall? A) potassium B) glucose C) oxygen D) water E) albumin 5. In which of the following vessels do red cells move with the fastest speed (distance/time)? A) arteries B) arterioles C) capillaries D) venules E) veins

27 C

Vascular Control David E. Mohrman and Lois Jane Heller

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Define basal tone. List several substances potentially involved in local metabolic control of vascular tone. State the local metabolic vasodilator hypothesis. Describe how vascular tone is influenced by locally produced endothelial factors and chemicals such as prostaglandins, histamine, and bradykinin. Describe the myogenic response of blood vessels. Define active and reactive hyperemia and indicate a possible mechanism for each. Define autoregulation of blood flow and briefly describe the metabolic, myogenic, and tissue pressure theories of autoregulation. Define neurogenic tone and describe how sympathetic (and parasympathetic) neural influences can alter it. Describe how vascular tone is influenced by circulating catecholamines, vasopressin, and angiotensin II. List the major influences on the diameter of veins. Describe in general how control of blood flow differs between organs with strong local metabolic control of arteriolar tone and organs with strong neurogenic control of arteriolar tone. State the relative importance of local metabolic and neural control of coronary blood flow. Define systolic compression and indicate its relative importance to blood flow in the endocardial and epicardial regions of the right and left ventricular walls. Describe the major mechanisms of blood flow control in skeletal muscle and brain.

VASCULAR SMOOTH MUSCLE The cardiovascular system must adjust the diameter of its vessels to efficiently distribute the cardiac output among tissues with different current needs (the job of arterioles), and to regulate the distribution of blood volume and cardiac filling (the job of veins). Vascular diameter adjustments are made by regulating the con-

Ch27_263-274.indd 263

tractile activity of vascular smooth muscle cells, which are present in the walls of all vessels except capillaries. Vascular smooth muscle is unique because it must maintain its vessel diameter in the face of the continuous distending pressure of the blood within it, and therefore sustain active tension for prolonged periods. The basics of smooth muscle operation were presented in Chapter 11. Here the focus is on the functional consequences of

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influences on vascular smooth muscle that have particular relevance to the operation of the cardiovascular system. In general, these influences on vascular smooth muscle can be separated into those that originate locally (and therefore have only local consequences) and those that have global influences on vessels throughout the body. Examples of the latter are general changes in autonomic nerve activity and changes in the blood concentrations of hormones that affect vascular smooth muscle. Such influences have much different functional consequences on arterioles than on veins. Consequently, the operations of arterioles and veins are described separately in this chapter.

of basal tone is that it serves as a baseline from which arteriolar tone can be regulated, either increased or decreased as necessary to meet the needs of changing situations. Another important consequence is that the basal tone of arterioles throughout the body collectively contributes directly to the total peripheral resistance (TPR) and thus to arterial blood pressure in a resting individual.

VASCULAR TONE

The arterioles that control flow through a given organ lie within the organ tissue itself. Thus, arterioles and the smooth muscle in their walls are exposed to the chemical composition of the interstitial fluid of the organ they serve. The interstitial concentrations of many substances reflect the balance between the metabolic activity of the tissue and its blood supply. Interstitial oxygen levels, for example, decrease when cells are using oxygen faster than it is being supplied to the tissue by blood flow. Conversely, interstitial oxygen levels increase whenever more oxygen is delivered than is used by a tissue. In nearly all vascular beds, exposure to low oxygen reduces arteriolar tone and causes vasodilation, whereas high oxygen levels cause arteriolar vasoconstriction. Thus, a local feedback mechanism exists that automatically operates on arterioles to regulate blood flow to a tissue in accordance with its metabolic needs. Many substances in addition to oxygen are present within tissues and can affect the tone of vascular smooth muscle. When the metabolic rate of skeletal muscle is increased by exercise, for example, tissue levels of carbon dioxide, H+, and K+ increase. These chemical alterations cause arteriolar dilation. In addition, with increased metabolic activity or oxygen deprivation, cells in many tissues may release adenosine, which is a potent vasodilator agent. At present, it is not known which of these (or possibly other) metabolically related chemical alterations within tissues are most important in the local metabolic control of blood flow. It is likely that arteriolar tone depends on the combined action of many factors. Figure 27–1 summarizes current understanding of local metabolic control. Vasodilator factors enter the interstitial

Vascular tone is a term commonly used to characterize the general contractile state of a vessel or a vascular region. The “vascular tone” of a region can be taken as an indication of the “level of activation” of the individual smooth muscle cells in that region. An increase in arteriolar tone is automatically taken to imply a decrease in arteriolar vessel diameter, the functional consequences of which are an increase in arteriolar resistance and a decrease in flow. The primary functional consequence of an increase in venous tone is a decrease in venous volume and thus a peripheral-to-central shift of blood volume that increases cardiac filling.

CONTROL OF ARTERIOLAR TONE As described in Chapter 26, the blood flow through any organ is determined largely by its vascular resistance, which is dependent primarily on the diameter of its arterioles. Consequently, an organ’s flow is controlled by factors that influence the arteriolar smooth muscle tone.

BASAL TONE The arterioles in a healthy individual at rest have a certain level of basal tone that lies somewhere between complete relaxation and maximum possible constriction. A myriad of influences on arteriolar smooth muscle contribute collectively to the establishment of this basal tone. One important consequence

LOCAL INFLUENCES ON ARTERIOLES Local Metabolic Influences

Release proportional to tissue metabolism Tissue cells

Vasodilator factors

FIGURE 27–1

Local metabolic vasodilator

Removal rate proportional to blood flow

Blood flow

hypothesis. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

Arterioles

Capillaries

Veins

CHAPTER 27 Vascular Control space from the tissue cells at a rate proportional to tissue metabolism. These vasodilatory factors are removed from the tissue at a rate proportional to blood flow. Whenever tissue metabolism is at a rate for which the blood flow is inadequate, the interstitial vasodilator concentrations build up and cause the arterioles to dilate and blood flow to increase. The process continues until blood flow has increased sufficiently to appropriately match the tissue metabolic rate and prevent further accumulation of vasodilator factors. The same system also operates to reduce blood flow when it is greater than required by the tissue metabolic activity because the interstitial concentrations of metabolic vasodilator factors are decreased. Local metabolic mechanisms are usually the most important means of local blood flow control in most tissues. Individual organs are therefore able to regulate their own blood flow in accordance with their metabolic needs. As indicated below, there are several other types of local influences on blood vessels. However, many of these represent fine-tuning mechanisms and may be important only in certain, usually pathological, situations.

Local Nonmetabolic Influences An ever-increasing number of local factors unrelated to tissue metabolism have been shown to influence arterioles within an organ. Table 27–1 contains a list of some of these more important factors and summarizes some of the information about their actions. Many of these factors exert their vascular effects by action on endothelial cells. Thus, endothelial cells can actively participate in the control of arteriolar diameter by producing local chemicals that affect the tone of the surrounding smooth muscle cells. The vasodilatory influence produced by endothelial cells is mediated by nitric oxide (NO). NO is produced within endothelial cells from the amino acid, l-arginine, by the action of an enzyme, NO synthase, that is activated by an increase in the intracellular level of Ca2+. NO is a small lipid-soluble molecule that, once formed, easily diffuses into adjacent smooth muscle cells where it causes relaxation by stimulating cGMP production as mentioned in Chapter 11. Acetylcholine and several other agents (including bradykinin, vasoactive intestinal peptide, and substance P) stimulate endothelial cell NO production because their receptors on endothelial cells are linked to receptor-operated Ca2+ channels. Blood flow–related shear stresses on endothelial cells stimulate NO production through stretch-sensitive channels for Ca2+. This phenomenon may explain why exercise and increased blood flow through muscles of the lower leg can cause dilation of the bloodsupplying femoral artery at points far upstream from the exercising muscle itself.

Transmural Pressure The passive elastic mechanical properties of arteries and veins and how changes in transmural pressure affect their diameters were discussed in Chapter 26. The effect of transmural pressure on arteriolar diameter is actually more complex because arterioles respond both passively and actively to changes in

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transmural pressure. For example, a sudden increase in the internal pressure within an arteriole produces first an initial slight passive mechanical distention (slight because arterioles are relatively thick-walled and muscular), and second, an active constriction that, within seconds, may completely reverse the initial distention. A sudden decrease in transmural pressure elicits essentially the opposite response, that is, an immediate passive decrease in diameter followed shortly by a decrease in active tone that returns the arteriolar diameter to near that which existed before the pressure change. The active phase of such behavior is referred to as a myogenic response, because it seems to originate within the smooth muscle itself. The mechanism of the myogenic response is not known for certain, but stretch-sensitive ion channels on arteriolar vascular smooth muscle cells are likely candidates for involvement. All arterioles have some normal distending pressure to which they probably are actively responding. Therefore, the myogenic mechanism is likely to be a fundamentally important factor in determining the basal tone of arterioles everywhere. The myogenic response is potentially involved in the vascular reaction to any cardiovascular disturbance that involves a change in arteriolar transmural pressure, as will be discussed in the next section.

FLOW RESPONSES CAUSED BY LOCAL MECHANISMS In organs with a highly variable metabolic rate, such as skeletal and cardiac muscle, the blood flow closely follows the tissue metabolic rate. For example, skeletal muscle blood flow increases within seconds of the onset of muscle exercise and returns to control values shortly after exercise ceases. This phenomenon, which is illustrated in Figure 27–2A, is known as exercise or active hyperemia (hyperemia means high flow). It should be clear how active hyperemia could result from the local metabolic vasodilator feedback on arteriolar smooth muscle. As mentioned previously, once initiated by local metabolic influences on small resistance vessels, endothelial flow–dependent mechanisms may assist in propagating the vasodilation to larger vessels upstream, which helps promote the delivery of blood to the exercising muscle. Reactive or post-occlusion hyperemia is a greater-thannormal blood flow that occurs transiently after the removal of any restriction that has caused a period of lower-than-normal blood flow. The phenomenon is illustrated in Figure 27–2B. For example, flow through an extremity is greater than normal for a period after a tourniquet is removed from the extremity. Both local metabolic and myogenic mechanisms may be involved in producing reactive hyperemia. The magnitude and duration of reactive hyperemia depend on the duration and severity of the occlusion as well as the metabolic rate of the tissue. These findings are best explained by an interstitial accumulation of metabolic vasodilator substances during the period of flow restriction. However, unexpectedly large flow increases can follow arterial occlusions lasting only 1 or 2 seconds. These may be best explained by a myogenic dilation response to the

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TABLE 27–1 Local influences on vascular smooth muscle. Substance

Description

Vascular Response

Other Information

Nitric oxide (NO), endothelial-derived relaxing factor (EDRF)

From endothelial cells in response to: acetylcholine, vasoactive intestinal peptide, substance P, bradykinin, shear stress, others

Vasodilation

Basal release may reduce normal net resting tone of vascular smooth muscle locally throughout the body

Acetylcholine

Neurotransmitter—normal dilation mediated by NO

Vasodilation and/or vasoconstriction

Important local effects on GI circulation (from enteric plexus neurons)

-Constriction occurs when endothelium is absent/ damaged Vasoactive intestinal peptide (VIP)

Neurotransmitter (also a peptide hormone)—action is mediated by NO

Vasodilation

GI neurotransmitter from enteric plexus neuron, causes smooth muscle relaxation, promotes secretion in the gut

Substance P

Neurotransmitter—action is mediated by NO

Vasodilation

Important local roles in pain nociception, GI function, vomiting, skin circulation

Bradykinin

Polypeptide formed from plasma protein by action of enzyme, kallikrein—action is mediated by NO

Vasodilation

Shear stress

Action is mediated by NO

Vasodilation

Dependent on flow velocity

Endothelial-derived hyperpolarizing factor (EDHF)

Unknown factor from endothelial cells

Vasodilation

May be K+, cANP, electrogenic spread of hyperpolarization, other possible factors

Endothelin

Polypeptide from endothelial cells

Vasoconstriction

Basal release may reduce normal net resting tone of vascular smooth muscle locally in tissues throughout the body

Prostacyclin (PGI2)

Arachidonic acid (AA) metabolite of the cyclooxygenase (CO) pathway

Vasodilation

Inflammatory responses, blocked by cyclooxygenase inhibitors such as aspirin

Thromboxane

AA metabolite of the CO pathway (made by platelets)

Vasoconstriction

Important for platelet aggregation and blood clotting, also blocked by aspirin

Other prostaglandins

AA metabolites of the CO pathway

Vasoconstriction and/or vasodilation

Actions vary with the specific organ and local conditions

Leukotrienes

AA metabolites of the lipoxygenase pathway

Vasoconstriction and/or vasodilation

Increase vascular permeability during inflammatory responses

Histamine

Secretory granules of tissue mast cells and circulating basophils

Vasodilation

Leads to an increase in vascular permeability, edema formation

-Increases vascular permeability -Involved in pain mechanisms

-Involved in inflammatory and immune reactions

reduced intravascular pressure and decreased stretch of the arteriolar walls during the period of occlusion. Except when displaying active and reactive hyperemia, nearly all organs tend to keep their blood flow constant despite variations in arterial pressure—that is, they display autoregulation of blood flow. As shown in Figure 27–3A, an abrupt increase in arterial pressure is normally accompanied by an initial abrupt increase in organ blood flow that then gradually returns toward normal despite the sustained increase in arterial pressure. The initial increase in flow with increased pres˙ = Δ P / R). The sure is expected from the basic flow equation (Q subsequent return of flow toward the normal level is caused by a gradual increase in active arteriolar tone and resistance to blood flow. Ultimately, a new steady state is reached with only

slightly increased blood flow because the increased driving pressure is counteracted by a greater-than-normal vascular resistance. As with the phenomenon of reactive hyperemia, blood flow autoregulation may be caused by both local metabolic feedback mechanisms and myogenic mechanisms. The arteriolar vasoconstriction responsible for the autoregulatory response shown in Figure 27–3A, for example, may be partially due to (1) a “washout” of metabolic vasodilator factors from the interstitium by the excessive initial blood flow and (2) a myogenic increase in arteriolar tone stimulated by the increase in stretching forces that the increase in pressure imposes on the vessel walls. There is also a tissue pressure hypothesis of blood flow autoregulation for which it is assumed that an abrupt increase in arterial pressure causes transcapillary fluid

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267

A

Active hyperemia

Blood flow autoregulation

B

FIGURE 27–2 Organ blood flow responses caused by local mechanisms: A) active and B) reactive hyperemia. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

filtration and thus leads to a gradual increase in interstitial fluid volume and pressure. Presumably the increase in extravascular pressure would cause a decrease in vessel diameter by simple compression. This mechanism might be especially important in organs such as the kidney and brain whose volumes are constrained by external structures. Although not illustrated in Figure 27–3A, autoregulatory mechanisms operate in the opposite direction in response to a decrease in arterial pressure below the normal value. One important general consequence of local autoregulatory mechanisms is that the steady-state blood flow in many organs tends to remain near the normal value over quite a wide range of arterial pressure. This is illustrated in the graph of Figure 27–3B. As will be discussed later, the inherent ability of certain organs to maintain adequate blood flow despite lower-than-normal arterial pressure is of considerable importance in situations such as hypotension (low arterial pressure) from blood loss.

NEURAL INFLUENCES ON ARTERIOLES Sympathetic Vasoconstrictor Nerves These neural fibers innervate arterioles in all systemic organs and provide by far the most important means of reflex control

Steady-state Organ blood flow

Reactive hyperemia

Period of arrested blood flow

Steady state

Autoregulatory range

Normal

Normal

B

Organ blood flow

Sustained pressure increase

Organ blood flow

Period of increased metabolic rate

Arterial pressure

Organ blood flow

A

100 200 Mean arterial pressure (mm Hg)

FIGURE 27–3

A and B) Autoregulation of organ blood flow.

(Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

of the vasculature. Sympathetic vasoconstrictor nerves are the backbone of the system for controlling TPR and thus are essential participants in global cardiovascular tasks such as regulating arterial blood pressure. Sympathetic vasoconstrictor nerves release norepinephrine from their terminal structures in amounts generally proportional to their electrical activity. Norepinephrine causes an increase in the tone of arterioles after combining with an α1-adrenergic receptor on smooth muscle cells. Sympathetic vasoconstrictor nerves normally have a continuous or tonic firing activity. Thus, arterioles have a certain level of neurogenic tone as a normal component of their normal baseline state of contraction. When the firing rate of sympathetic vasoconstrictor nerves is increased above normal, arterioles constrict and cause organ blood flow to fall below normal. Conversely, vasodilation and increased organ blood flow occurs when the normal tonic activity of sympathetic vasoconstrictor nerves is reduced.

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Other Neural Influences Most blood vessels do not receive innervation from the parasympathetic division of the autonomic nervous system and systemic vascular resistance is not significantly influenced by parasympathetic nerve activity. However, parasympathetic vasodilator nerves, which release acetylcholine, are present in vessels of the brain and heart but their influence on arteriolar tone in these organs appears to be inconsequential. Parasympathetic vasodilator nerves are also present in the vessels of the salivary glands, pancreas, gastric mucosa, and external genitalia (where they are responsible for the vasodilation of inflow vessels responsible for erection).

HORMONAL INFLUENCES ON ARTERIOLES Circulating Catecholamines During activation of the sympathetic nervous system, catecholamines epinephrine and norepinephrine are released from the adrenal medulla into the bloodstream (see Chapter 65). Under normal circumstances, the concentrations of these agents in the blood are probably not high enough to cause significant cardiovascular effects. However, circulating catecholamines may have cardiovascular effects in situations (such as vigorous exercise or hemorrhagic shock) that involve increased activity of the sympathetic nervous system. In general, the cardiovascular effects of greatly increased levels of circulating catecholamines parallel the direct effects of sympathetic activation that have already been discussed; both epinephrine and norepinephrine can activate cardiac β1-adrenergic receptors to increase heart rate and myocardial contractility and can activate vascular α1-receptors to cause vasoconstriction. Recall that in addition to the α1-receptors that mediate vasoconstriction, arterioles in a few organs also possess β2-adrenergic receptors that mediate vasodilation. Because vascular β2-receptors are more sensitive to epinephrine than are vascular α1-receptors, moderately increased levels of circulating epinephrine can cause vasodilation—whereas higher levels cause α1-receptor-mediated vasoconstriction. Vascular β2-receptors are not innervated and therefore are not activated by norepinephrine released directly from sympathetic vasoconstrictor nerves. The physiological importance of these vascular β2-receptors is unclear because adrenal epinephrine release occurs during periods of increased sympathetic activity when arterioles would simultaneously be undergoing direct neurogenic vasoconstriction.

Vasopressin The polypeptide hormone vasopressin (also known as antidiuretic hormone (ADH), plays an important role in extracellular fluid homeostasis and is released into the bloodstream from the posterior pituitary gland in response to low blood volume and/or high extracellular fluid osmolarity (see Chapter 45). Vasopressin acts on collecting ducts in the kid-

neys to decrease renal excretion of water. Its role in body fluid balance has some very important indirect influences on cardiovascular function, which will be discussed in more detail in Chapter 29. Because it is such a potent vasoconstrictor agent, even the normally low levels of circulating vasopressin are likely to have some normal tonic effect on the basal tone of arterioles throughout the body. Moreover, abnormally high levels of vasopressin are clearly important in the intense arteriolar constriction that accompanies certain disturbances such as severe blood loss through hemorrhage.

Angiotensin II Angiotensin II is a circulating polypeptide that regulates aldosterone release from the adrenal cortex as part of the system for controlling body sodium balance. This system, to be discussed in greater detail in Chapter 29, is very important in blood volume regulation. Angiotensin II is also a very potent vasoconstrictor agent. Like vasopressin, even the normal low circulating level of angiotensin II likely has a role in producing the normal basal tone of arterioles throughout the body. In addition, an abnormally high blood level of angiotensin II seems to be an important contributing factor in certain forms of hypertension.

CONTROL OF VENOUS TONE Recall that venules and veins are relatively large-diameter vessels that have little resistance to flow but do contain relatively large amounts of blood. Therefore, venous tone or diameter has relatively little direct effect on the flow through organs. However, venous diameter does have a large effect on the fraction of total blood volume that is located in the periphery versus centrally. Consequently, when one considers what peripheral veins are doing, one should be thinking primarily about what the effects will be on central venous pressure and cardiac output. Veins contain vascular smooth muscle that is influenced by many of the same things that influence the vascular smooth muscle of arterioles. Constriction of the veins (venoconstriction) is largely mediated through activity of the sympathetic nerves that innervate them. As in arterioles, these sympathetic nerves release norepinephrine, which interacts with α1-receptors and produces an increase in venous tone and a decrease in vessel diameter. There are, however, several functionally important differences between veins and arterioles. Compared with arterioles, veins normally have little basal tone. Thus, veins are normally in a dilated state. One important consequence of the lack of basal venous tone is that vasodilator metabolites that may accumulate in the tissue have little effect on veins. Because of their thin walls, veins are much more susceptible to physical influences than are arterioles. The large effect of internal venous pressure on venous diameter was discussed in Chapter 26 and is evident in the pooling of blood in the veins of the lower extremities that occurs during prolonged standing (as will be discussed further in Chapter 30).

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External compression is an important determinant of venous volume. This is especially true of veins in skeletal muscle. Very high pressures are developed inside skeletal muscle tissue during contraction and cause venous vessels to collapse. Because veins and venules have one-way valves, the blood displaced from veins during skeletal muscle contraction is forced in the forward direction toward the right heart. In fact, rhythmic skeletal muscle contractions can produce a considerable pumping action, often called the skeletal muscle pump, which helps return blood to the heart during exercise.

organs is very strongly regulated by sympathetic nerve activity. Consequently, some organs are automatically forced to participate in overall cardiovascular reflex responses to a greater extent than are other organs. The overall plan seems to be that in cardiovascular emergency, flow to the brain and heart will be preserved at the expense of everything else.

SUMMARY OF PRIMARY VASCULAR CONTROL MECHANISMS

The details of vascular control in many specific organs are presented in several other sections of this book. Included below are descriptions of vascular control in some important organs that are not covered elsewhere.

Certain general factors dominate the primary control of the peripheral vasculature when it is viewed from the standpoint of overall cardiovascular system function; these influences are summarized in Figure 27–4. Basal tone, local metabolic vasodilator factors, and sympathetic vasoconstrictor nerves acting through α1-receptors are the major factors controlling arteriolar tone and therefore the blood flow through peripheral organs. Sympathetic vasoconstrictor nerves, internal pressure, and external compression are the most important influences on venous diameter and therefore on peripheral–central distribution of blood volume. The flow in organs such as the brain, heart muscle, and skeletal muscle is very strongly regulated by local metabolic control, whereas the flow in the kidneys, skin, and splanchnic

VASCULAR CONTROL OF CORONARY BLOOD FLOW

Reflex influences

Sympathetic constrictor nerves

Local influences

Basal tone NE α Vasodilator metabolites Arterioles

Sympathetic constrictor nerves

Passive distention

α NE

P

The major right and left coronary arteries that serve the heart tissue are the first vessels to branch off the aorta. Thus, the driving force for myocardial blood flow is the systemic arterial pressure, just as it is for other systemic organs. Most of the blood that flows through the myocardial tissue returns to the right atrium by way of a large cardiac vein called the coronary sinus.

Local Metabolic Control As emphasized before, coronary blood flow is controlled primarily by local metabolic mechanisms and thus it responds rapidly and accurately to changes in myocardial oxygen consumption. In a resting individual, the myocardium extracts 70–75% of the oxygen in the blood that passes through it, which is more than any other organ does. Myocardial oxygen extraction cannot increase significantly from its resting value. Consequently, increases in myocardial oxygen consumption must be accompanied by appropriate increases in coronary blood flow. The issue of which metabolic vasodilator factors play the dominant role in modulating the tone of coronary arterioles is unresolved. Many believe that adenosine, released from myocardial muscle cells in response to increased metabolic rate, may be an important local coronary metabolic vasodilator influence. Regardless of the specific details, myocardial oxygen consumption is the most important influence on coronary blood flow.

Systolic Compression P

External compression

Veins

FIGURE 27–4 Primary influences on arterioles and veins. NE, norepinephrine; α, alpha-adrenergic receptor; P, pressure. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

VASCULAR CONTROL IN SPECIFIC ORGANS

Large forces and/or pressures are generated within the myocardial tissue during cardiac muscle contraction. Such intramyocardial forces press on the outside of coronary vessels and cause them to collapse during systole. Because of this systolic compression and the associated collapse of coronary vessels, coronary vascular resistance is greatly increased during systole. The result, at least for much of the left ventricular myocardium, is that coronary flow is lower during systole than

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Aortic pressure

Left ventricular pressure

0

Left coronary flow 0

FIGURE 27–5

Phasic flows in the left and right coronary arteries in relation to aortic and left ventricular pressures. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular

Right coronary flow

Physiology, 6th ed. New York: Lange Medical Books/ McGraw-Hill, 2006.)

0

during diastole, even though systemic arterial pressure (i.e., coronary perfusion pressure) is highest during systole. This is illustrated in the left coronary artery flow trace shown in Figure 27–5. Systolic compression has much less effect on flow through the right ventricular myocardium. This is because the peak systolic intraventricular pressure is much lower for the right heart than for the left, and the systolic compressional forces in the right ventricular wall are correspondingly less than those in the left ventricular wall. Because the endocardial surface of the left ventricle is exposed to intraventricular pressure (∼120 mm Hg during systole), and the epicardial surface is exposed only to intrathoracic pressure (∼0 mm Hg), systolic compressional forces on coronary vessels are greater in the endocardial layers of the left ventricular wall than in the epicardial layers. Thus, the flow to the endocardial layers of the left ventricle is impeded more than the flow to epicardial layers by systolic compression. Normally, the endocardial region of the myocardium can make up for the lack of flow during systole by a high flow in the diastolic interval. However, when coronary blood flow is limited—for example, by coronary disease and stenosis—the endocardial layers of the left ventricle are often the first regions of the heart to have difficulty maintaining a flow sufficient for their metabolic needs. Myocardial infarcts (areas of tissue killed by lack of blood flow) occur most frequently in the endocardial layers of the left ventricle.

Neural Influences on Coronary Flow Coronary arterioles are densely innervated with sympathetic vasoconstrictor fibers, yet when the activity of the sympathetic nervous system increases, the coronary arterioles normally vasodilate rather than vasoconstrict. This is because an increase in sympathetic tone increases myocardial oxygen

consumption by increasing heart rate and contractility. The increased local metabolic vasodilator influence outweighs the concurrent neurogenic vasoconstrictor. Whether these coronary vasoconstrictor fibers might be functionally important in certain pathological situations is an open question.

VASCULAR CONTROL OF SKELETAL MUSCLE BLOOD FLOW Because of the large mass of skeletal muscle, blood flow through it is an important factor in overall cardiovascular hemodynamics. Collectively, the skeletal muscles constitute 40–45% of body weight—more than any other single body organ. Even at rest, about 15% of the cardiac output goes to skeletal muscle, and during strenuous exercise skeletal muscle may receive more than 80% of the cardiac output. Resting skeletal muscle has a high level of intrinsic vascular tone. Because of this high tone of smooth muscle in resistance vessels of resting skeletal muscles, the blood flow per gram of tissue is low when compared with that of other organs such as the kidneys. However, resting skeletal muscle blood flow is still substantially above that required to sustain its metabolic needs. Resting skeletal muscles normally extract only 25–30% of the oxygen delivered to them in arterial blood. Thus, changes in the activity of sympathetic vasoconstrictor fibers can reduce resting muscle blood flow without compromising resting tissue metabolic processes. Local metabolic control of arteriolar tone is the most important influence on blood flow through exercising muscle. A particularly important characteristic of skeletal muscle is its very wide range of metabolic rates. During strenuous exercise, the oxygen consumption rate of and oxygen extraction by

CHAPTER 27 Vascular Control skeletal muscle tissue can reach the high values typical of the myocardium. In most respects, the factors that control blood flow to exercising muscle are similar to those that control coronary blood flow. Local metabolic control of arteriolar tone is very strong in exercising skeletal muscle, and muscle oxygen consumption is the most important determinant of its blood flow. Blood flow in skeletal muscle can increase 20-fold during a bout of strenuous exercise. Alterations in sympathetic neural activity can alter nonexercising skeletal muscle blood flow. For example, maximum sympathetic discharge rates can decrease blood flow in a resting muscle to less than one fourth its normal value, and, conversely, if all neurogenic tone is removed, resting skeletal muscle blood flow may double. This is a modest increase in flow compared with what can occur in an exercising skeletal muscle. Nonetheless, because of the large mass of tissue involved, changes in the vascular resistance of resting skeletal muscle brought about by changes in sympathetic activity are very important in the overall reflex regulation of arterial pressure. Alterations in sympathetic neural activity can influence exercising skeletal muscle blood flow. As will be discussed in Chapter 72, the cardiovascular response to muscle exercise involves a general increase in sympathetic activity. This reduces flow to susceptible organs, which include nonexercising muscles. In exercising muscles, the increased sympathetic vasoconstrictor nerve activity is not evident as outright vasoconstriction but does limit the degree of metabolic vasodilation. One important function that this seemingly counterproductive process may serve is preventing an excessive reduction in TPR during exercise. Indeed, if arterioles in most of the skeletal muscles in the body were allowed to dilate to their maximum capacity simultaneously, TPR would be so low that the heart could not possibly supply enough cardiac output to maintain arterial pressure. Rhythmic contractions can increase venous return from exercising skeletal muscle. As in the heart, muscle contraction produces large compressional forces within the tissue, which can collapse vessels and impede blood flow. Strong, sustained (tetanic) skeletal muscle contractions may actually stop muscle blood flow. About 10% of the total blood volume is normally contained within the veins of skeletal muscle, and during rhythmic exercise the skeletal muscle pump is very effective in displacing blood from skeletal muscle veins. Valves in the veins prevent reverse flow back into the muscles. Blood displaced from skeletal muscle into the central venous pool is an important factor in the hemodynamics of strenuous wholebody exercise. Veins in skeletal muscle can constrict in response to increased sympathetic activity. However, they are sparsely innervated with sympathetic vasoconstrictor fibers, and the rather small volume of blood that can be mobilized from skeletal muscle by sympathetic nerve activation is probably not of much significance to total body hemodynamics. This is in sharp contrast to the large displacement of blood from exercising muscle by the muscle pump mechanism. (This will be

271

discussed in more detail when postural reflexes are considered in Chapter 30.)

VASCULAR CONTROL OF CEREBRAL BLOOD FLOW Interruption of cerebral blood flow for more than a few seconds leads to unconsciousness. One rule of overall cardiovascular system function is that, in all situations, measures are taken that are appropriate to preserve adequate blood flow to the brain. Cerebral blood flow is regulated almost entirely by local mechanisms. The brain as a whole has a nearly constant rate of metabolism that, on a per gram basis, is nearly as high as that of myocardial tissue. Flow through the cerebrum is autoregulated very strongly and is little affected by changes in arterial pressure unless it falls below about 60 mm Hg. When arterial pressure decreases below 60 mm Hg, brain blood flow decreases proportionately. It is presently unresolved whether metabolic mechanisms or myogenic mechanisms or both are involved in the phenomenon of cerebral autoregulation. Local changes in cerebral blood flow may be influenced by local metabolic conditions. Presumably because the overall average metabolic rate of brain tissue shows little variation, total brain blood flow is remarkably constant in most situations. The cerebral activity in discrete locations within the brain, however, changes from situation to situation. As a result, blood flow to discrete regions is not constant but closely follows the local neuronal activity. The mechanisms responsible for this strong local control of cerebral blood flow are as yet undefined, but H+, K+, oxygen, and adenosine seem most likely to be involved. As in most organs, cerebral blood flow increases whenever the partial pressure of carbon dioxide (Pco2) in arterial blood increases and, conversely, cerebral blood flow decreases whenever Pco2 decreases below normal. This is the normal state of affairs in most tissues but it has important nonvascular consequences when it happens in the brain. For example, the dizziness, confusion, and even fainting that can occur when a person hyperventilates (and “blows off ” CO2) are direct results of cerebral vasoconstriction. It appears that cerebral arterioles respond not to changes in Pco2 but to changes in the extracellular H+ concentration (i.e., pH) caused by changes in Pco2. Cerebral arterioles also dilate whenever the partial pressure of oxygen (Po2) in arterial blood decreases significantly below normal values. However, higher-than-normal arterial blood Po2, such as that caused by pure oxygen inhalation, produces little decrease in cerebral blood flow. Sympathetic and parasympathetic neural influences on cerebral blood flow are minimal. Although cerebral vessels receive both sympathetic vasoconstrictor and parasympathetic vasodilator fiber innervation, cerebral blood flow is influenced very little by changes in the activity of either under normal circumstances. Sympathetic vasoconstrictor responses may, however, be important in protecting cerebral vessels from excessive passive distention following large, abrupt increases in arterial pressure.

272

SECTION V Cardiovascular Physiology

The blood–brain barrier refers to the tightly connected vascular endothelial cells that severely restrict transcapillary movement of all polar and many other substances. Because of this blood–brain barrier, the extracellular space of the brain represents a special fluid compartment in which the chemical composition is regulated separately from that in the plasma and general body extracellular fluid compartment. The extracellular compartment of the brain encompasses both interstitial fluid and cerebrospinal fluid (CSF) that surrounds the brain and spinal cord and fills the brain ventricles. The CSF is formed from plasma by selective secretion (not simple filtration) by specialized tissues, the choroid plexus, located within the cerebral ventricles. These processes regulate the chemical composition of the CSF. The interstitial fluid of the brain takes on the chemical composition of CSF through free diffusional exchange. The blood–brain barrier serves to protect the cerebral cells from ionic disturbances in the plasma because it is not very permeable to charged substances. Also, by exclusion and/or endothelial cell metabolism, it prevents many circulating hormones (and drugs) from influencing the parenchymal cells of the brain and the vascular smooth muscle cells in brain vessels. Brain capillaries have a special carrier system for glucose and present no barrier to oxygen and carbon dioxide diffusion. Thus, the blood–brain barrier does not restrict nutrient supply to the brain tissue.

VASCULAR INFLUENCES ON PULMONARY BLOOD FLOW See Chapter 34.

VASCULAR CONTROL OF RENAL BLOOD FLOW See Chapter 40.

VASCULAR CONTROL OF SPLANCHNIC BLOOD FLOW See Chapter 49.

VASCULAR CONTROL OF CUTANEOUS BLOOD FLOW See Chapter 70.

CLINICAL CORRELATION A 58-year-old man comes to the emergency room complaining of weakness and severe chest pain. He is a salesman in a high stress industry, has smoked two packs of

cigarettes a day for more than 25 years, and eats a high-fat, high-salt diet. He is overweight, pale, and sweaty and is clutching his chest. His heart rate is 110 beats/min and his blood pressure is 110/90 mm Hg. His medical record indicates that he has been treated with sublingual nitroglycerin for mild angina pectoris for several years and had been instructed about lifestyle changes. The angina has been getting more severe and required increasingly more nitroglycerin to achieve relief. This time, the nitroglycerin has not worked. An ECG indicates that he has a myocardial infarction in the anterior wall of the left ventricle. He is taken immediately to the cardiac catheterization laboratory and an angiogram reveals an almost complete occlusion of his left anterior descending coronary artery. A stent is placed in the artery and blood flow is restored to the ischemic tissue. The condition experienced by this man occurs whenever coronary blood flow decreases below that required to meet the metabolic needs of the heart. The myocardium becomes ischemic and pumping capability of the heart is impaired. The most common cause of coronary artery disease is atherosclerosis of the large coronary arteries and this man had several of the known risk factors (smoking, obesity, high stress, poor diet, high blood cholesterol). Localized lipid deposits called plaques develop within the arterial walls and with severe disease may become large enough to permanently narrow the lumen of arteries. If the coronary artery narrowing (stenosis) is not too severe, local metabolic vasodilator mechanisms may reduce arteriolar resistance sufficiently to compensate for the abnormally increased coronary arterial resistance. Coronary artery disease can jeopardize cardiac function in several ways. (1) Ischemic muscle cells are electrically irritable and the danger of fibrillation is enhanced (see Chapter 25) because ectopic pacemaker foci may develop. (2) Platelet aggregation and clotting function may be abnormal in atherosclerotic coronary arteries and the danger of thrombi or emboli formation is enhanced (see Chapter 22). (3) Myocardial ischemia produces intense, debilitating chest pain called angina pectoris. Anginal pain is often absent in individuals with coronary artery disease when they are resting but is induced during physical exertion or emotional excitement when sympathetic activity is increased and myocardial oxygen consumption is elevated. Primary treatment of coronary artery disease includes lifestyle alterations and attempts to lower blood lipids by dietary and pharmacological techniques. Treatment of angina that is a result of coronary artery disease may first involve quick-acting vasodilator drugs such as nitroglycerin to provide relief during an anginal attack. These “nitrate” drugs are NO donors and directly vasodilate coronary vessels to acutely increase coronary blood flow. In addition to increasing myocardial oxygen delivery, nitrates

CHAPTER 27 Vascular Control ■

reduce myocardial oxygen demand by dilating systemic veins (reducing preload) and by decreasing arterial resistance (reducing afterload). Second, β-adrenergic blocking agents such as propranolol may be used to block the effects of cardiac sympathetic nerves on heart rate and contractility. These agents limit myocardial oxygen consumption and prevent it from increasing above the level that the compromised coronary blood flow can sustain. Third, calcium channel blockers such as verapamil may be used to dilate coronary and systemic blood vessels, and to lower blood pressure and heart rate. These drugs, which block entry of calcium into the vascular smooth muscle cell, interfere with normal excitation–contraction coupling. Invasive or surgical interventions may be used to treat coronary artery stenosis. Fluoroscopic techniques combined with radio-opaque contrast injections can be used to visualize the coronary arteries. A balloon-tipped catheter can be threaded into the occluded region of the coronary artery and rapidly inflated to squeeze the plaque against the vessel wall and improve the patency of the vessel. This technique, called coronary angioplasty, may also be effective in opening occlusions produced by intravascular clots associated with acute myocardial infarction. A small, mesh tubular device called a stent is often implanted inside the vessel at the angioplasty site. This rigid implant has been shown to improve continued patency of the vessel over a longer period than angioplasty alone. If angioplasty and stent placement is inappropriate or unsuccessful, coronary bypass surgery may be performed. The stenotic coronary artery segments are bypassed by implanting parallel low-resistance pathways formed from either natural (e.g., saphenous vein or mammary artery) or artificial vessels.

CHAPTER SUMMARY ■

■ ■

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■

Continuous adjustments of vascular diameter are required to properly distribute the cardiac output to the various systemic tissues (the role of arterioles) and maintain adequate cardiac filling (the role of veins). Vascular adjustments are made by changes in the tone of vascular smooth muscle. Vascular smooth muscle has many properties that make it sensitive to a wide array of local and reflex stimuli and capable of maintaining tone for long periods of time. The tone of arterioles, but not veins, can be strongly influenced by local vasodilator factors produced by local tissue metabolism. In abnormal situations (such as tissue injury or severe blood volume depletion), certain local factors such as histamine and bradykinin, and hormonal factors such as vasopressin and angiotensin have significant vascular influences.

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273

Sympathetic vasoconstrictor nerves provide the primary reflex mechanisms for regulating both arteriolar and venous tone. Sympathetic vasoconstrictor nerves release norepinephrine, which interacts with α1-adrenergic receptors on vascular smooth muscle to induce vasoconstriction. The relative importance of local metabolic versus reflex sympathetic control of arteriolar tone (and therefore blood flow) varies from organ to organ. In many organs (such as brain, heart muscle, and exercising skeletal muscle), blood flow normally closely follows metabolic rate because of local metabolic influences on arterioles. In other organs (such as skin and kidneys), blood flow is normally regulated more by sympathetic nerves than by local metabolic conditions.

STUDY QUESTIONS 1. Vascular smooth muscle differs from cardiac muscle in that it A) contains no actin molecules. B) can be directly activated in the absence of action potentials. C) is unresponsive to changes in intracellular calcium levels. D) is unresponsive to changes in membrane potentials. E) is unresponsive to changes in muscle length. 2. Arteriolar constriction tends to do which of the following? A) decrease total peripheral resistance B) decrease mean arterial pressure C) decrease capillary hydrostatic pressure D) increase transcapillary fluid filtration E) increase blood flow through the capillary bed 3. When an organ responds to an increase in metabolic activity with a decrease in arteriolar resistance, this is known as A) active hyperemia. B) reactive hyperemia. C) autoregulation of blood flow. D) flow-dependent vasodilation. E) metabolic vasoconstriction. 4. A particular vascular bed demonstrates the phenomenon of autoregulation of blood flow. This means that A) when flow increases, capillary pressure increases. B) when metabolic activity increases, flow increases. C) when arterial pressure increases, arteriolar resistance increases. D) when blood flow is interrupted, arteriolar resistance decreases. E) when arterial pressure falls, sympathetic vasoconstriction occurs. 5. Which of the following is most likely to increase coronary blood flow? A) decreased arterial pressure B) decreased heart rate C) increased sympathetic neural activity D) reduced left ventricular end-diastolic volume E) reduced left ventricular ejection fraction

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28 C

Venous Return and Cardiac Output David E. Mohrman and Lois Jane Heller

H A

P

T

E

R

O B J E C T I V E S ■

■ ■ ■ ■ ■ ■ ■ ■ ■ ■ ■

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Describe the overall arrangement of the systemic circulation and identify the primary functional properties of each of its major components. Define mean circulatory filling pressure and state the primary factors that determine it. Define venous return and explain how it is distinguished from cardiac output. State why cardiac output and venous return must be equal in the steady state. List the factors that control venous return. Describe the relationship between central venous pressure and venous return and draw the normal venous return curve. Define peripheral venous pressure. List the factors that determine peripheral venous pressure. Predict the shifts in the venous return curve that occur with altered blood volume and altered venous tone. Describe how the output of the left heart pump is matched to that of the right heart pump. Draw the normal venous return and cardiac output curves on a graph and describe the significance of the point of curve intersection. Predict how normal venous return, cardiac output, and central venous pressure will be altered with any given combination of changes in cardiac sympathetic tone, peripheral venous sympathetic tone, or circulating blood volume. Identify conditions that may result in abnormally high or low central venous pressure.

INTERACTION OF SYSTEM COMPONENTS As illustrated in Figure 28–1, the systemic cardiovascular system is a closed hydraulic circuit that includes the heart, arteries, arterioles, capillaries, and veins. (Note: The pulmonary circuit and lymphatics are not included because they do not influence the major points to be made in this chapter.) The

Ch28_275-284.indd 275

venous side of this system is often conceptually separated into two different compartments: (1) a large and diverse peripheral section (the peripheral venous compartment) and (2) a smaller intrathoracic section that includes the venae cavae and the right atrium (the central venous compartment). Each of the segments of this circuit has a distinctly different role to play in the overall operation of the system because of inherent differences in anatomical volume, resistance to blood flow, and compliance that are summarized in Table 28–1.

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11/26/10 11:51:25 AM

276

SECTION V Cardiovascular Physiology

Th

Arteries

ora

x

Arterioles Ventricle

Atrium

Capillaries Central venous compartment

FIGURE 28–1 Major functionally distinct components of the systemic cardiovascular circuit. (Modified with permission from Mohrman DE, Heller

Peripheral venous compartment

LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

Note especially the surprisingly high ventricular diastolic compliance of 24 mL/mm Hg in Table 28–1. This value indicates how sensitive the ventricular end-diastolic volume (and therefore stroke volume and cardiac output) is to small changes in cardiac filling pressure (i.e., central venous pressure). Cardiac filling pressure is a crucial factor that determines how well the cardiovascular system functions.

MEAN CIRCULATORY FILLING PRESSURE Imagine the heart arrested in diastole with no flow around the circuit shown in Figure 28–1. It will take a certain amount of blood just to fill the anatomical space contained by the systemic system without stretching any of its walls or developing

any internal pressure. In a 70-kg adult, this amount is 3.5 L, as indicated by the total systemic circuit volume (V0) in Table 28–1. Normally, however, the systemic circuit contains about 4.5 L of blood and thus is somewhat inflated. From the total systemic circuit compliance (C) given in Table 28–1, one can see that an extra 1,000 mL of blood would result in an internal pressure of about 7 mm Hg (i.e., 1,000 mL/140 mL/mm Hg). This theoretical pressure is called the mean circulatory filling pressure and is the pressure that would exist throughout the system in the absence of flow. The two major factors that affect mean circulatory filling pressure are the circulating blood volume and the state of the peripheral venous vessel tone. In the latter case, look at Figure 28–1 and imagine how constriction of the vessels of the large venous compartment (increasing venous tone) will significantly increase pressure throughout the system. In con-

TABLE 28–1 Typical properties of the major components of the systemic cardiovascular circuit.a Compartment

V0 (mL)

C (mL/mm Hg)

R (mm Hg/(L/min))

Ventricle in diastole

30

24

0

Arteries

600

2

1

Arterioles

100

0

13

Capillaries

250

0

5

2,500

110

1

80

4

0

3,560

140

20

Peripheral venous compartment Central venous compartment Entire circuit a

Values are for a normal, young, resting 70-kg adult. V0, anatomical volume of compartment at zero pressure: C, compliance of compartment; R, resistance to flow through compartment. Reproduced with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.

CHAPTER 28 Venous Return and Cardiac Output

Venous return

Central venous compartment

277

Cardiac output

FIGURE 28–2 Distinction between cardiac output and venous return. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/

Great veins in thorax and right atrium

trast, squeezing on arterioles (increasing arteriolar tone) will have a negligible effect on mean circulatory filling pressure because arterioles contain so little blood in any state. The other major components of the system (arteries and capillaries) do not actively change their contained volume.

FLOW-INDUCED DISTRIBUTION OF BLOOD VOLUME AND PRESSURE The presence of flow around the circuit does not change the total volume of blood in the system or the mean circulatory filling pressure. The flow caused by cardiac pumping action does, however, tend to shift some of the blood volume from the venous side of the circuit to the arterial side. This causes pressures on the arterial side to increase above the mean circulatory pressure while pressures on the venous side decrease below it. Because veins are about 50 times more compliant than arteries (Table 28–1), the flow-induced decrease in venous pressure is only about 1/50th as large as the accompanying increase in arterial pressure. Thus, flow or no flow, pressure in the peripheral venous compartment is normally quite close to the mean circulatory filling pressure.

CENTRAL VENOUS PRESSURE: AN INDICATOR OF CIRCULATORY STATUS The cardiovascular system must continuously adjust to meet changing metabolic demands of the body. Because the cardiovascular system is a closed hydraulic loop, adjustments in any one part of the circuit will have pressure, flow, and volume effects throughout the circuit. Because of the critical influence of cardiac filling on cardiovascular function, the remainder of this chapter will focus on the factors that determine the pressure in the central venous compartment. In addition, the way in which measures of central venous pressure can provide

McGraw-Hill, 2006.)

clinically useful information about the state of the circulatory system will be discussed. The central venous compartment corresponds roughly to the volume enclosed by the right atrium and the great veins in the thorax. Blood leaves the central venous compartment by entering the right ventricle at a rate that is equal to the cardiac output. Venous return, in contrast, is the rate at which blood returns to the thorax from the peripheral vascular beds and thus is the rate at which blood enters the central venous compartment. The important distinction between venous return to the central venous compartment and cardiac output from the central venous compartment is illustrated in Figure 28–2. In any stable situation, venous return must equal cardiac output or blood would gradually accumulate in either the central venous compartment or the peripheral vasculature. However, there often are temporary differences between cardiac output and venous return. Whenever such differences exist, the volume of the central venous compartment must be changing. Because the central venous compartment is enclosed by elastic tissues, any change in central venous volume produces a change in central venous pressure. As discussed in Chapter 24, the central venous pressure (i.e., cardiac filling pressure) has an extremely important positive influence on cardiac output (Starling’s law of the heart). As explained below, central venous pressure has an equally important negative effect on venous return. Thus, central venous pressure is always automatically driven to a value that makes cardiac output equal to venous return.

INFLUENCE OF CENTRAL VENOUS PRESSURE ON VENOUS RETURN The important factors involved in the process of venous return can be summarized as shown in Figure 28–3A. Anatomically the peripheral venous compartment is scattered throughout the systemic organs, but functionally it can be viewed as a single vascular space that has a particular pressure

278

SECTION V Cardiovascular Physiology

A Thorax

Intrathoracic pressure ≅ 0 mm Hg From capillaries

P PV ≅ 7 mm Hg

Venous return

P CV

Cardiac output

Peripheral venous compartment Venous resistance

Central venous compartment

B

Venous return (L/min)

8

6

Ve n

ou

s

fu

nc

4

tio

n

cu

rv

e

2

0

FIGURE 28–3

2 4 6 8 Central venous pressure (mm Hg)

10

Venous Return A) Factors influencing venous return. B) The venous function curve. (Modified with permission from Mohrman DE,

Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

(PPV) at any instant. The normal operating pressure in the peripheral venous compartment is usually very close to mean circulatory filling pressure. Moreover, the same factors that influence mean circulatory filling pressure have essentially equal influences on peripheral venous pressure. Thus, “peripheral venous pressure” can be viewed as essentially equivalent to “mean circulatory filling pressure.” The blood flow between the peripheral venous compartment and the central venous compartment is governed by the basic flow ˙ = Δ P/R, where ΔP is the pressure decrease between equation Q the peripheral and central venous compartments and R the small resistance associated with the peripheral veins. In the example in Figure 28–3, peripheral venous pressure is assumed to be 7 mm Hg. Thus, there will be no venous return when the central venous pressure (PCV) is also 7 mm Hg as shown in Figure 28–3B. If the peripheral venous pressure remains at 7 mm Hg, decreasing central venous pressure will increase the pressure difference across the venous pathway and consequently cause an increase in venous return to the central venous pool. This relationship is summarized by the venous function curve, which shows how venous return increases as central venous

pressure decreases. There are two minor additional points to be made about this venous function curve. First, changes in venous resistance can influence the slope of the venous function curve but, in the example given, venous return will be 0 L/min when PCV = 7 mm Hg at any level of venous vascular resistance. Second, if central venous pressure reaches very low values and decreases below the intrathoracic pressure, the veins in the thorax collapse and tend to limit venous return. In the example of Figure 28–3, intrathoracic pressure is taken to be 0 mm Hg and the flat portion of the venous function curve indicates that lowering central venous pressure below 0 mm Hg produces no additional increase in venous return. Just as a cardiac function curve shows how central venous pressure influences cardiac output, a venous function curve shows how central venous pressure influences venous return. (By convention, these relationships are plotted with the independent variable on the horizontal axis and the dependent variable on the vertical axis and they must be read in that sense. For example, Figure 28–3B says that increasing central venous pressure tends to cause decreased venous return. Figure 28–3B does not imply that increasing venous return will tend to lower central venous pressure.)

CHAPTER 28 Venous Return and Cardiac Output

Venous return (L/min)

As can be deduced from Figure 28–3A, it is the pressure difference between the peripheral and central venous compartments that determines venous return. Therefore, an increase in peripheral venous pressure can be just as effective in increasing venous return as a decrease in central venous pressure. The two ways in which peripheral venous pressure can change were discussed in Chapter 26. First, because veins are elastic vessels, changes in the volume of blood contained within the peripheral veins alter the peripheral venous pressure. Moreover, because the veins are much more compliant than any other vascular segment, changes in circulating blood volume produce larger changes in the volume of blood in the veins than in any other vascular segment. For example, blood loss by hemorrhage or loss of body fluids through severe sweating, vomiting, or diarrhea will decrease circulating blood volume and significantly reduce the volume of blood contained in the veins and thus decrease the peripheral venous pressure. Conversely, transfusion, fluid retention by the kidney, or transcapillary fluid reabsorption will increase circulating blood volume and venous blood volume. Whenever circulating blood volume increases, so does peripheral venous pressure. Recall from Chapter 27 that the second way that peripheral venous pressure can be altered is through changes in venous tone produced by increasing or decreasing the activity of sympathetic vasoconstrictor nerves supplying the venous smooth muscle. Peripheral venous pressure increases whenever the activity of sympathetic vasoconstrictor fibers to veins increases. In addition, an increase in any force compressing veins from the outside has the same effect on the pressure inside veins as an increase in venous tone. Thus, such things as muscle exercise and wearing elastic stockings tend to increase peripheral venous pressure. Whenever peripheral venous pressure is altered, the relationship between central venous pressure and venous return is also altered. For example, whenever peripheral venous pressure is increased by increases in blood volume or by sympathetic stimulation, the venous function curve shifts upward and to the right (Figure 28–4). This phenomenon can be most easily understood by focusing first on the central venous pressure at which there will be no venous return. When peripheral venous pressure is 7 mm Hg, venous return is 0 L/min when central venous pressure is 7 mm Hg. When peripheral venous pressure is increased to 10 mm Hg, considerable venous return occurs with a central venous pressure of 7 mm Hg, and venous return stops only when central venous pressure is increased to 10 mm Hg. Thus, increasing peripheral venous pressure shifts the whole venous function curve to the right. By similar logic, decreased peripheral venous pressure caused by blood loss or decreased sympathetic vasoconstriction of peripheral veins shifts the venous function curve to the left.

10

In

cr

8

ea

se

d

6

bl o

od

Co

nt

4

or

0

De

vo l

um

ro

2

lv en

e

or ve s no ve ea f un us no se ct us d b to i o ne l n to oo cu ne d rv vo e lu m e cr

ou

2 4 6 8 Central venous pressure (mm Hg)

10

FIGURE 28–4 Effect of changes in blood volume and venous tone on venous function curves. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/ McGraw-Hill, 2006.)

CENTRAL VENOUS PRESSURE DETERMINES BOTH CARDIAC OUTPUT AND VENOUS RETURN The significance of the fact that central venous pressure simultaneously affects both cardiac output and venous return can be best seen by plotting the cardiac function curve (the Starling curve) and the venous function curve on the same graph, as in Figure 28–5.

Cardiac output or Venous return (L/min)

INFLUENCE OF PERIPHERAL VENOUS PRESSURE ON VENOUS RETURN

279

10

8 Cardiac function curve 6

4 Venous function curve 2

0

2 4 6 8 10 Central venous pressure (mm Hg)

FIGURE 28–5 Interaction of cardiac output and venous return through central venous pressure. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

SECTION V Cardiovascular Physiology

Central venous pressure, as defined earlier, is the filling pressure of the right heart. Strictly speaking, this pressure directly affects only the stroke volume and output of the right heart pump. In most contexts, however, “cardiac output” implies the output of the left heart pump. How is it then, as has often been previously implied, that central venous pressure (the filling pressure of the right heart) profoundly affects cardiac output (the output of the left heart)? The short answer is that in the steady state, the right and left hearts have equal outputs. (Since the right and left hearts always beat with identical rates, this implies that their stroke volumes must be equal in the steady state.) The detailed answer is that changes in central venous pressure automatically cause essentially parallel changes in the filling pressure of the left heart (i.e., in left atrial pressure). Consider, for example, the following sequence of consequences that a small step-wise increase in central venous pressure has on a heart that previously was in a steady state: (1) Increased central venous pressure → (2) increased right ventricular stroke volume via Starling’s law → (3) increased output of right heart → (4) right heart output temporarily exceeds that of the left heart → (5) as long as this imbalance exists, blood accumulates in the pulmonary vasculature and raises pulmonary venous and left atrial pressure → (6) increased left atrial pressure increases left ventricular stroke volume via Starling’s law → (7) very quickly, a new steady state will be reached when left atrial pressure has risen sufficiently to make left ventricular stroke volume exactly equal to the increased right ventricular stroke volume. The major conclusion here is that left atrial pressure will change in the correct direction to match left ventricular stroke volume to the current right ventricular stroke volume. Consequently, it is usually an acceptable simplification to say that central venous pressure affects cardiac output as if the heart consisted only of a single pump as is shown in Figure 28–1. Note that in Figure 28–5, cardiac output and venous return are equal (at 5 L/min) only when the central venous pressure is 2 mm Hg. If central venous pressure were to decrease to 0 mm Hg, cardiac output would decrease (to 2 L/min) and venous return would increase (to 7 L/min). With a venous return of 7 L/min and a cardiac output of 2 L/min, the volume of the central venous compartment would necessarily be increasing and this would produce a progressively increasing central venous pressure. In this manner, central venous pressure would return to the original level (2 mm Hg) in a very short time. Moreover, if central venous pressure were to increase from 2 to 4 mm Hg, venous return would decrease (to 3 L/min) and cardiac output would increase (to 7 L/min). This would quickly reduce the volume of blood in the central venous pool, and the central venous pressure would soon fall back to the original level. The cardiovascular system automatically adjusts to operate at the point where the cardiac and venous function curves intersect. Central venous pressure is always inherently driven to the value that makes cardiac output and venous return equal. Cardiac output and venous return always stabilize at the level where the cardiac function and venous function curves intersect.

Cardiac output or Venous return (L /min)

280

10 Normal cardiac function curve 8

6

4

N

or

Fu

m

al

nc

tio

2

n

0

ve n

cu

rv e

ou

s

2 4 6 8 Central venous pressure (mm Hg)

10

FIGURE 28–6 Families of cardiac function and venous function curves. Intersection points indicate equilibrium values for cardiac output, venous return, and central venous pressure. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

Recall from Chapter 24 that cardiac output is affected by more than just cardiac filling pressure and that at any moment, the heart may be operating on any one of a number of cardiac function curves, depending on the existing level of cardiac sympathetic tone (see Figure 24–8). The family of possible cardiac function curves may be plotted along with the family of possible venous function curves, as shown in Figure 28–6. At a particular moment, the existing influences on the heart dictate the cardiac function curve on which it is operating, and similarly, the existing influences on peripheral venous pressure dictate the venous function curve that applies. Thus, the influences on the heart and on the peripheral vasculature determine where the cardiac and venous function curves intersect and thus what the central venous pressure and cardiac output (and venous return) are in the steady state. In the intact cardiovascular system, cardiac output can rise only when the point of intersection of the cardiac and venous function curves is raised. All changes in cardiac output are caused by a shift in the cardiac function curve, a shift in the venous function curve, or both. The cardiac function and venous function curves are useful for understanding the complex interactions that occur in the intact cardiovascular system. With the help of Figure 28–7, let us consider, for example, what happens to the cardiovascular system when there is a significant loss of blood (hemorrhage). Assume that before the hemorrhage, sympathetic activity to the heart and peripheral vessels is normal, as is the blood volume. Therefore, cardiac output is related to central venous pressure as indicated by the “normal” cardiac function curve in Figure 28–7. In addition, venous return is determined by central venous pressure as indicated by the

Cardiac output or Venous return (L /min)

CHAPTER 28 Venous Return and Cardiac Output

Increased cardiac sympathetic nerve activity

10

8 Normal cardiac function curve 6 A

D 4

Venous constriction after hemorrhage

C B

Normal venous function curve

2 Hemorrhage 0

2

4

6

8

10

Central venous pressure (mm Hg)

FIGURE 28–7

Cardiovascular adjustments to hemorrhage.

(Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

“normal” venous function curve shown. The normal cardiac and venous function curves intersect at point A, so cardiac output is 5 L/min and central venous pressure is 2 mm Hg in the normal state. When blood volume decreases due to hemorrhage, the peripheral venous pressure decreases and the venous function curve is shifted to the left. In the absence of any reflex responses, the cardiovascular system must switch its operation to point B because this is now the point at which the cardiac function curve and the new venous function curve intersect. This automatically occurs because at the moment of blood loss, the venous function curve is shifted to the left and venous return decreases below cardiac output at the central venous pressure of 2 mm Hg. This is what leads to the decrease in the central venous compartment’s volume and pressure that causes the shift in operation from point A to point B. By comparing points A and B in Figure 28–7, note that blood loss itself decreases cardiac output and central venous pressure by shifting the venous function curve. In going from point A to point B, cardiac output decreases solely because of decreased filling pressure and Starling’s law of the heart. Subnormal cardiac output evokes a number of compensatory mechanisms to bring cardiac output back to more normal levels. One of these is an increase in the activity of cardiac sympathetic nerves that, as discussed in Chapter 24, causes a shift to a cardiac function curve that is higher than normal. The effect of increasing cardiac sympathetic activity is illustrated by a shift in cardiovascular operation from point B to point C. In itself, the increased cardiac sympathetic nerve activity increases cardiac output (from 3 to 4 L/min) but causes a further decrease in central venous pressure. This decrease in central venous pressure occurs because points B and C lie on

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the same venous function curve. Cardiac sympathetic nerves do not affect the venous function curve. Venous return is higher at point C than at point B, but the venous function curve has not shifted. An additional compensatory mechanism evoked by blood loss is increased activity of the sympathetic nerves leading to veins. Recall that this increases peripheral venous pressure and causes a rightward shift of the venous function curve. Therefore, increased sympathetic activity to veins tends to shift the venous function curve, originally decreased by blood loss, back toward normal. As a consequence of the increased peripheral venous tone and the shift to a more normal venous function curve, the cardiovascular operation shifts from point C to point D in Figure 28–7. Thus, peripheral venous constriction raises cardiac output by increasing central venous pressure and moving upward along a fixed cardiac function curve. It must be pointed out that separating the response to hemorrhage into distinct, progressive steps (i.e., A to B to C to D) is only a conceptualization for appreciating the individual effects of the different processes involved. In reality, the reflex venous and cardiac responses occur simultaneously and so quickly that they will keep up with the blood loss as it occurs. Thus, the actual response to hemorrhage would follow nearly a straight line from point A to point D. In summary, point D illustrates that normal cardiac output can be sustained in the face of blood loss by the combined effect of peripheral and cardiac adjustments. Hemorrhage is only one of the numerous potential disturbances to the cardiovascular system. Plots such as those shown in Figure 28–7 are very useful for understanding the many disturbances to the cardiovascular system and the ways by which they may be compensated.

CLINICAL IMPLICATIONS OF ABNORMAL CENTRAL VENOUS PRESSURES Although there is no way to actually determine the position of either cardiac function or venous function curves, important information about a patient’s circulatory status can be obtained from measures of central venous pressure. From what has been presented in this chapter, it is possible to conclude that a patient with abnormally high central venous pressure must have a depressed cardiac function curve, a right-shifted venous function curve, or both. Very high central venous pressures are a hallmark of patients with congestive heart failure because they have the combination of dysfunctional heart muscle (depressed cardiac function curve) and excessive fluid volume (right-shifted venous function curve). Abnormally low central venous pressures, on the other hand, could theoretically be caused by either an increased cardiac function curve or a leftshifted venous function curve. The clinical reality is that abnormally low central venous pressures are invariably the

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result of a left shift of the venous function curve caused by either low blood volume or lack of venous tone. Rough estimates of a patient’s central venous pressure can be obtained by observing the external jugular veins. Because gravity keeps veins in the head and neck collapsed when a normal individual is upright, there is no distention (or retrograde pulsations from atrial contractions) observed in these neck veins. Conversely, when fully recumbent, neck veins are full and pulsations are detected. If a normal individual is placed in a semi-recumbent position so that external jugular veins are positioned at 7 cm above the right atrium, the point between the collapsed venous segment and the filled segment can often be visualized. Abnormally high central venous pressure is associated with neck vein distention at a higher level (perhaps even when the patient is upright). Because of its diagnostic value in critical care situations, central venous pressure is often monitored continuously via a catheter inserted in a peripheral vein and advanced centrally until its tip is in the central venous compartment (i.e., near or in the right atrium). In some situations, it is desirable to assess left atrial pressure, which is the filling pressure for the left side of the heart. This is commonly done with a specialized, flow-directed venous catheter with a small inflatable balloon at its tip to drag it with the blood flow through the right ventricle and pulmonic valve into the pulmonary artery. The balloon is then deflated and the cannula is advanced further until it wedges into a terminal branch of the pulmonary vasculature. The pulmonary wedge pressure recorded at this junction provides a useful estimate of left atrial pressure because there are no valves between the left atrium and the catheter tip.

CLINICAL CORRELATION A 75-year-old woman visits her doctor complained of increasing weakness and fatigue, shortness of breath on minimal exertion, and a recent increase in body weight. She often has to get up at night to urinate and has noticed that her feet and ankles seem to be swollen. She reports several episodes of waking up at night feeling like she could not catch her breath until she got out of bed and stood at her open window. She has been physically well until this condition developed over the last few months. She does not smoke or drink and takes no medicines except for an occasional aspirin or antacid. She is 5′3″ (160 cm), 146 lb (66 kg) with heart rate of 88 beats/min and blood pressure 165/95 mm Hg (normal values 120–140/80–90 mm Hg). Auscultation of the chest with a stethoscope indicates normal heart sounds but abnormal breath sounds with fine crackles heard over both lung bases late in expiration. An ECG indicates mild left ventricular hypertrophy and her chest x-ray shows an enlarged cardiac silhouette and pleural effusion, an accumulation of fluid between the visceral

pleura and parietal pleura. An echocardiogram revealed dilated cardiac chambers, thickened left ventricular wall, and a left ventricular ejection fraction of 0.35 (normal value >0.55) (see Chapter 25). She was diagnosed with chronic congestive heart failure secondary to chronic hypertension. She was treated with a diuretic to increase her urine output and relieve her symptoms of congestion and an angiotensin converting enzyme (ACE) inhibitor to reduce her high blood pressure. Once her condition stabilizes, she will be treated with beta-adrenergic receptor blockers at a low dose to decrease sympathetic stimulation of the heart. Chronic heart failure (CHF) exists whenever ventricular function is depressed through conditions that directly impair the mechanical performance of heart muscle such as (1) progressive coronary artery disease, (2) sustained increase in cardiac afterload as that which accompanies arterial hypertension or aortic valve stenosis, (3) reduced functional muscle mass following myocardial infarction, or (4) primary cardiomyopathy. Regardless of the precipitating cause, most forms of heart failure are associated ultimately with a reduced myocyte function. Systolic heart failure is associated with a left ventricular ejection fraction of less than 0.40. This also implies that the heart is operating on a lowerthan-normal cardiac function curve, that is, a reduced cardiac output at any given filling pressure. An example of the progression of events leading to CHF is well illustrated by the cardiac output and venous function curves shown in Figure 28–8. Initially, normal cardiac output and normal venous function curves will intersect at point A with cardiac output of 5 L/min at a central venous pressure of less than 2 mm Hg. With an abrupt heart failure as might accompany a myocardial infarction and severe damage to the ventricular muscle, the heart’s operation will shift to a much lower-than-normal cardiac output curve and the “equilibrium” will shift from the normal point A to point B—that is, cardiac output decreases below normal while central venous pressure increases above normal. The decreased cardiac output leads to decreased arterial pressure and reflex activation of the cardiovascular sympathetic nerves. Increased sympathetic nerve activity tends to (1) raise the cardiac function curve toward normal and (2) increase peripheral venous pressure through venous constriction and thus raises the venous function curve above normal. The heart’s operation will now shift from point B to point C. Thus, the depressed cardiac output is substantially improved by the immediate consequences of increased sympathetic nerve activity. Note, however, that the cardiac output at point C is still below normal. The arterial pressure associated with cardiovascular operation at point C is likely to be near normal, however, because higher-than-normal total peripheral resistance

CHAPTER 28 Venous Return and Cardiac Output

↑↑ Fluid retention

283

Normal heart

Cardiac output or Venous return (L/min)

12 Normal sympathetic activity ↑ Fluid retention 10 ↑ Venous tone

↑↑ Sympathetic activity

8 ↑ Sympathetic activity

Normal 6 A

C

D

4

E

Failing heart

Normal sympathetic activity

B

2

0

2

4

6

8

10

Central venous pressure (mm Hg)

FIGURE 28–8

Cardiovascular alterations with compensated chronic systolic heart failure. (Modified with permission from Mohrman DE, Heller

LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

will also accompany higher-than-normal sympathetic nerve activity. In the long term, cardiovascular operation cannot remain at point C in Figure 28–8. Operation at point C involves higher-than-normal sympathetic activity, and this will inevitably cause a gradual increase in blood volume by mechanisms that will be described in Chapter 29. Over several days, there is a progressive rise in the venous function curve as a result of increased blood volume and, consequently, increased mean circulatory filling pressure. This will progressively shift the cardiovascular operating point from C to D to E. Note that increased fluid retention (C → D → E in Figure 28–8) causes a progressive increase in cardiac output toward normal and simultaneously allows a reduction in sympathetic nerve activity toward the normal value. Reduced sympathetic activity is beneficial for several reasons. First, decreased arteriolar constriction permits renal and splanchnic blood flow to return toward more normal values. Second, myocardial oxygen consumption may fall as sympathetic nerve activity falls, even though cardiac output tends to increase. Recall that increased heart rate and increased cardiac contractility greatly increase myocardial oxygen consumption. Reduced myocardial oxygen consumption is especially beneficial in situations where inadequate coronary blood flow is the cause of the heart failure. In any case, once a normal cardiac output has been achieved, the individual is said to be in a “compensated” state. The extracellular fluid volume remains expanded

after reaching the compensated state even though sympathetic activity may have returned to near-normal levels. (Net fluid loss from this new steady state with expanded body fluid volume requires a period of less-than-normal sympathetic activity.) Unfortunately, the consequences of fluid retention in cardiac failure are not all beneficial. Note in Figure 28–8 that fluid retention (C → D → E) will cause both peripheral and central venous pressures to be much higher than their normal values. Chronically high central venous pressure causes chronically increased end-diastolic volume (cardiac dilation). Up to a point, cardiac performance is improved by increased cardiac filling volume through Starling’s law. Excessive cardiac dilation, however, can impair cardiac function because according to the law of Laplace, increased total wall tension is required to generate pressure within an enlarged ventricular chamber. The high venous pressure associated with fluid retention also adversely affects organ function because high venous pressure produces transcapillary fluid filtration, edema formation, and congestion (hence the commonly used term congestive heart failure). Left heart failure may lead to pulmonary edema with dyspnea (shortness of breath) and respiratory crisis. Patients often complain of difficulty breathing especially during the night (paroxysmal nocturnal dyspnea). Being recumbent promotes a fluid shift from the extremities into the central venous pool and lungs, making the horizontal patient’s pulmonary problems worse. Such patients often sleep more comfortably when propped

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up. Right heart failure results in distended neck veins, ankle edema, and fluid accumulation in the abdomen (ascites) with liver congestion and dysfunction. Plasma volume expansion combines with abnormal liver function to reduce the concentration of plasma proteins by as much as 30%. This reduction in plasma oncotic pressure further contributes to the development of interstitial edema of congestive heart failure. In the example shown in Figure 28–8, the depression in the cardiac output curve because of heart failure is only moderately severe. Thus, it is possible, through moderate fluid retention, to achieve a new steady state with a normal cardiac output and essentially normal sympathetic activity (point E). The situation at point E is relatively stable because the stimuli for further fluid retention have been removed. If, however, the heart failure is more severe, the cardiac output curve may be so depressed that normal cardiac output cannot be achieved by any amount of fluid retention. In these cases fluid retention is extremely marked, as is the elevation in venous pressure, and the complications of congestion are very serious problems.

CHAPTER SUMMARY ■

■

■

■

■ ■

Mean circulatory filling pressure is a theoretical measure of pressure in the systemic circuit when flow is stopped and is influenced primarily by blood volume and peripheral venous tone. Central venous pressure has a negative influence on venous return that can be illustrated graphically as a venous function curve. Peripheral venous pressure has a positive influence on venous return and can be elevated by increased blood volume and/or increased venous tone. Because of its opposing influences on cardiac output and venous return, central venous pressure automatically attains a value that makes cardiac output and venous return equal. Central venous pressure gives clinically relevant information about circulatory status. Central venous pressure can be estimated noninvasively by noting the fullness of a patient’s jugular veins.

STUDY QUESTIONS 1. In a severely dehydrated patient, you would expect to find A) a depressed cardiac function curve. B) an increased mean circulatory filling pressure. C) an increased central venous pressure. D) distended jugular veins. E) decreased cardiac output. 2. If you gave a blood transfusion to a patient who had recently experienced a severe hemorrhage, you would expect A) to expand arterial volume. B) to expand venous volume. C) to decrease central venous pressure. D) to decrease the mean circulatory filling pressure. E) to reduce cardiac output. 3. Which of the following would directly (by themselves in the absence of any compensatory responses) tend to decrease central venous (cardiac filling) pressure? A) increased sympathetic nerve activity to only the heart B) increased parasympathetic nerve activity to only the heart C) increased blood volume D) decreased total peripheral resistance E) immersion in water up to the waist 4. Which of the following will decrease the mean circulatory filling pressure? A) increased circulating blood volume B) increased cardiac output C) decreased arteriolar tone D) decreased venous tone E) increased arterial stiffness 5. In a steady state, venous return will be greater than cardiac output when A) peripheral venous pressure is higher than normal. B) blood volume is higher than normal. C) heart rate is lower than normal. D) cardiac contractility is lower than normal. E) Never, because in a steady state venous return must equal cardiac output.

29 C

Arterial Pressure Regulation David E. Mohrman and Lois Jane Heller

H A

P

T

E

R

O B J E C T I V E S ■

■ ■

■

■ ■

■

■ ■ ■

Identify the sensory receptors, afferent pathways, central integrating centers, efferent pathways, and effector organs that participate in the arterial baroreceptor reflex. State the location of the arterial baroreceptors and describe their operation. Describe how changes in the afferent input from arterial baroreceptors influence the activity of the sympathetic and parasympathetic preganglionic fibers. Describe how the sympathetic and parasympathetic outputs from the medullary cardiovascular centers change in response to changes in arterial pressure. Diagram the chain of events that are initiated by the arterial baroreceptor reflex to compensate for a change in arterial pressure. Describe how inputs to the medullary cardiovascular centers from cardiopulmonary baroreceptors, and arterial and central chemoreceptors influence sympathetic activity, parasympathetic activity, and mean arterial pressure. Describe and indicate the mechanisms involved in the cerebral ischemic response, the Cushing reflex, the alerting reaction, blushing, vasovagal syncope, and the cardiovascular responses to emotion and pain. Describe baroreceptor adaptation. Describe the influence of changes in body fluid volume on arterial pressure and diagram the steps involved in this process. Describe how mean arterial pressure is adjusted in the long term to that which causes fluid output rate to equal fluid intake rate.

REGULATION OF ARTERIAL PRESSURE Appropriate systemic arterial pressure is the single most important requirement for the proper function of the cardiovascular system. Without sufficient arterial pressure, the brain and the heart do not receive adequate blood flow no matter what adjustments are made in their vascular resistance by local control mechanisms. In contrast, excessive arterial pressure

Ch29_285-294.indd 285

puts unnecessary demands on the heart and vessels. Arterial pressure is continuously monitored by sensors located within the body. Whenever arterial pressure varies from normal, multiple reflex responses are initiated that cause the adjustments in cardiac output and total peripheral resistance necessary to return arterial pressure to its normal value. In the short term (seconds), these adjustments are brought about by changes in the activity of the autonomic nerves leading to the heart and peripheral vessels. In the long term (minutes to days), other mechanisms such as changes in cardiac output

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brought about by changes in blood volume play an increasingly important role in the control of arterial pressure. The short- and long-term regulations of arterial pressure will be discussed in order in this chapter.

nerves. The effector organs are the heart and peripheral blood vessels.

Efferent Pathways Previous chapters have discussed the many actions of the sympathetic and parasympathetic nerves leading to the heart and blood vessels. For both systems, postganglionic fibers, whose cell bodies are in ganglia outside the central nervous system, form the terminal link to the heart and vessels. The influences of these postganglionic fibers on key cardiovascular variables are summarized in Figure 29–1. The activity of the terminal postganglionic fibers of the autonomic nervous system is determined by the activity of preganglionic fibers whose cell bodies lie within the central nervous system (see Chapter 19). In the sympathetic pathways, the cell bodies of the preganglionic fibers are located within the spinal cord. These preganglionic neurons have spontaneous activity that is modulated by excitatory and inhibitory inputs, which arise from centers in the brainstem and descend

SHORT-TERM REGULATION OF ARTERIAL PRESSURE ARTERIAL BARORECEPTOR REFLEX The arterial baroreceptor reflex is the single most important mechanism providing short-term regulation of arterial pressure. Recall that the usual components of a reflex pathway include sensory receptors, afferent pathways, integrating centers in the central nervous system, efferent pathways, and effector organs. As shown in Figure 29–1, the efferent pathways of the arterial baroreceptor reflex are the cardiovascular sympathetic and cardiac parasympathetic

Medulla Spinal cord

rvlm −

+ +

−

nts

+ na

rn

Sympathetic preganglionic fibers

??

Parasympathetic preganglionic fibers

+ + Ganglia

+ Ganglia

Pcv

− + + SV × HR = CO

+

Central venous pool

Arterial baroreceptor + − Pa = CO × TPR

Heart

Systemic organs Veins

Arterioles

Ppv +

TPR +

FIGURE 29–1 Components of the arterial baroreceptor reflex pathway. nts, nucleus tractus solitarius; rvlm, rostral ventrolateral medullary group; rn, raphe nucleus; na, nucleus ambiguus; ??, incompletely mapped integration pathways that may also involve structures outside the medulla. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

CHAPTER 29 Arterial Pressure Regulation in distinct excitatory and inhibitory spinal pathways. In the parasympathetic system, the cell bodies of the preganglionic fibers are located within the brainstem. Their spontaneous activity is modulated by inputs from adjacent centers in the brainstem.

Afferent Pathways Sensory receptors, called arterial baroreceptors, are found in abundance in the walls of the aorta and carotid arteries. Major concentrations of these receptors are found near the arch of the aorta (the aortic baroreceptors) and at the bifurcation of the common carotid artery into the internal and external carotid arteries on either side of the neck (the carotid sinus baroreceptors). The receptors are mechanoreceptors that sense arterial pressure indirectly from the degree of stretch of the elastic arterial walls. In general, increased stretch causes an increased action potential generation rate by the arterial baroreceptors. Baroreceptors actually sense not only absolute stretch, but also the rate of change of stretch. For this reason, both the mean arterial pressure and arterial pulse pressure affect baroreceptor firing rate as indicated in Figure 29–2. The dashed curve shows how baroreceptor firing rate is affected by different levels of a steady arterial pressure. The solid curve indicates how baroreceptor firing rate is affected by the mean value of a pulsatile arterial pressure. Note that the presence of pulsations increases the baroreceptor firing rate at any given level of mean arterial pressure. Note also that changes in mean arterial pressure near the normal value of 100 mm Hg produce the largest changes in baroreceptor discharge rate and there is very little output at low pressures. If arterial pressure remains above normal over a period of several days, the arterial baroreceptor firing rate will gradually return toward normal. Thus, arterial baroreceptors are said to adapt to long-term changes in arterial pressure. For this reason, the arterial baroreceptor reflex does not serve as a mechanism for the long-term regulation of arterial pressure.

Baroreceptor nerve activity

Max

Pulsatile Steady

0

50 100 150 200 Mean arterial pressure (mm Hg)

FIGURE 29–2 Effect of mean arterial pressure on baroreceptor nerve activity. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/ McGraw-Hill, 2006.)

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Central Integration Much of the central integration involved in reflex regulation of the cardiovascular system occurs in the medulla oblongata in what are traditionally referred to as the medullary cardiovascular centers. The neural interconnections between the diffuse structures in this area are complex and not completely mapped. Moreover, these structures appear to serve multiple functions including respiratory control. What is known with a fair degree of certainty is where the cardiovascular afferent and efferent pathways enter and leave the medulla. As indicated in Figure 29–1, the afferent sensory information from the arterial baroreceptors enters the medullary nucleus tractus solitarius, where it is relayed via polysynaptic pathways to other structures in the medulla (and higher brain centers, such as the hypothalamus, as well). The cell bodies of the efferent vagal parasympathetic cardiac nerves are located primarily in the medullary nucleus ambiguus. The sympathetic autonomic efferent information leaves the medulla predominantly from the rostral ventrolateral medulla group of neurons (via an excitatory spinal pathway) or the raphe nucleus (via an inhibitory spinal pathway). The intermediate processes involved in the actual integration of the sensory information into appropriate sympathetic and parasympathetic responses are not well understood. Much of this integration takes place within the medulla, but higher centers such as the hypothalamus are probably involved as well. In this context, knowing the details of the integration process is not as important as appreciating the overall effects that changes in arterial baroreceptor activity have on the activities of parasympathetic and sympathetic cardiovascular nerves. Several functionally important points about the central control of the autonomic cardiovascular nerves are illustrated in Figure 29–1. The major external influence on the cardiovascular centers comes from the arterial baroreceptors. Because the arterial baroreceptors are active at normal arterial pressures, they supply a tonic input to the central integration centers. As indicated in Figure 29–1, the integration process is such that increased input from the arterial baroreceptors tends to simultaneously: (1) inhibit the activity of the spinal sympathetic excitatory tract, (2) stimulate the activity of the spinal sympathetic inhibitory tract, and (3) stimulate the activity of parasympathetic preganglionic nerves. Thus, an increase in the arterial baroreceptor discharge rate (caused by increased arterial pressure) causes a decrease in the tonic activity of cardiovascular sympathetic nerves and a simultaneous increase in the tonic activity of cardiac parasympathetic nerves. Conversely, decreased arterial pressure causes increased sympathetic and decreased parasympathetic activity.

OPERATION OF THE ARTERIAL BARORECEPTOR REFLEX The arterial baroreceptor reflex is a continuously operating control system that automatically makes adjustments to prevent disturbances in the heart and/or vessels from causing

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↓ Mean arterial pressure (primary disturbance) 29 ↓ Baroreceptor discharge 29 29

29 Medullary cardiovascular centers ↓ Parasympathetic activity

↑ Sympathetic activity 27

24

27 ↑ Arteriolar tone

↑ Venous tone 27 27

↑ Cardiac contractility

↑ Blood volume ↑ Peripheral venous pressure 27

28

23

23

28

Transcapillary fluid reabsorption

+ − Central venous pressure

26

↓ Capillary pressure ↑ Vasoconstriction

26

26 ↑ Total peripheral resistance 26

24

24

↑ Stroke volume 24

↑ Heart rate

↑ Cardiac output

24

26

↑ Mean arterial pressure (counteracting response)

FIGURE 29–3 Immediate cardiovascular adjustments caused by a decrease in arterial blood pressure. Circled numbers indicate the chapter in which each interaction is discussed. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

large changes in mean arterial pressure. The arterial baroreceptor reflex mechanism acts to regulate arterial pressure in a negative feedback fashion as was described in Chapter 1. Figure 29–3 shows many events in the arterial baroreceptor reflex pathway that occur in response to a disturbance of decreased mean arterial pressure. All of the events shown in Figure 29–3 have already been discussed, and each should be carefully examined (and reviewed if necessary) at this point because a great many of the interactions that are essential to understanding cardiovascular physiology are summarized in this figure. Note in Figure 29–3 that the overall response of the arterial baroreceptor reflex to the disturbance of decreased mean arterial pressure is to increase mean arterial pressure (i.e., the response tends to counteract the disturbance). A disturbance of increased mean arterial pressure would elicit events opposite to those shown in Figure 29–3 and produce a decrease in mean arterial pressure; again, the response tends to counteract the disturbance. Recall that neural control of vessels is more

important in some areas such as the kidney, the skin, and the splanchnic organs than in the brain and heart muscle. Thus, the reflex response to a decrease in arterial pressure may, for example, include a significant increase in renal vascular resistance and a decrease in renal blood flow without changing the cerebral vascular resistance or blood flow. The peripheral vascular adjustments associated with the arterial baroreceptor reflex take place primarily in organs with strong sympathetic vascular control.

OTHER CARDIOVASCULAR REFLEXES & RESPONSES In spite of the arterial baroreceptor reflex mechanism, large and rapid changes in mean arterial pressure occur in certain physiological and pathological situations. These reactions are caused by influences on the medullary cardiovascular centers other than those from the arterial baroreceptors. As outlined

CHAPTER 29 Arterial Pressure Regulation in the following sections, these inputs to the medullary cardiovascular centers arise from many types of peripheral and central receptors as well as from “higher centers” in the central nervous system such as the hypothalamus and the cortex. An analogy was made between the arterial baroreceptor reflex operating to control arterial pressure to a home heating system acting to control room temperature (see Chapter 1). The temperature setting on the thermostat determines the set point for temperature regulation. Most of the influences that are about to be discussed influence arterial pressure as if they changed the arterial baroreceptor reflex’s set point for pressure regulation. Consequently, the arterial baroreceptor reflex does not resist most of these pressure disturbances but actually assists in producing them.

REFLEXES FROM RECEPTORS IN HEART & LUNGS A host of mechanoreceptors and chemoreceptors that elicit reflex cardiovascular responses have been identified in the atria, ventricles, coronary vessels, and lungs. The role of these cardiopulmonary receptors in the control of the cardiovascular system is, in most cases, incompletely understood, but they are likely involved in many physiological and pathological states. Cardiopulmonary baroreceptors (sometimes referred to as low-pressure receptors) sense the pressure (or volume) in the atria and central venous pool. Increased central venous pressure (or volume) causes activation of these receptors by stretch, and elicits a reflex decrease in sympathetic activity. Decreased central venous pressure (or volume) produces the opposite response. These cardiopulmonary baroreflexes normally exert a tonic inhibitory influence on sympathetic activity. Alterations in sympathetic activity evoked by increases or decreases in central venous pressure not only have short-term influences on arterial pressure, but also influence renal mechanisms that influence blood volume and long-term regulation of arterial pressure.

CHEMORECEPTOR REFLEXES Low Po2, low pH, and/or high Pco2 levels in the arterial blood cause reflex increases in breathing and mean arterial pressure. These responses appear to be a result of increased activity of arterial chemoreceptors, located in the carotid arteries and the arch of the aorta, and central chemoreceptors, located within the central nervous system. Chemoreceptors probably play little role in the normal regulation of arterial pressure because arterial blood Po2 and Pco2 are normally held very nearly constant by respiratory control mechanisms. See Chapter 38 for more details. An extremely strong reaction called the cerebral ischemic response is triggered by inadequate blood flow (ischemia) to the brain and can produce a more intense sympathetic vasoconstriction and cardiac stimulation than is elicited by any other influence on the cardiovascular control centers. Presum-

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ably the cerebral ischemic response is initiated by chemoreceptors located within the central nervous system. However, if cerebral blood flow is severely inadequate for several minutes, the cerebral ischemic response wanes and is replaced by marked loss of sympathetic activity. This results when function of the nerve cells in the cardiovascular centers becomes directly depressed by the unfavorable chemical conditions in the cerebrospinal fluid. Whenever intracranial pressure is increased—for example, by increased cerebral spinal fluid (CSF) pressure or traumainduced bleeding within the rigid cranium—there is a parallel increase in arterial pressure. This is called the Cushing reflex. It can cause mean arterial pressures of more than 200 mm Hg in severe cases of increased intracranial pressure. The benefit of the Cushing reflex is that it prevents collapse of cranial vessels and thus preserves adequate brain blood flow in the face of large increases in intracranial pressure. The mechanisms responsible for the Cushing reflex are not known but could involve the central chemoreceptors. A hallmark of the Cushing reflex is acutely increased arterial pressure in spite of accompanying bradycardia. It seems as if the short-term arterial baroreceptor reflex is attempting to counteract this disturbance by activating parasympathetic nerves to the SA node of the heart.

CARDIOVASCULAR RESPONSES ASSOCIATED WITH EMOTION Cardiovascular responses are frequently associated with certain states of emotion. These responses originate in the cerebral cortex and reach the medullary cardiovascular centers through corticohypothalamic pathways. The least complicated of these responses is the blushing that is often detectable in individuals with lightly pigmented skin during states of embarrassment. The blushing response involves a loss of sympathetic vasoconstrictor activity only to particular cutaneous vessels, and this produces the blushing by allowing engorgement of the cutaneous venous sinuses. Excitement or a sense of danger often elicits a complex behavioral pattern called the alerting reaction (also called the “defense” or “fight-or-flight” response). The alerting reaction involves a host of responses such as pupillary dilation and increased skeletal muscle tenseness that are generally appropriate preparations for some form of intense physical activity. The cardiovascular component of the alerting reaction is an increase in blood pressure caused by a general increase in cardiovascular sympathetic nervous activity and a decrease in cardiac parasympathetic activity. Some individuals respond to situations of extreme stress by fainting, a situation referred to clinically as vasovagal syncope. The loss of consciousness is due to decreased cerebral blood flow that is itself produced by a sudden dramatic loss of arterial blood pressure that occurs as a result of a sudden loss of sympathetic tone and a simultaneous large increase in parasympathetic tone and decrease in heart rate.

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CENTRAL COMMAND

phasize that the arterial baroreceptors normally and continuously supply the major input to the medullary centers. The arterial baroreceptor input is shown as inhibitory because an increase in arterial baroreceptor firing rate results in a decrease in sympathetic output. (Decreased sympathetic output should be taken to imply also a simultaneous increase in parasympathetic output that is not shown in this figure.) As is indicated in Figure 29–4, the nonarterial baroreceptor influences on the medullary cardiovascular centers fall into two categories: (1) those that increase arterial pressure by raising the set point for the arterial baroreceptor reflex and thus cause an increase in sympathetic activity and (2) those that decrease arterial pressure by lowering the set point for the arterial baroreceptor reflex and thus cause a decrease in sympathetic activity.

The term central command is used to imply an input from the cerebral cortex to lower brain centers during voluntary muscle exercise. The concept is that the same cortical drives that initiate somatomotor (skeletal muscle) activity also simultaneously initiate cardiovascular (and respiratory) adjustments appropriate to support that activity. In the absence of any other obvious causes, central command is at present the best explanation as to why both mean arterial pressure and respiration increase during voluntary exercise.

REFLEX RESPONSES TO PAIN Pain can have either a positive or a negative influence on arterial pressure. Generally, superficial or cutaneous pain causes an increase in blood pressure in a manner similar to that associated with the alerting response and perhaps over many of the same pathways. Deep pain from receptors in the viscera or joints, however, often causes a cardiovascular response similar to that which accompanies vasovagal syncope, that is, decreased sympathetic tone, increased parasympathetic tone, and a significant decrease in blood pressure. This response may contribute to the state of shock that often accompanies crushing injuries and/or joint displacement.

LONG-TERM REGULATION OF ARTERIAL PRESSURE Long-term regulation of arterial pressure is a topic of clinical relevance because of the prevalence of hypertension (sustained excessive arterial blood pressure) in our society. The most long-standing and generally accepted theory of long-term pressure regulation is that it crucially involves the kidneys, their sodium handling, and ultimately the regulation of blood volume. This theory is sometimes referred to as the “renalMAP set point” or “fluid balance” model of long-term arterial blood pressure control. In essence, this theory asserts that in the long term, mean arterial pressure is whatever it needs to be to maintain an appropriate blood volume through arterial pressure’s direct effects on renal function.

SUMMARY The influences on the medullary cardiovascular centers that have been discussed in the preceding sections are summarized in Figure 29–4. This figure is intended first to reem-

Response to exercise (central command) Sense of danger (alerting/defense reaction) Cerebral ischemic response ↑ Intracranial pressure (cushing reflex) ↓ PO2, ↑ PCO2 in arterial blood ↓ Central venous pressure (cardiopulmonary baroreflexes) Cutaneous pain Increase set point

+ Sympathetic output

Medullary centers

−

Arterial baroreceptor

−

FIGURE 29–4

Summary of the factors that influence the set point of the arterial baroreceptor reflex. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

Lower set point Vasovagal syncope Deep pain ↑ Central venous pressure (cardiopulmonary baroreflexes)

input

CHAPTER 29 Arterial Pressure Regulation

FLUID BALANCE & ARTERIAL PRESSURE

pressure, hours or even days may be required before a change in urinary output rate produces a significant accumulation or loss of total body fluid volume. What this fluid volume mechanism lacks in speed, however, it more than makes up for in persistence. As long as there is any inequality between the fluid intake rate and the urinary output rate, body fluid volume is changing and this fluid volume mechanism has not completed its adjustment of arterial pressure. The fluid volume mechanism is in equilibrium only when the urinary output rate equals the fluid intake rate. (In the present discussion, assume that fluid intake rate represents that in excess of the obligatory fluid losses that normally occur in the feces and by transpiration from the skin and structures in the respiratory tract. The processes that regulate thirst are not well understood but seem to involve many of the same factors that influence urinary output.) In the long term, the arterial pressure must be that which makes the urinary output rate equal to the fluid intake rate. The arterial baroreceptor reflex is, of course, essential for counteracting rapid changes in arterial pressure. The fluid volume mechanism, however, determines the long-term level of arterial pressure because it slowly overwhelms all other influences. Through adaptation, the baroreceptor mechanism adjusts itself so that it operates to prevent acute changes in blood pressure from the prevailing long-term level as determined through fluid balance.

Several key factors in the long-term regulation of arterial blood pressure have already been considered. First is the fact that the baroreceptor reflex, however well it counteracts temporary disturbances in arterial pressure, cannot effectively regulate arterial pressure in the long term for the simple reason that the baroreceptor firing rate adapts to prolonged changes in arterial pressure. The second pertinent fact is that circulating blood volume can influence arterial pressure because: ↑ blood volume → ↑ peripheral venous pressure → right shift of venous function curve → ↑ central venous pressure → ↑ cardiac output → ↑ arterial pressure. Arterial pressure has a profound influence on urinary output rate and thus affects total body fluid volume. Because blood volume is one of the components of the total body fluid, blood volume alterations accompany changes in total body fluid volume. The mechanisms are such that a decrease in arterial pressure causes a decrease in urinary output rate and thus an increase in blood volume. But, as outlined in the preceding sequence, increased blood volume tends to increase arterial pressure. Thus, the complete sequence of events that are initiated by a decrease in arterial pressure can be listed as follows: ↓ Arterial pressure (disturbance) → ↓ urinary output rate → ↑ fluid volume → ↑ blood volume → ↑ cardiac output → ↑ arterial pressure (compensation). As indicated in Figure 29–5, both the arterial baroreceptor reflex and this fluid volume mechanism are negative feedback loops that regulate arterial pressure. Whereas the arterial baroreceptor reflex is very quick to counteract disturbances in arterial

SHORT-TERM

LONG-TERM

Baroreceptor reflex

Fluid balance

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EFFECT OF ARTERIAL PRESSURE ON URINARY OUTPUT RATE As discussed above, an increase in arterial pressure normally leads to an increase in urine output rate. Many mechanisms are involved in this phenomenon and are discussed in detail

Fluid intake rate

Blood volume −

−

+

TPR +

CO +

+ Fluid Volume

Arterial pressure

− Kidney +

Urinary output rate

FIGURE 29–5 Mechanisms of short- and long-term regulations of arterial pressure. TPR, total peripheral resistance; CO, cardiac output. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

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Heathy person

ic t

2

1

Normal fluid intake

N

Un tre ate d

he rap y

Hypertensive person

Diu ret

Urine output rate × normal

3

A C B 50

100

Restricted fluid intake 150

200

Mean arterial pressure (mm Hg)

FIGURE 29–6 Renal function curves in a normal person and in a hypertensive person with and without antihypertensive therapy. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

in Section 7. At this point, it is only important to recognize that, because of many synergistic influences, arterial pressure has a huge positive effect on renal urine output rate as is indicated by the very steep slope of the relationship shown in Figure 29–6. In a steady state, urine output (plus fluid lost from the body by other means) is equal to fluid intake (point N in this figure). At arterial pressures below point N, fluid intake exceeds urinary output and bodily fluid volume will necessarily be increasing. The opposite is true at arterial blood pressure higher than that at point N. Thus, a healthy person with a normal fluid intake rate will have, as a long-term average, the arterial pressure associated with point N in Figure 29–6. Because of the steepness of the curve shown in Figure 29–6, even marked changes in fluid intake rate have minor influences on the arterial pressure of a normal individual.

CLINICAL CORRELATION A 35-year-old African American male has come to the doctor for a general physical exam. He has not been to see a physician for at least 10 years. At present, he has no specific complaints about health conditions, but admits to not getting as much exercise as he did while in his twenties. His father had a mild heart attack at 50 years of age, received a coronary artery stent, and has been treated for hypertension for the 15 years since that time. His mother has recently been diagnosed with type 2 diabetes mellitus. He is 5′11″ (180 cm), 240 lb (109 kg), and has a heart rate of 64 beats/min and an arterial pressure of 150/92 mm Hg. Chest sounds and heart sounds are normal. All other aspects of the physical exam are within normal ranges. An

ECG shows left deviation of the ventricular mean electrical axis (−35°) (see Chapter 25). A tentative diagnosis of chronic hypertension is made. He has access to blood pressure monitoring equipment at home and was instructed to monitor his blood pressure daily for 1 week and to report his results to the doctor. At that time, a decision about therapeutic strategies will be made. Systemic hypertension is defined as a chronic increase in mean systemic arterial pressure above 140/90 mm Hg. It is an extremely common cardiovascular problem, affecting more than 20% of the adult population of the Western world. It has been established that hypertension increases the risk of coronary artery disease, myocardial infarction, heart failure, stroke, and many other serious cardiovascular problems. Moreover, it has been clearly demonstrated that the risk of serious cardiovascular incidents is reduced by proper treatment of hypertension. In approximately 90% of cases, the primary abnormality that produces high blood pressure is unknown. (This condition is sometimes referred to as primary or essential hypertension because the elevated level was previously thought to be “essential” to drive the blood through the systemic circulation, particularly the brain.) Genetic factors contribute importantly to the development of hypertension (generally being more common in males than females and in blacks than whites) and environmental factors such as obesity, high-salt diets, diabetes mellitus, and/or certain forms of psychological stress may either aggravate or precipitate hypertension in susceptible individuals. Structural changes in the left heart and arterial vessels occur in response to hypertension. Early alterations include hypertrophy of muscle cells and thickening of the walls of the ventricle and resistance vessels. Late changes associated with deterioration of function include increases in connective tissue and increased tissue stiffness. The established phase of hypertension is associated with increased total peripheral resistance. Cardiac output and/or blood volume may be increased during the early developmental phase, but are usually normal after the hypertension is established. The increased total peripheral resistance associated with established hypertension may be due to microvessel rarefaction (decrease in density), pronounced structural adaptations of the peripheral vascular bed, increased basal vascular smooth muscle tone, increased sensitivity and reactivity of the vascular smooth muscle cells to external vasoconstrictor stimuli, and/or diminished production and/or effect of endogenous vasodilator substances (e.g., nitric oxide). Chronic hypertension is not due to a sustained increase in sympathetic vasoconstrictor neural discharge nor is it due to a sustained increase of any blood-borne vasoconstrictive factor. (Both neural and hormonal influences,

CHAPTER 29 Arterial Pressure Regulation

however, may help initiate primary hypertension.) Blood pressure–regulating reflexes (both the short-term arterial and cardiopulmonary baroreceptor reflexes and the long-term, renal-dependent, pressure-regulating reflexes) become adapted or “reset” to regulate blood pressure at a higher-than-normal level. Disturbances in renal function contribute importantly to the development and maintenance of primary hypertension. Recall that, in the long term, arterial pressure can stabilize only at the level that makes urinary output rate equal to fluid intake rate. As shown by point N in Figure 29–6, this pressure is approximately 100 mm Hg in a normal individual. All forms of hypertension involve an alteration somewhere in the chain of events by which changes in arterial pressure produce changes in urinary output rate such that the renal function curve is shifted rightward as indicated in Figure 29–6. Higher-than-normal arterial pressure is required to produce a normal urinary output rate in a hypertensive individual. The untreated hypertensive individual in Figure 29–6 would have a very low urinary output rate at the normal mean arterial pressure of 100 mm Hg. With a normal fluid intake rate, this untreated hypertensive patient retains fluid to ultimately stabilize at point A (mean arterial pressure = 150 mm Hg). Baroreceptors adapt within days so that they will have a normal discharge rate at the prevailing average arterial pressure. Thus, once the hypertensive individual has been at point A for a week or more, even the baroreceptor mechanism will begin resisting acute changes from the 150-mm Hg pressure level. In certain hypertensive individuals, dietary salt restriction produces a substantial reduction in blood pressure because of the reduced requirement for water retention to osmotically balance the salt load. This effect is illustrated by a shift from point A to point B. The efficacy of lowering salt intake to lower arterial pressure depends heavily on the slope of the renal function curve in the hypertensive individual. The arterial pressure of a normal individual, for example, is affected only slightly by changes in salt intake because the normal renal function curve is so steep. A second common treatment of hypertension is diuretic therapy (see Chapters 44 and 46). The net effect of diuretic therapy is that the urinary output rate for a given arterial pressure is increased, that is, diuretic therapy shifts the renal function curve upward. The combined result of restricted fluid intake and diuretic therapy for the hypertensive individual of Figure 29–6 is illustrated by point C. A variety of antihypertensive pharmacological approaches are available that may include β-adrenergic blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and calcium channel blockers (see Section 7). Alterations in lifestyle, including reduction of stress, decreases in caloric intake, limitation

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of the amount of saturated fats in the diet, and establishment of a regular exercise program, may also help reduce blood pressure in certain individuals.

CHAPTER SUMMARY ■ ■

■

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Arterial pressure is closely regulated to ensure adequate blood flow to the tissues. The arterial baroreceptor reflex is responsible for regulating arterial pressure in the short term on a second-to-second and moment-to-moment basis. The arterial baroreceptor reflex involves the following: pressure sensing by stretch-sensitive baroreceptor nerve endings in the walls of arteries, neural integrating centers in the brainstem that adjust autonomic nerve activity in response to the pressure information they receive from the arterial baroreceptors, and responses of the heart and vessels to changes in autonomic nerve activity. Overall, the arterial baroreflex operates such that increases in arterial pressure lead to an essentially immediate decrease in sympathetic nerve activity and a simultaneous increase in parasympathetic nerve activity (and vice versa). The brainstem integrating centers also receive nonarterial baroreceptor inputs that can raise or lower the set point for short-term arterial pressure regulation. In the long term, arterial pressure is regulated by changes in blood volume that come about because arterial pressure has a strong influence on urinary output rate by the kidney.

STUDY QUESTIONS 1. In the normal operation of the arterial baroreceptor reflex, a cardiovascular disturbance that decreases mean arterial pressure will evoke a decrease in A) urine output rate. B) sympathetic nerve activity. C) heart rate. D) total peripheral resistance. E) myocardial contractility. 2. Which one of the following, after all reflex adjustments are complete, will result in an increase in mean arterial pressure? A) low carbon dioxide levels in arterial blood B) increased intracranial pressure C) decreased cardiac filling pressure D) low blood volume E) supraventricular tachycardia 3. An individual has higher-than-normal mean arterial pressure and lower-than-normal pulse rate. Which of the following is most likely to cause such a combination? A) low oxygen levels in arterial blood B) anxiety C) exercise D) significant blood loss E) a drug that selectively stimulates alpha-adrenergic receptors

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4. Which of the following best describes, first, the immediate direct effect and, second, the reflex cardiovascular consequences of giving a normal person a drug that blocks beta1-adrenergic receptors? A) decreased heart rate, increased total peripheral resistance B) decreased ejection fraction, decreased total peripheral resistance C) increased heart rate, increased urine production D) increased cardiac output, decreased total peripheral resistance E) decreased end-diastolic volume, increased heart rate

5. An increase in arterial baroreceptor firing rate will reflexly result in A) an increase in vagal activity to the heart. B) an increase in sympathetic activity to arterioles in the brain. C) an increase in renal blood flow. D) an increase in mean arterial pressure. E) an increase in cardiac ejection fraction.

30 C

Cardiovascular Responses to Physiological Stress Lois Jane Heller and David E. Mohrman

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Identify the primary disturbance(s) that any given normal homeostatic disturbance (such as changes in body position) places on the cardiovascular system. List how any such given primary disturbance changes the influence on the medullary cardiovascular centers from (1) arterial baroreceptors and (2) other sources. State what immediate reflex compensatory changes will occur in sympathetic and parasympathetic nerve activities as a result of the altered influences on the medullary cardiovascular centers. Indicate what immediate compensatory changes will occur to influence mean arterial pressure in response to any given primary disturbance, including changes in: heart rate, cardiac contractility, stroke volume, arteriolar tone, venous tone, peripheral venous pressure, central venous pressure, total peripheral resistance, resistance in any major organ, blood flow through any major organ, cutaneous blood flow, transcapillary fluid movement, and long-term renal adjustments in urine output and total body fluid balance. State how gravity influences arterial, venous, and capillary pressures at any height above or below the heart in a standing individual. Describe and explain the changes in central venous pressure and the changes in transcapillary fluid balance and venous volume in the lower extremities caused by standing upright. Describe the operation of the “skeletal muscle pump” and explain how it simultaneously promotes venous return and decreases capillary hydrostatic pressure in the muscle vascular beds. Identify the primary disturbances and compensatory responses evoked by acute changes in body position. Describe the chronic effects of long-term bed rest on cardiovascular variables. List the cardiovascular consequences of respiratory activity. Identify the major maternal cardiovascular adjustments that occur during pregnancy. Follow the pathway of blood flow through the fetal heart and describe the changes that occur at birth. Indicate the normal changes that occur in cardiovascular variables during childhood. Identify age-dependent changes that occur in cardiovascular variables Describe gender-dependent differences in cardiovascular variables.

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CARDIOVASCULAR RESPONSES TO PHYSIOLOGICAL STRESSES

EFFECT OF GRAVITY

A wide variety of normal, everyday situations can disturb homeostasis within the cardiovascular system and can evoke an equally wide variety of reflex responses. The key to understanding the cardiovascular adjustments in each situation is to recall that the arterial baroreceptor reflex and renal fluid balance mechanisms always act to blunt changes in arterial pressure. The overall result is that adequate blood flow to the brain and the heart muscle is maintained in any circumstance. The cardiovascular alterations in the following example is produced by the combined effects of (1) the primary, direct influences of the disturbance on the cardiovascular variables and (2) the reflex compensatory adjustments that are triggered by the primary disturbances. As you will see in later sections of this book, the general pattern of reflex adjustment is similar in all situations. Rather than trying to memorize the cardiovascular alterations that accompany each situation, the reader should strive to understand each response in terms of the primary disturbances and reflex compensatory reactions involved.

A

RESPONSES TO CHANGES IN BODY POSITION Significant cardiovascular readjustments accompany changes in body position because gravity has an effect on pressures within the cardiovascular system. In the preceding chapters, the influence of gravity was ignored and pressure differences between various points in the systemic circulation were related only to ˙ R). As shown in Figure flow and vascular resistance (Δ P = Q 30–1, this is approximately true only for a recumbent individual. In a standing individual, additional cardiovascular pressure differences exist between the heart and regions that are not at heart level. This is most important in the lower legs and feet of a standing individual. As indicated in Figure 30–1B, intravascular pressures in the feet may be increased by 90 mm Hg simply from the weight of the blood in the arteries and veins leading to and from the feet. Note by comparing Figure 30–1A and B that standing upright does not in itself change the flow through the lower extremities, since gravity has the same effect on arterial and venous pressures and thus does not change the arteriovenous pressure difference at any given level above or below the heart.

RECUMBENT

P = 100 mm Hg

P = 95 mm Hg

Arteries Arterioles Capillaries

Heart Veins

Foot P = 25 mm Hg

Valves

P = 0 mm Hg

P = 5 mm Hg

STANDING Surface P = 0 mm Hg

P = 100 mm Hg

Heart level P = 0 mm Hg

P = 95 mm Hg P = 95 mm Hg

Foot level P = 90 mm Hg

P =100 mm Hg

Arteries

Lymphatics

Veins

1.5-m depth

P = 0 mm Hg

P = 185 mm Hg

P = 185 mm Hg Filtration P = 115 mm Hg

P = 20 mm Hg

P = 105 mm Hg

P = 185 mm Hg P = 40 mm Hg

Without compensation With sympathetic stimulation During skeletal muscle contraction Shortly after contraction

B

C

D

E

FIGURE 30–1 Effect of gravity on vascular pressure (A and B) with compensatory influences of sympathetic stimulation (C) and the skeletal muscle pump (D and E). (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/ McGraw-Hill, 2006.)

CHAPTER 30 Cardiovascular Responses to Physiological Stress There are, however, two major direct effects of the increased pressure in the lower extremities that are shown in Figure 30–1B: (1) the increase in venous transmural pressure distends the compliant peripheral veins and greatly increases peripheral venous volume by as much as 500 mL in a normal adult and (2) the increase in capillary transmural hydrostatic pressure causes a tremendously high transcapillary filtration rate. For reasons to be described, reflex activation of sympathetic nerves accompanies the transition from a recumbent to an upright position. However, Figure 30–1C shows how vasoconstriction from sympathetic activation is only marginally effective in ameliorating the adverse effects of gravity on the lower extremities. Arteriolar constriction can cause a greater pressure drop across arterioles, but this has only a limited effect on capillary pressure because venous pressure remains extremely high. Filtration will continue at a very high rate. In fact, the normal cardiovascular reflex mechanisms alone are incapable of dealing with upright posture without the aid of the skeletal muscle pump. A person who remained upright without intermittent contraction of the skeletal muscles in the legs would lose consciousness in 10–20 minutes because of the decreased brain blood flow that would stem from diminished central blood volume, stroke volume, cardiac output, and arterial pressure. The effectiveness of the skeletal muscle pump in counteracting venous blood pooling and edema formation in the lower extremities during standing is illustrated in Figure 30–1D and E. The compression of vessels during skeletal muscle contraction expels both venous blood and lymphatic fluid from the lower extremities (Figure 30–1D). Immediately after a skeletal muscle contraction, both veins and lymphatic vessels are relatively empty because their one-way valves prevent the backflow of previously expelled fluid (Figure 30–1E). Most important, the weight of the venous and lymphatic fluid columns is temporarily supported by the closed one-way valve leaflets. Consequently, venous pressure is drastically lowered immediately after skeletal muscle contraction and rises only gradually as veins refill with blood from the capillaries. Thus, capillary pressure and transcapillary fluid filtration rate are dramatically reduced for some period after a skeletal muscle contraction. Some transcapillary fluid filtration is still present, but the increased lymphatic flow resulting from the skeletal muscle pump is normally sufficient to prevent noticeable edema formation in the feet. The actions of the skeletal muscle pump, however beneficial, do not completely prevent an increase in the average venous pressure and blood pooling in the lower extremities on standing. Thus, assuming an upright position upsets the cardiovascular system and elicits reflex cardiovascular adjustments, as shown in Figure 30–2. As with all cardiovascular responses, the key to understanding the alterations associated with standing is to distinguish the primary disturbances from the compensatory responses. As shown in the top part of Figure 30–2, the immediate consequence of standing is an increase in both arterial and venous pressures in the lower extremities. The latter causes a major redistribution of blood volume out of the central venous pool. By the chain of events shown, the primary disturbances influ-

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ence the cardiovascular centers by lessening the normal input from both the arterial and the cardiopulmonary baroreceptors. The result of a decreased baroreceptor input to the cardiovascular centers will be reflex adjustments appropriate to increase blood pressure—that is, decreased cardiac parasympathetic nerve activity and increased activity of the cardiovascular sympathetic nerves as shown in the bottom part of Figure 30–2. Heart rate and cardiac contractility will increase, as will arteriolar and venous constriction in most systemic organs (brain and heart excepted). Heart rate and total peripheral resistance are greater when an individual stands than when the individual is lying down. Note that these particular cardiovascular variables are not directly influenced by standing but are changed by the compensatory responses. Stroke volume and cardiac output, conversely, are usually decreased below their recumbent values during quiet standing despite the reflex adjustments that tend to increase them. This is because the reflex adjustments do not quite overcome the primary disturbance on these variables caused by standing. This is in keeping with the general dictum that short-term cardiovascular compensations never completely correct the initial disturbance. Mean arterial pressure is often found to increase when a person changes from the recumbent to the standing position. At first glance, this is a violation of many rules of cardiovascular system operation. How can a compensation be more than complete? Moreover, how is increased sympathetic activity compatible with higher-than-normal mean arterial pressure in the first place? In the case of standing, there are many answers to these apparent puzzles. First, the average arterial baroreceptor discharge rate can actually decrease in spite of a small increase in mean arterial pressure if there is simultaneously a sufficiently large decrease in pulse pressure. Second, the influence on the medullary cardiovascular centers from cardiopulmonary receptors is interpreted as a decrease in blood volume and may increase arterial pressure by mechanisms that increase the set point. Third, mean arterial pressure determined by sphygmomanometry from the arm of a standing individual overestimates the mean arterial pressure actually being sensed by the baroreceptors in the carotid sinus region of the neck because of gravitational effects. The kidney is especially susceptible to changes in sympathetic nerve activity (as will be discussed in Section 7). Consequently, as shown in Figure 30–2, every reflex alteration in sympathetic activity has influences on fluid balance that become important in the long term. Standing, which is associated with an increase in sympathetic tone, ultimately results in an increase in fluid volume. The ultimate benefit of this is that an increase in blood volume generally reduces the magnitude of the reflex alterations required to tolerate upright posture.

RESPONSES TO LONG-TERM BED REST The cardiovascular system of an individual who is subjected to long-term bed rest undergoes a variety of adaptive changes. The most significant immediate change that occurs on

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Standing

↑ Venous pressure (lower extremities)

↑ Arterial pressure (lower extremities)

Primary disturbances (uncompensated)

Central → Peripheral blood volume shift

↑ Capillary pressure (lower extremities)

↓ Blood volume

Capillary filtration (lower extremities)

↓ Central venous pressure

Edema (lower extremities)

↓ Stroke volume

↓ Cardiac output ↓ Pulse pressure

↓ Mean arterial pressure

↓ Firing rate of cardiopulmonary baroreceptors

↓ Firing rate of arterial baroreceptors (increases set point)

FIGURE 30–2

Cardiovascular mechanisms involved when changing from a recumbent to a standing position. (Modified with permission from

Compensatory responses

Medullary cardiovascular centers ↓ Parasympathetic activity

↑

Heart rate

↑ Contractility

↑ Sympathetic activity

↑ Venous constriction

Heart

↑ Arteriolar constriction

Systemic organs

↑ Fluid retention Kidney

Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/McGraw-Hill, 2006.)

assuming a recumbent position is a shift of fluid from the lower extremities to the upper portions of the body. The consequences of this shift include distention of the head and neck veins, facial edema, nasal stuffiness, and decreases in calf girth and leg volume. In addition, the increase in central blood volume stimulates the cardiopulmonary mechanoreceptors, which influence renal function by neural and hormonal pathways to reduce sympathetic drive and promote fluid loss. The individual begins to lose weight and, within just a few days, becomes hypovolemic. When the bedridden patient initially tries to stand up, the normal responses to gravity as described in Figure 30–2 are not as effective, primarily because of the substantial decrease in circulating blood volume. Upon standing, blood shifts out of the central venous pool into the peripheral veins, stroke volume decreases, and the individual often becomes dizzy and may faint due to a dramatic decrease in blood pressure. This phenomenon is referred to as orthostatic or postural hypotension. Because there are other cardiovascular changes that may accompany bed rest, complete reversal of this orthostatic intol-

Immediate

Long-term

erance may take several days or even weeks. Efforts made to diminish the cardiovascular changes for the bedridden patient may include intermittent sitting up or tilting the bed to lower the legs and trigger fluid retention mechanisms.

NORMAL CARDIOVASCULAR ADAPTATIONS RESPONSES TO RESPIRATORY ACTIVITY The physical processes associated with inhaling air into and exhaling air out of the lungs have major effects on venous return and cardiac output. The decrease in intrathoracic pressure with inspiration transiently increases the pressure gradient between the peripheral and central venous pools and contributes to venous return from the systemic vascular beds to the right side

CHAPTER 30 Cardiovascular Responses to Physiological Stress of the heart. Because the one-way valves in peripheral veins prevent backflow during expiration, the thoracic pressure changes constitute a respiratory pump (also called the thoracoabdominal pump). Details of the effects of the respiratory pump on venous return in exercise and the effects of positive pressure ventilation on venous return and cardiac output are presented in Chapters 34 and 72. A variety of complex signals from cardiopulmonary receptors during the respiratory cycle contribute to a respiratory-based cardiac arrhythmia that is mediated primarily by changing activity of vagal efferents to the SA node. There are other instances when the cardiovascular effect of respiratory efforts has physiological consequences (i.e., yawning, coughing, laughing). One of the more important situations occurs during the Valsalva maneuver, which is a forced expiration against a closed glottis. This maneuver is normally performed by individuals during defecation (“straining at stool”), or when attempting to lift a heavy object. The sustained increase in intrathoracic pressure leads to decreases in venous return and blood pressure, which evokes a compensatory reflex increase in heart rate and peripheral vasoconstriction. (During this period, the red face and distended peripheral veins are indicative of high peripheral venous pressures.) At the cessation of the maneuver, there is an abrupt decrease in pressure for a few heart beats due to the reduction of intrathoracic pressure. Venous blood then moves rapidly into the central venous pool; stroke volume, cardiac output, and arterial pressure increase rapidly; and a reflex bradycardia occurs. The combination of an episode of high peripheral venous pressure followed by an episode of high arterial pressure and pulse pressure is particularly dangerous for people who are candidates for cerebral vascular accidents (strokes) because this combination may rupture a weakened blood vessel.

CARDIOVASCULAR CHANGES DURING PREGNANCY Pregnancy causes alterations in vascular structure and blood flow to many maternal organs in order to support growth of the developing fetus. These organs include not only the

A

B Foramen ovale pv

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uterus and developing placenta, but also the kidneys and the gastrointestinal organs. However, one of the most striking cardiovascular changes of pregnancy is the nearly 50% increase in circulating blood volume. The placenta, being a low-resistance organ added in parallel with the other systemic organs, reduces the overall systemic total peripheral resistance by about 40%. Without the substantial increase in circulating blood volume to support cardiac filling, the necessary increase in cardiac output to balance the decrease in total peripheral resistance would not be possible and pregnancy would result in a substantial decrease in mean arterial pressure. At birth, the loss of the placenta contributes to an abrupt increase of maternal total peripheral resistance back toward normal levels.

FETAL CIRCULATION & CHANGES AT BIRTH During fetal development, the exchange of nutrients, gases, and waste products between fetal and maternal blood occurs in the placenta. This exchange occurs by diffusion between separate fetal and maternal capillaries without any direct connection between the fetal and maternal circulations. From a hemodynamic standpoint, the placenta represents a temporary additional large systemic organ for both the fetus and the mother. The fetal component of the placenta has a low vascular resistance and receives a substantial portion of the fetal cardiac output. Blood circulation in the developing fetus almost completely bypasses the collapsed, fluid-filled fetal lungs. Very little blood flows into the pulmonary artery because the vascular resistance in the collapsed fetal lungs is very high. By the special structural arrangements shown in Figure 30–3, the fetal right and left hearts operate in parallel to pump blood through the systemic organs and the placenta. As shown in Figure 30–3A, fetal blood returning from the systemic organs and placenta fills both the left and right hearts together because of an opening in the intra-atrial septum called the foramen ovale. As indicated in Figure 30–3B, most of the blood that is pumped

Ductus arteriosus a

pv pa la

vc ra

rv

lv

rv

lv

FIGURE 30–3 Fetal circulation (A) during cardiac filling and (B) during cardiac ejection. pv, pulmonary veins; la, left atrium; lv, left ventricle; rv, right ventricle; ra, right atrium; vc, venae cavae; a, aorta; pa, pulmonary artery. (Modified with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 6th ed. New York: Lange Medical Books/ McGraw-Hill, 2006.)

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SECTION V Cardiovascular Physiology

by the fetal right heart does not enter the constricted pulmonary circulation but rather is diverted into the aorta through a vascular connection between the pulmonary artery and the aorta called the ductus arteriosus. At birth, an abrupt decrease in pulmonary vascular resistance occurs in the newborn with the onset of lung ventilation. This is a partly a result of the introduction of oxygen into the airways and the decrease in hypoxic pulmonary vasoconstriction as discussed in Chapter 34. This permits more blood to flow into the lungs from the pulmonary artery and tends to lower pulmonary arterial pressure. Meanwhile, total systemic vascular resistance of the newborn increases greatly because of the interruption of flow through the placenta. This causes an increase in aortic pressure. The combination of the reduced pulmonary and elevated systemic arterial pressure retards or even reverses the flow through the ductus arteriosus. Through mechanisms that are incompletely understood but clearly linked to an increase in blood oxygen tension, the ductus arteriosus gradually constricts and completely closes in a few hours to a few days. The circulatory changes that occur at birth tend to simultaneously increase the pressure afterload on the left ventricle and decrease that on the right ventricle. This indirectly causes left atrial pressure to increase above that in the right atrium so that the pressure gradient for flow through the foramen ovale is reversed. Reverse flow through the foramen ovale is, however, prevented by a flaplike valve that covers the opening in the left atrium. Normally, the foramen ovale eventually is closed permanently by the growth of fibrous tissue.

PEDIATRIC CARDIOVASCULAR CHARACTERISTICS Cardiovascular variables change significantly during the childhood. The normal neonate has, by adult standards, a high resting heart rate (average of 140 beats/min) and a low arterial blood pressure (average of 60/35 mm Hg). These values rapidly change over the first year (to 120 beats/min and 100/65 mm Hg, respectively). By the time the child enters adolescence, these values are near adult levels. Pulmonary vascular resistance decreases precipitously at birth as described above and then continues to decline during the first year, at which time pulmonary vascular pressures resemble adult levels. These resistance changes appear to be due to a progressive remodeling of the microvascular arterioles from thick-walled, small-diameter vessels to thin-walled, large-diameter microvessels. Also as the lung grows, the number of alveoli and therefore pulmonary vessels increases. (At birth there are only about 20 million alveoli, compared to 300–450 million in adults. Most of the growth occurs in the first 8 years). It is noteworthy that distinct differences between right and left ventricular mass and wall thickness develop only after birth. Presumably these differences arise because of a hypertrophic response of the left ventricle to the increased afterload it must assume at birth. Accordingly, the electrocardiogram of children shows an early right ventricular dominance (electri-

cal axis orientation) that converts to the normal left ventricular dominance during childhood. Heart murmurs are also quite common in childhood and have been reported to be present in as many as 50% of healthy children. Most of these murmurs fall in the category of “innocent” murmurs resulting from normal cardiac tissue vibrations, high flow through valves, and thin chest walls that make noises from the vasculature easy to hear. Less than 1% of them result from various congenital heart defects. Growth and development of the vascular system parallels growth and development of the body with most of the local and reflex regulatory mechanisms becoming operational shortly after birth.

CARDIOVASCULAR CHANGES WITH NORMAL AGING Changes in cardiovascular function occur over the normal human lifetime. These changes are generally associated with a slowing of some of the basic processes and a reduction in the ability of the cardiovascular system as a whole to respond to various stresses. Details of the aging process are discussed in Chapter 73. Age-dependent cardiac alterations include: (1) a decrease in the resting and maximum cardiac index, (2) a decrease in the maximum heart rate, (3) an increase in the contraction and relaxation times of the heart muscle, (4) an increase in the myocardial stiffness during diastole, (5) a decrease in number of functioning myocytes, and (6) an accumulation of pigment in the myocardial cells. Age-dependent vascular changes include: (1) a decrease in capillary density in some tissues, (2) a decrease in arterial and venous compliance, and (3) an increase in total peripheral vascular resistance. These changes combine to produce the age-dependent increases in arterial pulse pressure and mean arterial pressure that were discussed in Chapter 26 (see Figure 26–10). The increases in arterial pressure impose a greater afterload on the heart, and this may be partially responsible for the age-dependent decreases in cardiac index. Arterial baroreceptor–induced responses to changes in blood pressure are blunted with age. This is due in part to a decrease in afferent activity from the arterial baroreceptors because of the age-dependent increase in arterial rigidity. In addition, the total amount of norepinephrine contained in the sympathetic nerve endings of the myocardium decreases with age, and the myocardial responsiveness to catecholamines declines. Thus, the efferent component of the reflex is also compromised. These changes may partially account for the apparent age-dependent sluggishness in the responses to postural changes and recovery from exercise.

EFFECT OF GENDER There are a few well-documented gender-dependent differences in the cardiovascular system. Compared with age-matched men, premenopausal women have a lower left ventricular mass

CHAPTER 30 Cardiovascular Responses to Physiological Stress to body mass ratio, which may reflect a lower cardiac afterload in women. This may result from their lower arterial blood pressure, greater aortic compliance, and improved ability to induce vasodilatory mechanisms (such as endothelial-dependent flowmediated vasodilation). These differences are thought to be related to protective effects of estrogen and may account for the lowered risk of premenopausal women for developing cardiovascular disease. After menopause, these gender differences disappear. In fact, older women with ischemic heart disease often have a worse prognosis than men. There are also gender-dependent differences in cardiac electrical properties. Women often have lower intrinsic heart rates and longer QT intervals than do men. They are at greater risk for developing long-QT syndrome and torsades de pointes. They are also twice as likely as men to have atrioventricular nodal reentry tachycardias.

CLINICAL CORRELATION An elderly man was hunting with some friends when he inadvertently shot himself in the foot. This resulted in a significant loss of blood and, by the time he was brought to the hospital, he was very weak and pale, his skin was cold and clammy, and he was somewhat confused. His heart rate was 105 beats/min, and blood pressure was 85/65 mm Hg. His breathing was rapid and shallow and jugular venous pulses could not be observed when he was recumbent. An intravenous catheter advanced from a peripheral vein into his right atrium recorded central venous pressure to be 0 mm Hg (normal 2–6 mm Hg). A

blood sample was obtained and his hematocrit was 34 (normal 41–53%). The most immediate problem was determined to be hemorrhagic hypovolemic shock and he was given a liter of blood. Within an hour, his heart rate was 90 beats/min and his blood pressure was 115/85 mm Hg. He was still weak and pale but more alert. He had not yet urinated and was very thirsty. Additional blood was infused and his vital signs returned to normal. Circulatory shock exists whenever there is a severe reduction in blood supply to the body tissues and the metabolic needs of the tissues are not met. Even with all cardiovascular compensatory mechanisms activated, arterial pressure is usually (though not always) low in shock. The shock state is precipitated by one of the following two conditions: (1) severely depressed myocardial function or (2) grossly inadequate cardiac filling due to low mean circulatory filling pressure. The former situation is called cardiogenic shock and the latter situation can result from a variety of non-cardiac causes. These shock states are described in Table 30–1 along with the primary disturbance on the cardiovascular system and the consequences on cardiac filling pressure. The common primary disturbances in all forms of shock lead to decreased mean arterial pressure and decreased arterial baroreceptor discharge rate. In the case of hypovolemic, anaphylactic, and septic shock, diminished activity of the cardiopulmonary baroreceptors due to a decrease in central venous pressure and/or volume acts on the medullary cardiovascular centers to stimulate sympathetic output. In the case of cardiogenic shock, central venous pressure will increase, and in the case of neurogenic shock, central venous pressure cannot be predicted because both cardiac

TABLE 30–1 Circulatory Shock Type of Shock

Causes

Primary Disturbance

Effect on Central Venous Pressure

Cardiogenic

-Myocardial infarction

-Decreased cardiac output

-Increased CVP

-Severe arrhythmia

-Right shift of cardiac function curve

-Abrupt valve malfunction Hypovolemic

-Hemorrhage -Severe burns

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-Decreased circulating blood volume

-Decreased CVP

-Chronic vomiting or diarrhea -Dehydration Anaphylactic

-Severe systemic allergic reaction associated with release of histamine, prostaglandins, leukotrienes, bradykinin

-Decreased total peripheral resistance, reduced venous tone

-Decreased CVP

Septic

-Circulating infective agents releasing vasodilator substances such as endotoxin (lipopolysaccharide) inducing NO synthesis

-Decreased total peripheral resistance, reduced venous tone

-Decreased CVP

Neurogenic

-Reduced sympathetic and/or increased parasympathetic activity (vasovagal syncope)

-Decreased cardiac output, total peripheral resistance, and venous tone

-Variable effect on CVP because both cardiac output and venous return will decrease

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output and venous return are likely to be depressed. If arterial pressure decreases below the autoregulatory range for cerebral blood flow (below about 60 mm Hg), perfusion of the brain begins to decrease, eliciting the cerebral ischemic response that causes the most intense of all signals to activate sympathetic nerves. Unless the primary disturbance precludes these compensatory responses, the increase in sympathetic activity (and decrease in parasympathetic activity) will lead to an increase in cardiac output (by increasing heart rate and cardiac contractility), an increase in total peripheral resistance (by generalized arteriolar constriction), and an increase in peripheral venous tone (which will shift blood into the central venous pool). Many of the commonly recognized symptoms of shock (e.g., pallor, cold clammy skin, rapid heart rate, muscle weakness, venous constriction) are a result of greatly increased sympathetic nerve activity. When the immediate compensatory processes are inadequate, the individual may also show signs of abnormally low arterial pressure, such as dizziness, confusion, or loss of consciousness. Additional compensatory processes during a shock state may include (1) rapid, shallow breathing, which promotes venous return to the heart by action of the respiratory pump (see Chapter 72), (2) release of various powerful vasoconstrictor hormones such as epinephrine (see Chapter 19), angiotensin II, and vasopressin (see Chapter 45), which contribute to the increase in total peripheral resistance, (3) a net shift of fluid from the interstitial space into the vascular space due to the very low capillary hydrostatic pressure downstream of the vasoconstricted arterioles, and (4) an increase in extracellular osmolarity (as a result of increased glycogenolysis in the liver induced by epinephrine and norepinephrine) that will induce a shift of fluid from the intracellular space into the extracellular (including intravascular) space. The latter two processes result in a sort of autotransfusion that can move as much as a liter of fluid into the vascular space in the first hour after the onset of the shock episode (see Chapter 26). This fluid shift accounts for the reduction in hematocrit that is commonly observed in hemorrhagic shock. In addition to the immediate compensatory responses described above, fluid retention mechanisms are evoked that promote renal retention of fluid and an increase in circulating blood volume. These processes are described in detail in Chapter 45 and contribute to the replenishment of extracellular fluid volume within a few days of the shock episode. If the primary disturbances are not corrected soon, the strong compensatory responses can reduce perfusion of

tissues (other than the heart and brain) despite nearly normal arterial pressure. Intense sympathetic activation can lead to renal, splanchnic, or hepatic ischemic damage. If this ischemia is prolonged, self-reinforcing decompensatory mechanisms (positive feedback described in Chapter 1) will progressively drive arterial pressure down and unless corrective measures are taken quickly, death will ultimately result.

CHAPTER SUMMARY ■

■

■ ■

Cardiovascular responses to physiological stresses should be evaluated in terms of the initial effects of the primary disturbance and the subsequent effects of the reflex compensatory responses. Gravity, and hence body position, has a significant effect on the cardiovascular system, and various reflex compensatory mechanisms are required to overcome venous pooling that accompanies the upright position. Long-term bed rest causes decreases in circulating blood volume that contributes to orthostatic hypotension. Cardiovascular characteristics are influenced by a variety of conditions including respiratory activity, gender, pregnancy, growth and development from the fetal period, through birth, pediatric stages, adulthood, and old age.

STUDY QUESTIONS 1. All of the following tend to occur when a person lies down. Which one is the primary disturbance that causes all the others to happen? A) Heart rate will decrease. B) Stroke volume will decrease. C) Sympathetic activity will decrease. D) Parasympathetic activity will increase. E) Central venous pressure will increase. 2. A 35-year-old man has had a severe bout of the flu with vomiting and diarrhea for several days. All of the following conditions would be expected to be present except A) orthostatic hypotension. B) increased cardiac preload. C) increased cardiac ejection fraction. D) increased hematocrit. E) increased total peripheral vascular resistance. 3. Total systemic peripheral vascular resistance of a newborn baby undergoes an abrupt and sustained increase at birth. This is because A) circulating blood volume increases. B) the high-resistance lungs inflate. C) the low-resistance placental circulation is removed. D) sympathetic neural stimulation is increased. E) cardiac output increases.

CHAPTER 30 Cardiovascular Responses to Physiological Stress 4. Vertical immersion to the chest in tepid water produces a diuresis in many individuals. What mechanisms might account for this phenomenon? A) an increase in sympathetic activity to the kidney B) an increase in mean arterial pressure C) a shift of blood from the central to the peripheral venous pool D) decreased firing of arterial baroreceptors E) increased firing of the cardiopulmonary baroreceptors

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5. All of the following help maintain circulation during states of hypovolemic shock except A) an increase in heart rate. B) rapid respiratory effort to promote venous return of blood to the heart. C) vasoconstrictive contributions from increases in circulating epinephrine. D) autotransfusion of interstitial fluid into capillary beds. E) transcapillary filtration of plasma into interstitial space.

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SECTION VI PULMONARY PHYSIOLOGY

31 C

Function and Structure of the Respiratory System Michael Levitzky

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■

Describe the exchange of oxygen and carbon dioxide with the atmosphere and relate gas exchange to the metabolism of the tissues of the body. List the functions of the lungs. Describe functions and structures of the conducting airways, the alveolar–capillary unit, and the chest wall. Describe the central nervous system initiation of breathing and the innervation of the respiratory muscles.

The main functions of the respiratory system are to obtain oxygen from the external environment and supply it to the cells, and to remove from the body the carbon dioxide produced by cellular metabolism. The respiratory system is composed of the lungs, the conducting airways, the parts of the central nervous system concerned with the control of the muscles of respiration, and the chest wall. The chest wall consists of the muscles of respiration— the diaphragm, the intercostal muscles, and the abdominal muscles—and the rib cage.

FUNCTIONS OF THE RESPIRATORY SYSTEM The functions of the respiratory system include gas exchange, acid–base balance, phonation, pulmonary defense and metabolism, and the handling of bioactive materials.

Ch31_305-312.indd 305

GAS EXCHANGE The exchange of carbon dioxide for oxygen takes place in the lungs. As shown in Figure 31–1, fresh air, containing oxygen, is inspired into the lungs through the conducting airways. The forces needed to cause the air to flow are generated by the respiratory muscles, acting on commands initiated by the central nervous system. At the same time, venous blood returning from the various body tissues is pumped into the lungs by the right ventricle of the heart. This mixed venous blood has a high carbon dioxide content and a low oxygen content. In the pulmonary capillaries, carbon dioxide is exchanged for oxygen. The blood leaving the lungs, which now has a high oxygen content and a lower carbon dioxide content, is distributed to the tissues of the body by the left side of the heart. During expiration, gas with a high concentration of carbon dioxide is expelled from the body.

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EXTERNAL ENVIRONMENT High O2, Low CO2

Expiration

Inspiration

O2

CONDUCTING AIRWAYS

CO2 ALVEOLI O2 CO2 PULMONARY CAPILLARIES

PULMONARY ARTERY

PULMONARY VEINS

Low O2 High CO2

High O2 Low CO2 LEFT ATRIUM

RIGHT VENTRICLE

LEFT VENTRICLE

RIGHT ATRIUM

VEINS

Low O2 High CO2

High O2 Low CO2 SYSTEMIC CAPILLARIES

AORTA

O2

CO2 METABOLIZING TISSUES

FIGURE 31–1

Schematic representation of gas exchange between the tissues of the body and the environment. (Modified with

permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

OTHER FUNCTIONS OF THE RESPIRATORY SYSTEM Acid–Base Balance In the body, increases in carbon dioxide lead to increases in hydrogen ion concentration (and vice versa) because of the following reaction: CO2 + H2O

H2CO3

H+ + HCO3–

The respiratory system can therefore participate in acid– base balance by removing CO2 from the body. The central nervous system has sensors for the CO2 and the hydrogen ion levels in the arterial blood and in the cerebrospinal fluid that send information to the controllers of breathing. Acid–base balance is discussed in greater detail in Chapter 37; the control of breathing is discussed in Chapter 38.

Phonation Phonation is the production of sounds by the movement of air through the vocal cords. Speech, singing, and other sounds are produced by the actions of the central nervous system controllers on the muscles of respiration, causing air to flow through the vocal cords and the mouth. The physiology of speech is discussed in Chapter 21.

Pulmonary Defense Mechanisms Each breath brings into the lungs a small sample of the local atmospheric environment. This may include microorganisms such as bacteria, dust, particles of silica or asbestos, toxic gases, smoke (cigarette and other types), and other pollutants. In addition, the temperature and humidity of the local atmosphere can vary tremendously. As will be described below, as

CHAPTER 31 Function and Structure of the Respiratory System air passes through the airways, it is warmed to body temperature and filtered to remove particulate matter. Most of the particles in inspired air are removed before they reach the alveoli. The mechanisms by which these impurities are removed from the respiratory tract are described in the section “Structure of the Respiratory System.”

Pulmonary Metabolism and the Handling of Bioactive Materials The cells of the lung must metabolize substrates to supply energy and nutrients for their own maintenance. Some specialized pulmonary cells also produce substances necessary for normal pulmonary function. These substances include pulmonary surfactant, which is synthesized in type II alveolar epithelial cells (described below) and released at the alveolar surface. Surfactant plays an important role in reducing the alveolar elastic recoil due to surface tension and in stabilizing the alveoli, as discussed later in Chapter 32. Histamine, lysosomal enzymes, prostaglandins, leukotrienes, plateletactivating factor, neutrophil and eosinophil chemotactic factors, and serotonin can be released from mast cells in the lungs in response to conditions such as pulmonary embolism (see Chapter 34) and anaphylaxis (an acute life-threatening systemic allergic reaction). These substances may cause bronchoconstriction or immune or inflammatory responses, or they may initiate cardiopulmonary reflexes. Many substances are also produced by cells of the lung and released into the alveoli and airways, including mucus and other tracheobronchial secretions; surface enzymes, proteins, and other factors; and immunologically active substances. These substances are produced by goblet cells, submucosal gland cells, Clara cells, and macrophages. Substances produced by lung cells and released into the blood under various circumstances include bradykinin, histamine, serotonin, heparin, prostaglandins E2 and F2α, and the endoperoxides (prostaglandins G2 and H2). In addition, the pulmonary capillary endothelium contains a great number of enzymes that can produce, metabolize, or modify naturally occurring vasoactive substances. For exam-

ple, prostaglandins E1, E2, and F2α are nearly completely removed in a single pass through the lungs. On the other hand, prostaglandins A1, A2, and I2 (prostacyclin) are not affected by the pulmonary circulation. Similarly, about 30% of the norepinephrine in mixed venous blood is removed by the lung, but epinephrine is unaffected. It appears that some substances released into specific vascular beds for local effects are inactivated or removed as they pass through the lungs, preventing them from entering the systemic circulation; other substances, apparently intended for more general effects, are not affected.

STRUCTURE OF THE RESPIRATORY SYSTEM THE AIRWAYS Air enters the respiratory system through the nose or mouth. Air entering through the nose is filtered, warmed to body temperature, and humidified as it passes through the nose and nasal turbinates. The upper airways (airways above the trachea) are shown in Figure 31–2. The mucosa of the nose, the nasal turbinates, the oropharynx, and the nasopharynx have a rich blood supply and constitute a large surface area. The nasal turbinates alone have a surface area said to be about 160 cm2. As inspired air passes through these areas and continues through the tracheobronchial tree, it is warmed to body temperature and humidified. This protective function is more effective if one is breathing through the nose than through the mouth. Because the olfactory receptors are located in the posterior nasal cavity rather than in the trachea or alveoli, a person can sniff to attempt to detect potentially hazardous gases or dangerous material in the inspired air. This rapid, shallow inspiration brings gases into contact with the olfactory sensors without bringing them into the lung. Chapter 17 discusses the physiology of olfaction (the sense of smell).

  



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FIGURE 31–2 Schematic drawing of the upper airways. (Reproduced with permission from Proctor DF. Physiology of the upper airway. In: Fenn WO, Rahn H, eds. Handbook of Physiology, sec 3: Respiration. Vol. 1. Washington, DC: American Physiological Society; 1964:309–345.)

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SECTION VI Pulmonary Physiology

Conducting zone

Name of branches

Number of tubes in branch

Trachea

1

Bronchi

2

4 8 Bronchioles

16 32

Terminal bronchioles

6 x 104

Respiratory zone

Respiratory bronchioles 5 x 105

Alveolar ducts

Alveolar sacs

8 x 106

FIGURE 31–3 Schematic representation of airway branching in the human lung. (Reproduced with permission from Weibel ER. Morphometry of the Human Lung. Berlin; Springer; 1963.)

Air then passes through the glottis and the larynx and enters the tracheobronchial tree. After passing through the conducting airways, the inspired air enters the alveoli, where it comes into contact with the mixed venous blood in the pulmonary capillaries. Starting with the trachea, the air may pass through as few as 10 or as many as 23 generations, or branchings, on its way to the alveoli. The branchings of the tracheobronchial tree and its nomenclature are shown in Figure 31–3. Alveolar gas exchange units are denoted by the U-shaped sacs. The first 16 generations of airways, the conducting zone, contain no alveoli and thus are anatomically incapable of gas exchange with the venous blood. They constitute the anatomic dead space, which is discussed in Chapter 33. Alveoli start to appear at the 17th to the 19th generations, in the respiratory bronchioles, which constitute the transitional zone. The 20th to 22nd generations are lined with alveoli. These alveolar ducts and the alveolar sacs, which terminate the tracheobronchial tree, are referred to as the respiratory zone. The portion of the lung supplied by a primary respiratory bronchiole is called an acinus. All of the airways of an acinus participate in gas exchange. The numerous branchings of the airways result in a tremendous total cross-sectional area

of the distal portions of the tracheobronchial tree, even though the diameters of the individual airways are quite small.

Structure of the Airways The structure of the airways varies considerably, depending on their location in the tracheobronchial tree. The trachea is a fibromuscular tube supported ventrolaterally by C-shaped cartilage and completed dorsally by smooth muscle. The cartilage of the large bronchi is semicircular, like that of the trachea, but as the bronchi enter the lungs, the cartilage rings disappear and are replaced by irregularly shaped cartilage plates. They completely surround the bronchi and give the intrapulmonary bronchi their cylindrical shape. These plates, which help support the larger airways, diminish progressively in the distal airways and disappear in airways about 1 mm in diameter. Airways with no cartilage are termed bronchioles. Because the bronchioles and alveolar ducts contain no cartilage support, they are subject to collapse when compressed, as will be discussed later in this chapter. This tendency is partly opposed by the attachment of the alveolar septa, containing elastic tissue, to their walls, as seen in Figure 31–4, a scanning electron micrograph of the alveolar–capillary surface (also shown schematically in Figure 32–18). As the cartilage plates become irregularly distributed around distal airways, the muscular layer completely surrounds these airways. The muscular layer is intermingled with elastic fibers. As the bronchioles proceed toward the alveoli, the muscle layer becomes thinner, although smooth muscle can even be found in the walls of the alveolar ducts. The outermost layer of the bronchiolar wall is surrounded by dense connective tissue with many elastic fibers. The entire respiratory tract, except for part of the pharynx, the anterior third of the nose, and the respiratory units distal to the terminal bronchioles, is lined with ciliated cells interspersed with mucus-secreting goblet cells and other secretory cells. In the bronchioles, the goblet cells become less frequent and are replaced by another type of secretory cell, the Clara cell. The ciliated epithelium, along with mucus secreted by glands along the airways and the goblet cells and the secretory products of the Clara cells, constitutes an important mechanism for the protection of the lung called the mucociliary escalator.

Filtration and Removal of Inspired Particles by the Airways Filtration of Inspired Air Air passing through the nose is first filtered by passing through the nasal hairs, or vibrissae. This removes most particles larger than 10–15 μm in diameter. Most of the particles greater than 10 μm in diameter are removed on impact in the large surface area of the nasal septum and turbinates (Figure 31–2). The inspired air stream changes direction abruptly at the nasopharynx so that many of these larger particles impact the posterior wall of the pharynx. The tonsils and adenoids are located near this impaction site, providing immunologic defense against biologically active material filtered at this point. Air entering the trachea contains few particles larger than 10 μm, and most

CHAPTER 31 Function and Structure of the Respiratory System

FIGURE 31–4 Scanning electron micrograph of human lung parenchyma. A, alveolus; S, alveolar septa; D, alveolar duct; PK, pore of Kohn; PA, small branch of the pulmonary artery. (Reproduced with permission from Fishman AP, Elias JA: Fishman’s Pulmonary Diseases and Disorders, 3rd ed. New York: McGraw-Hill, Health Professions Division, 1998.)

of these will impact mainly at the carina or within the bronchi. Sedimentation of most particles in the size range of 2–5 μm occurs by gravity in the smaller airways, where airflow rates are extremely low. Thus, most of the particles between 2 and 10 μm in diameter are removed by impaction or sedimentation and become trapped in the mucus that lines the upper airways, trachea, bronchi, and bronchioles. Smaller particles and all foreign gases reach the alveolar ducts and alveoli. Some smaller particles (0.1 μm and smaller) are deposited as a result of Brownian motion due to their bombardment by gas molecules. The other particles, between 0.1 and 0.5 μm in diameter, mainly stay suspended as aerosols, and about 80% of them are exhaled.

Removal of Filtered Material Filtered or aspirated material trapped in the mucus that lines the respiratory tract can be removed in several ways. Mechanical or chemical stimulation of receptors in the nose, trachea, larynx, or elsewhere in the respiratory tract may produce bronchoconstriction to prevent deeper penetration of the irritant into the airways and may also produce a cough or a sneeze. A sneeze results from stimulation of receptors in the nose or nasopharynx; a cough results from

309

stimulation of receptors in the trachea. In either case, a deep inspiration is followed by a forced expiration against a closed glottis. Pressure in the chest surrounding the lungs (intrapleural pressure) may rise to more than 100 mm Hg during this phase of the reflex. The glottis opens suddenly, and pressure in the airways decreases rapidly, resulting in compression of the airways and an explosive expiration, with linear airflow velocities said to approach the speed of sound. Such high airflow rates through the narrowed airways are likely to carry the irritant, along with some mucus, out of the respiratory tract. In a sneeze, the expiration is via the nose; in a cough, the expiration is via the mouth. The cough or sneeze reflex is also useful in helping to move the mucous lining of the airways toward the nose or mouth. The term “cough” is not specific to this complete involuntary respiratory reflex. Coughs can be initiated by many causes, including postnasal drip from allergies or viral infections, asthma, gastroesophageal reflux, as an adverse effect of the very commonly prescribed angiotensin-converting enzyme inhibitors, mucus production from chronic bronchitis, infections, and other airway disorders. Voluntary coughs are not usually as pronounced as the violent involuntary reflex described above. Particles that are trapped in the mucus lining the airways can be removed by the mucociliary escalator, which has an estimated total surface area of 0.5 m2. The mucus is a complex polymer of mucopolysaccharides. The mucous glands are found mainly in the submucosa near the supporting cartilage of the larger airways. In pathologic states, such as chronic bronchitis, the number of goblet cells may increase and the mucous glands may hypertrophy, resulting in greatly increased mucous gland secretion and increased viscosity of mucus. The cilia lining the airways beat in such a way that the mucus covering them is always moved up the airway, away from the alveoli and toward the pharynx. The mucous blanket appears to be involved in the mechanical linkage between the cilia. The cilia beat at frequencies between 600 and 900 beats/min, and the mucus moves progressively faster as it travels from the periphery. Several studies have shown that ciliary function is inhibited or impaired by cigarette smoke. The mucociliary escalator is an especially important mechanism for the removal of inhaled particles that come to rest in the airways. Material trapped in the mucus is continuously moved upward toward the pharynx. This movement can be greatly increased during a cough, as described previously. Mucus that reaches the pharynx is usually swallowed, expectorated, or removed by blowing one’s nose. Patients who cannot clear their tracheobronchial secretions (e.g., an intubated patient or a patient who cannot cough adequately) continue to produce secretions. If the secretions are not removed from the patient by suction or other means, airway obstruction may develop.

THE ALVEOLAR–CAPILLARY UNIT The alveolar–capillary unit is the site of gas exchange in the lung. The alveoli, traditionally estimated to number about 300 million in the adult (a more recent study calculated the mean

310

SECTION VI Pulmonary Physiology the lung to injury. As type I alveolar epithelial cells are injured, type II cells proliferate to reestablish a continuous epithelial surface. Studies in animals have shown that these type II cells can develop into type I cells after injury. A cross-section of a pulmonary capillary is shown in the transmission electron micrograph in Figure 31–6. An erythrocyte is seen in cross-section in the lumen of the capillary. Capillaries are formed by a single layer of squamous epithelial cells that are aligned to form tubes. The nucleus of one of the capillary endothelial cells can be seen in the micrograph. The barrier to gas exchange between the alveoli and pulmonary capillaries can also be seen in the figure. It consists of the alveolar epithelium, the capillary endothelium, and the interstitial space between them. Gases must also pass through the fluid lining the alveolar surface (not visible in Figure 32–6) and the plasma in the capillary. The barrier to diffusion is normally 0.2–0.5 μm thick. Gas exchange by diffusion is discussed in Chapter 35.

FIGURE 31–5 Scanning electron micrograph of the surface and cross-section of an alveolar septum. Capillaries (C) are seen sectioned in the foreground, with erythrocytes (EC) within them. A, alveolus; D, alveolar duct; PK, pore of Kohn; AR, alveolar entrance to duct; *, connective tissue fibers. The encircled asterisk is at a junction of three septa. (Reproduced with permission from Fishman AP, Elias JA: Fishman’s Pulmonary Diseases and Disorders, 3rd ed. New York: McGraw-Hill, Health Professions Division, 1998.)

number of alveoli to be 480 million), are almost completely enveloped in pulmonary capillaries. There may be as many as 280 billion pulmonary capillaries, or approximately 500–1,000 pulmonary capillaries per alveolus. The result of these staggering numbers of alveoli and pulmonary capillaries is a vast area of contact between alveoli and pulmonary capillaries— probably 50–100 m2 of surface area available for gas exchange by diffusion. The alveoli are about 200–250 μm in diameter. Figure 31–5 shows an even greater magnification of the site of gas exchange than that shown in Figure 31–4. The alveolar septum appears to be almost entirely composed of pulmonary capillaries. Red blood cells (erythrocytes) can be seen inside the capillaries at the point of section. Elastic and connective tissue fibers, not visible in the figure, are found between the capillaries in the alveolar septa. Also shown in these figures are the pores of Kohn that are interalveolar communications. The alveolar surface is mainly composed of a single thin layer of squamous epithelial cells, the type I alveolar cells. Interspersed among these are the larger cuboidal type II alveolar cells that produce the fluid layer that lines the alveoli. Although there are about twice as many type II cells as there are type I cells in the human lung, type I cells cover 90–95% of the alveolar surface, because the average type I cell has a much larger surface area than the average type II cell does. A third cell type, the free-ranging phagocytic alveolar macrophage, is found in varying numbers in the extracellular lining of the alveolar surface. These cells patrol the alveolar surface and phagocytize inspired particles such as bacteria. The type II alveolar epithelial cell also plays a major role in the response of

FIGURE 31–6

Transmission electron micrograph of a crosssection of a pulmonary capillary. An erythrocyte (EC) is seen within the capillary. C, capillary; EN, capillary endothelial cell (note its large nucleus); EP, alveolar epithelial cell; IN, interstitial space; BM, basement membrane; FB, fibroblast processes; 2, 3, and 4, diffusion pathway through the alveolar–capillary barrier, the plasma, and the erythrocyte, respectively.

(Reproduced with permission from Weibel, E.R. : Morphometric estimation of pulmonary diffusion capacity, I. Model and method. Respir Physiol 1970;11:54–75.)

CHAPTER 31 Function and Structure of the Respiratory System

Removal of Material from the Alveolar Surface Inspired material that reaches the terminal airways and alveoli may be removed in several ways, including ingestion by alveolar macrophages, enzymatic destruction, entry into the lymphatics, and immunologic reactions. Inhaled particles engulfed by alveolar macrophages may be destroyed by their lysosomes (see Chapter 1). Most bacteria are digested in this manner. Some material ingested by the macrophages, however, such as silica, is not degradable by the macrophages and may even be toxic to them. If the macrophages carrying such material are not removed from the lung, the material will be redeposited on the alveolar surface on the death of the macrophages. The mean life span of alveolar macrophages is believed to be 1–5 weeks. The main exit route of macrophages carrying such nondigestible material is migration to the mucociliary escalator via the pores of Kohn and eventual removal through the airways. Particle-containing macrophages may also migrate from the alveolar surface into the septal interstitium, from which they may enter the lymphatic system or the mucociliary escalator. Macrophage function has been shown to be inhibited by cigarette smoke. Alveolar macrophages are also important in the lung’s immune and inflammatory responses. They secrete many enzymes, arachidonic acid metabolites, immune response components, growth factors, cytokines, and other mediators that modulate the function of other cells, such as lymphocytes. Some particles reach the mucociliary escalator because the alveolar fluid lining itself is slowly moving upward toward the respiratory bronchioles. Others penetrate into the interstitial space or enter the blood, where they are phagocytized by interstitial macrophages or blood phagocytes, or enter the lymphatics. Particles may be destroyed or detoxified by surface enzymes and factors in the serum and in airway secretions.

THE MUSCLES OF RESPIRATION AND THE CHEST WALL The muscles of respiration and the chest wall are essential components of the respiratory system. The lungs are not capable of inflating themselves—the force for this inflation must be supplied by the muscles of respiration. The chest wall must be intact and able to expand if air is to enter the alveoli normally. The interactions among the muscles of respiration and the chest wall and the lungs are discussed in detail later in Chapter 32. The primary components of the chest wall include the rib cage; the external and internal intercostal muscles and the diaphragm, which are the main muscles of respiration; and the

311

lining of the chest wall, the visceral and parietal pleura. Other muscles of respiration include the abdominal muscles, including the rectus abdominis; the parasternal intercartilaginous muscles; and the sternocleidomastoid and scalenus muscles.

THE CENTRAL NERVOUS SYSTEM AND THE NEURAL PATHWAYS Another important component of the respiratory system is the central nervous system. Unlike cardiac muscle, the muscles of respiration do not contract spontaneously. Each breath is initiated in the brain, and this message is carried to the respiratory muscles via the spinal cord and the nerves innervating the respiratory muscles. Spontaneous automatic breathing is generated by groups of neurons located in the medulla. This medullary respiratory center is also the final integration point for influences from higher brain centers, for information from chemoreceptors in the blood and cerebrospinal fluid, and for afferent information from neural receptors in the airways, joints, muscles, skin, and elsewhere in the body. The control of breathing is discussed in Chapter 38.

CHAPTER SUMMARY ■

■

The main function of the respiratory system is the exchange of oxygen from the atmosphere for carbon dioxide produced by the cells of the body. Other functions of the respiratory system include participation in the acid–base balance of the body, phonation, pulmonary defense, and metabolism.

STUDY QUESTIONS 1. The functions of the respiratory system include A) gas exchange. B) acid–base balance. C) phonation. D) pulmonary defense and metabolism. E) handling bioactive materials. F) all of the above. 2. Particulate matter in the inspired air that enters the airways or alveoli may be removed by A) the mucociliary escalator. B) alveolar macrophages. C) surface enzymes. D) the lymphatics. E) all of the above.

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32 C

Mechanics of the Respiratory System Michael Levitzky

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■

■ ■ ■ ■ ■ ■

Describe the generation of a pressure gradient between the atmosphere and the alveoli. Describe the passive expansion and recoil of the alveoli. Define the mechanical interaction of the lung and the chest wall. Describe the pressure–volume characteristics of the lung and the chest wall, and predict changes in the compliance of the lung and the chest wall in different physiologic and pathologic conditions. State the roles of pulmonary surfactant and alveolar interdependence in the recoil and expansion of the lung. Define the functional residual capacity (FRC), and predict changes in FRC in different physiologic and pathologic conditions. Define airway resistance and list the factors that contribute to or alter the resistance to airflow. Describe the dynamic compression of airways during a forced expiration. List the factors that contribute to the work of breathing. Predict alterations in the work of breathing in different physiologic and pathologic states.

Air, like other fluids, moves from a region of higher pressure to one of lower pressure. Therefore, for air to be moved into or out of the lungs, a pressure difference between the atmosphere and the alveoli must be established. If there is no pressure gradient, no airflow will occur. Under normal circumstances, inspiration is accomplished by causing alveolar pressure to decrease below atmospheric pressure. When the mechanics of breathing are being discussed, atmospheric pressure is conventionally referred to as 0 cm H2O, so lowering alveolar pressure below atmospheric pressure is known as negative-pressure breathing. When a pressure gradient sufficient to overcome the resistance to airflow offered by the conducting airways is established between the atmosphere and the alveoli, air flows into the lungs. It is also possible to cause air to flow into the lungs by increasing the pressure at the nose or mouth above alveolar pressure. This positive-pressure ventilation is generally used on patients unable to generate a pressure gradi-

Ch32_313-330.indd 313

ent between the atmosphere and the alveoli by normal negative-pressure breathing. Air flows out of the lungs when alveolar pressure is sufficiently greater than atmospheric pressure to overcome the resistance to airflow offered by the conducting airways.

GENERATION OF A PRESSURE GRADIENT BETWEEN THE ATMOSPHERE AND THE ALVEOLI During normal negative-pressure breathing, alveolar pressure is made lower than atmospheric pressure. This is accomplished by causing the muscles of inspiration to contract, which increases the volume of the alveoli, thus lowering the alveolar pressure according to Boyle’s law: at constant temperature, the product of the pressure and the volume of a gas is constant. 313

12/15/10 11:46:29 AM

314

SECTION VI Pulmonary Physiology atmospheric pressure: 0 cm H2O

atmospheric pressure: 0 cm H2O

no air flow: atmospheric pressure = alveolar pressure

air flows in : atmospheric pressure>alveolar pressure outward recoil of chest wall

alveolar pressure: 0 cm H2O

force generated by inspiratory muscles

alveolar pressure: 1 cm H2O inward recoil of alveoli

intrapleural pressure: 5 cm H2O

transmural pressure  0 cm H2O(5 cm H2O)5 cm H2O

END EXPIRATION

intrapleural pressure: 8 cm H2O

transmural pressure  1 cm H2O (8 cm H2O)7 cm H2O DURING INSPIRATION

FIGURE 32–1 Representation of the interaction of the lung and chest wall. Left: At end expiration, the muscles of respiration are relaxed. The inward elastic recoil of the lung is balanced by the outward elastic recoil of the chest wall. Intrapleural pressure is –5 cm H2O; alveolar pressure is 0. The transmural pressure gradient across the alveolus is therefore 0 – (–5) cm H2O, or 5 cm H2O. Since alveolar pressure is equal to atmospheric pressure, no airflow occurs. Right: During inspiration, contraction of the muscles of inspiration causes intrapleural pressure to become more negative. The transmural pressure gradient increases and the alveoli are distended, decreasing alveolar pressure below atmospheric pressure, which causes air to flow into the alveoli. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.) The alveoli are not capable of expanding themselves. They expand passively in response to an increased distending pressure across the alveolar wall. This increased transmural pressure gradient, generated by the muscles of inspiration, further opens the highly distensible alveoli and thus decreases the alveolar pressure. The transmural pressure gradient is conventionally calculated by subtracting the outside pressure (in this case, the intrapleural pressure) from the inside pressure (in this case, the alveolar pressure). The pressure in the thin, liquid-filled space between the visceral and parietal pleura is normally slightly less than atmospheric pressure, even when no inspiratory muscles are contracting. This negative intrapleural pressure (sometimes also referred to as negative intrathoracic pressure) of –3 to –5 cm H2O is mainly caused by the mechanical interaction between the lung and the chest wall. At the end of expiration, when all the respiratory muscles are relaxed, the lung and the chest wall are acting on each other in opposite directions. The lung is tending to decrease its volume because of the inward elastic recoil of the distended alveolar walls; the chest wall is tending to increase its volume because of its outward elastic recoil. Thus, the chest wall is acting to hold the alveoli open in opposition to their elastic recoil. Similarly, the lung is acting by its elastic recoil to hold the chest wall in. Because of this interaction, the pressure is negative at the surface of the very thin (about 10–30 μm in thickness at normal lung volumes),

fluid-filled pleural space, as seen on the left in Figure 32–1. There is normally no free gas in the intrapleural space, and the lung is held against the chest wall by the thin layer of serous intrapleural liquid, estimated to have a total volume of about 15–25 mL in the average adult. Initially, before any airflow occurs, the pressure inside the alveoli is the same as atmospheric pressure—by convention 0 cm H2O. Alveolar pressure is greater than intrapleural pressure because it represents the sum of the intrapleural pressure plus the alveolar elastic recoil pressure: Alveolar pressure = Intrapleural pressure + Alveolar elastic recoil pressure

(1)

The muscles of inspiration act to increase the volume of the thoracic cavity. As the inspiratory muscles contract, expanding the thoracic volume and increasing the outward stress on the lung, the intrapleural pressure becomes more negative. Therefore, the transmural pressure gradient tending to distend the alveolar wall (also called the transpulmonary pressure) increases as shown in Figure 32–1, and the alveoli enlarge passively. Increasing alveolar volume lowers alveolar pressure and establishes the pressure gradient for airflow into the lung. In reality, only a small percentage of the total number of alveoli are directly exposed to the intrapleural surface pressure, and at first thought, it is difficult to see how alveoli located centrally in the lung could be expanded by a more negative intrapleural

CHAPTER 32 Mechanics of the Respiratory System

Intrapleural pressure

315

Negative pressure breathing (A)

Interdependence of alveolar units

Positive pressure ventilation (B)

FIGURE 32–2 Structural interdependence of alveolar units. The pressure gradient across the outermost alveoli is transmitted mechanically through the lung via the alveolar septa. The insets show the author’s idea of what might happen in negative-pressure breathing and positive-pressure ventilation. In negative-pressure breathing (inset A), the mechanical stress would likely be transmitted from the more exterior alveoli (those closest to the chest wall) to more interior alveoli, so the exterior alveoli might be more distended. In positive-pressure ventilation (inset B), the lungs must push against the diaphragm and rib cage to move them. The outermost alveoli might be more compressed than those located more interiorly. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

pressure. However, careful analysis has shown that the pressure at the pleural surface is transmitted through the alveolar walls to more centrally located alveoli and small airways. This structural interdependence of alveolar units is depicted in Figure 32–2.

THE MUSCLES OF RESPIRATION Inspiratory Muscles The muscles of respiration are skeletal muscles and their activity is normally initiated by the nervous system.The muscles of inspiration include the diaphragm, the external intercostal muscles, and the accessory muscles of inspiration. The diaphragm is a large (about 250 cm2 in surface area), domeshaped muscle that separates the thorax from the abdominal cavity. It is the primary muscle of inspiration. When a person is in the supine position, the diaphragm is responsible for about two thirds of the air that enters the lungs during normal quiet breathing (which is called eupnea). When a person is standing or seated in an upright posture, the diaphragm may be responsible for only about one third to one half of the tidal

volume. It is innervated by the two phrenic nerves, which are motor nerves that leave the spinal cord at the third to the fifth cervical segments. The muscle fibers of the diaphragm are inserted into the sternum and the six lower ribs and into the vertebral column by the two crura. The other ends of these muscle fibers converge to attach to the fibrous central tendon, which is also attached to the pericardium on its upper surface (Figure 32–3). During normal quiet breathing, contraction of the diaphragm causes its dome to descend 1–2 cm into the abdominal cavity, with little change in its shape. This elongates the thorax and increases its volume. These small downward movements of the diaphragm are possible because the abdominal viscera can push out against the relatively compliant abdominal wall. During a deep inspiration, the diaphragm can descend as much as 10 cm. With such a deep inspiration, the limit of the abdominal wall to expand is reached, abdominal pressure increases, and the indistensible central tendon becomes fixed against the abdominal contents. After this point, contraction of the diaphragm against the fixed central tendon elevates the lower ribs as shown in the figure. Contraction of the external intercostal, parasternal intercostal, and scalene muscles raises and enlarges the rib cage.

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SECTION VI Pulmonary Physiology

Pleura Rib cage Mediastinum Pericardium Central tendon Diaphragm Crura

END EXPIRATION

FIGURE 32–3

DEEP INSPIRATION

Illustration of the actions of diaphragmatic contraction in expanding the thoracic cavity. (Modified with permission from

Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

Figure 32–4 demonstrates how contraction of these muscles increases the anteroposterior dimension of the chest as the ribs rotate upward about their axes and also increases the transverse dimension of the lower portion of the chest. These muscles are innervated by nerves leaving the spinal cord at the 1st to the 11th thoracic segments. During inspiration, the diaphragm and inspiratory rib cage muscles contract simultaneously. If the diaphragm contracted alone, the rib cage muscles would be pulled inward (this is called retraction). If the

INSPIRATION

inspiratory muscles of the rib cage contracted alone, the diaphragm would be pulled upward into the thorax. The accessory muscles of inspiration are not involved during normal quiet breathing but may be called into play during exercise, during the inspiratory phase of coughing or sneezing, or in a pathologic state, such as asthma. Dyspnea, the feeling that breathing is difficult, is probably often related to fatigue of the inspiratory muscles. Other potential causes of dyspnea will be discussed in Chapter 38.

ACTIVE EXPIRATION

Accessory muscles

External intercostals Internal intercostals

Diaphragm

Abdominal muscles Posterior

FIGURE 32–4

Anterior

Illustration of the actions of contraction of the intercostal muscles, abdominal muscles, and accessory muscles.

(Modified with permission of the publisher from by Weibel ER: The Pathway for Oxygen. Cambridge, MA: Harvard University Press, p. 304. Copyright © 1984 by the President and Fellows of Harvard College.)

CHAPTER 32 Mechanics of the Respiratory System

Expiratory Muscles Expiration is passive during normal quiet breathing, and no respiratory muscles contract. As the inspiratory muscles relax, the increased elastic recoil of the distended alveoli is sufficient to decrease the alveolar volume and raise alveolar pressure above atmospheric pressure, establishing the pressure gradient for airflow from the lung. Although the diaphragm is usually considered to be completely relaxed during expiration, it is likely that some diaphragmatic muscle tone is maintained, especially when one is in the horizontal position. Active expiration occurs during exercise, speech, singing, the expiratory phase of coughing or sneezing, and in pathologic states such as chronic bronchitis. The main muscles of expiration are the muscles of the abdominal wall and the internal intercostal muscles. When the abdominal muscles contract, they increase abdominal pressure and push the abdominal contents against the relaxed diaphragm, forcing it upward into the thoracic cavity. They also help depress the lower ribs and pull down the anterior part of the lower chest. Contraction of the internal intercostal muscles depresses the rib cage downward in a manner opposite to the actions of the external intercostals. Active expiration compresses the thorax and causes positive intrapleural pressure. This has important effects on the respiratory system, which will be discussed later

in this chapter, and on pulmonary blood flow, which will be discussed in Chapter 34.

SUMMARY OF THE EVENTS OCCURRING DURING THE COURSE OF A BREATH The events occurring during the course of an idealized normal quiet breath (summarized in Table 32–1) are shown in Figure 32–5. For the purpose of clarity, inspiration and expiration are considered to be of equal duration, although during normal quiet breathing, the expiratory phase is longer than the inspiratory phase. Initially, alveolar pressure equals atmospheric pressure, so no air flows into the lung. Intrapleural pressure is –5 cm H2O. Contraction of the inspiratory muscles causes intrapleural pressure to become more negative as the lungs are pulled open and the alveoli are distended. As the alveoli are distended, the pressure inside them decreases below atmospheric pressure and air flows into the alveoli, as seen in the tidal volume panel. As the air flows into the alveoli, alveolar pressure returns to 0 cm H2O and airflow into the lung ceases. At the vertical line, the inspiratory effort ceases and the inspiratory muscles relax. Intrapleural pressure becomes less negative, and the elastic recoil of the

TABLE 32–1 Events involved in a normal tidal breath. Inspiration 1. Brain initiates inspiratory effort 2. Nerves carry the inspiratory command to the inspiratory muscles 3. Diaphragm (and/or external intercostal muscles) contracts 4. Thoracic volume increases as the chest wall expandsa 5. Intrapleural pressure becomes more negative 6. Alveolar transmural pressure gradient increases 7. Alveoli expand (according to their individual compliance curves) in response to the increased transmural pressure gradient. This increases alveolar elastic recoil 8. Alveolar pressure falls below atmospheric pressure as the alveolar volume increases, thus establishing a pressure gradient for airflow 9. Air flows into the alveoli until alveolar pressure equilibrates with atmospheric pressure Expiration (passive) 1. Brain ceases inspiratory command 2. Inspiratory muscles relax 3. Thoracic volume decreases, causing intrapleural pressure to become less negative and decreasing the alveolar transmural pressure gradientb 4. Decreased alveolar transmural pressure gradient allows the increased alveolar elastic recoil to return the alveoli to their preinspiratory volumes 5. Decreased alveolar volume increases alveolar pressure above atmospheric pressure, thus establishing a pressure gradient for airflow 6. Air flows out of the alveoli until alveolar pressure equilibrates with atmospheric pressure a

Note that numbers 4–8 occur simultaneously.

b

317

Note that numbers 3–5 occur simultaneously.

Reproduced with permission from Levitzky MG, Cairo JM, Hall SM: Introduction to Respiratory Care. Philadelphia: WB Saunders and Company, 1990.

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SECTION VI Pulmonary Physiology

100

–5

–10 +1

cm H2O

Alveolar pressure

0

75 Total lung volume, %

Intrapleural pressure

cm H2O

Expiration

Inspiration 50

25

–1 +0.5 L/sec

Air flow

0 –0.5

FIGURE 32–6

0.5

20 10 30 Transpulmonary pressure cm H2O

40

Pressure–volume curve for isolated lungs.

(Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed.

Change in lung volume

L

0 Onset of inspiration

0

End of inspiration

End of expiration

FIGURE 32–5 Volume, pressure, and airflow changes during a single idealized respiratory cycle. Described in text. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

alveolar walls (which is increased at the higher lung volume) is allowed to compress the alveolar gas. This raises alveolar pressure above atmospheric pressure so that air flows out of the lung until an alveolar pressure of 0 cm H2O is restored. At this point, airflow ceases until the next inspiratory effort.

PRESSURE–VOLUME RELATIONSHIPS IN THE RESPIRATORY SYSTEM The relationship between changes in the pressure distending the alveoli and changes in lung volume is important to understand because it dictates how the lung inflates with each breath. As mentioned before, the alveolar-distending pressure is often referred to as the transpulmonary pressure.

COMPLIANCE OF THE LUNG AND THE CHEST WALL The pressure–volume characteristics of the lung can be inspected in several ways. One of the simplest is to remove the

New York: McGraw-Hill Medical, 2007.)

lungs from an animal or a cadaver and then graph the changes in volume that occur for each change in transpulmonary pressure to which the lungs are subjected (Figure 32–6). Figure 32–6 shows that as the transpulmonary pressure increases, the lung volume increases. Of course, this relationship is not a straight line: the lung is composed of living tissue, and although the lung distends easily at low lung volumes, at high lung volumes the distensible components of alveolar walls have already been stretched, and large increases in transpulmonary pressure yield only small increases in volume. The lung also is difficult to distend at very low lung volumes because some alveoli may be collapsed and extra energy is necessary to reopen them. The slope between two points on a pressure–volume curve is known as the compliance. Compliance is defined as the change in volume divided by the change in pressure. Lungs with high compliance have a steep slope on their pressure–volume curves, that is, a small change in distending pressure will cause a large change in volume. It is important to remember that compliance is the inverse of elasticity, or elastic recoil. Compliance denotes the ease with which something can be stretched or distorted; elasticity refers to the tendency for something to oppose stretch or distortion, as well as to its ability to return to its original configuration after the distorting force is removed. There are several other interesting things to note about an experiment like that illustrated in Figure 32–6. The curve obtained is the same whether the lungs are inflated with positive pressure (by forcing air into the trachea) or with negative pressure (by suspending the lung, except for the trachea, in a closed chamber and pumping out the air around the lung). So when the lung alone is considered, only the transpulmonary pressure is important, not how the transpulmonary pressure is generated. A second feature of the curve in Figure 32–6 is that there is a difference between the pressure–volume curve for

CHAPTER 32 Mechanics of the Respiratory System

Clinical Evaluation of the Compliance of the Lung and the Chest Wall The compliance of the lung and the chest wall provides very useful data for the clinical evaluation of a patient’s respiratory system because many diseases or pathologic states affect the compliance of the lung, the chest wall, or both. The lung and the chest wall are physically in series with each other, and therefore their compliances add as reciprocals: 1 ____________ = Total compliance 1 1 _________________ + ____________________ Compliance of the lung Compliance of the chest wall

(2)

Compliances in parallel add directly. Therefore, both lungs together are more compliant than either one alone. The compliance curve for the lungs can be generated by having the patient take a very deep breath and exhale in stages, stopping periodically for pressure and volume determinations. During these determinations, no airflow is occurring; alveolar pressure therefore equals atmospheric pressure, 0 cm H2O. Similar measurements can be made as the patient inhales in stages from a low lung volume to a high lung volume. Such curves are called static compliance curves because all measurements are made when no airflow is occurring. The compliance of the chest wall is normally obtained by determining the compliance of the total system and the compliance of the lungs alone and then calculating the compliance of the chest wall according to the above formula. Dynamic compliance assesses pressure–volume characteristics during the breath. Representative static compliance curves for the lungs are shown in Figure 32–7. Note that these curves correspond to the expiratory curve in Figure 32–6. Many pathologic states shift the curve to the right; that is, for any increase in transpulmonary pressure, there is a smaller increase in lung volume. A proliferation of connective tissue called fibrosis may occur in sarcoidosis or after chemical or thermal injury to the lungs. This will make the lungs less compliant, or “stiffer,” and increase alveolar elastic recoil. Similarly, pulmonary vascular engorgement or areas of collapsed alveoli (atelectasis) also make the lung less compliant. Other conditions that interfere with the lung’s ability to expand (such as the presence of air, excess fluid, or blood in the intrapleural space) will decrease the measured compliance of the lungs. Emphysema increases

Compliance =

Δ Lung volume ΔV = Δ (P alv – P ip) Δ P tp

Increased compliance

Lung volume (ml)

inflation and the curve for deflation, as shown by the arrows. Such a difference is called hysteresis. One possible explanation for this hysteresis is the stretching on inspiration and the compression on expiration of the surfactant that lines the air– liquid interface in the alveoli (discussed later in this chapter). Another is that some alveoli or small airways may open on inspiration (“recruitment”) and close on expiration (“derecruitment”) as noted above. Some researchers believe that lung volume changes primarily by recruitment and derecruitment of alveoli rather than by volume changes of individual alveoli. Finally, it can be helpful to think of each alveolus as having its own pressure–volume curve like that shown in the figure.

319

0

Normal compliance

Decreased compliance

Transpulmonary pressure (P tp) (P alv – P ip)

FIGURE 32–7 Representative static pulmonary compliance curve for normal lungs; lungs with low compliance, for example, lungs with fibrosis; and lungs with high compliance, for example, lungs with emphysema. (Reproduced with permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

the compliance of the lungs because it destroys the alveolar septal tissue that normally opposes lung expansion. The compliance of the chest wall is decreased in obese people, for whom moving the diaphragm downward and the rib cage up and out is much more difficult. Musculoskeletal disorders that lead to decreased mobility of the rib cage, such as kyphoscoliosis, also decrease the chest wall compliance. Because they must generate greater transpulmonary pressures to breathe in the same volume of air, people with decreased compliance of the lungs must do more work to inspire than those with normal pulmonary compliance. Similarly, more muscular work must be done when chest wall compliance is decreased.

ELASTIC RECOIL OF THE LUNG So far, the elastic recoil of the lungs has been discussed as though it were only due to the elastic properties of the pulmonary parenchyma itself. However, there is another component of the elastic recoil of the lung—the surface tension at the air– liquid interface in the alveoli. Surface tension forces occur at any gas–liquid interface and are generated by the cohesive forces between the molecules of the liquid. These cohesive forces balance each other within the liquid phase but are unopposed at the surface of the liquid. Surface tension causes water to bead and form droplets, and a liquid to shrink to form the smallest possible surface

320

SECTION VI Pulmonary Physiology

Saline

200

Air

Volume (mL)

150 T

P

T  Pr

T

100

50 Resolved direction of tension 0

4

8 12 16 Pressure (cm H2O)

T

FIGURE 32–9 Relationship between the pressure inside a distensible sphere, such as an alveolus, and its wall tension.

20

FIGURE 32–8

Pressure–volume curves for excised cat lungs inflated with air or saline. (Modified from Radford EP. Recent studies of

(Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

mechanical properties of mammalian lungs. In: Remington JW. Tissue Elasticity. Washington: American Physiological Society; 1957.)

area. The role of the surface tension forces in the elastic recoil of the lung can be demonstrated in an experiment shown in Figure 32–8. In this experiment, a pressure–volume curve for an excised lung was first generated with air inflation, so an air–liquid interface was present in the lung, and surface tension forces contributed to alveolar elastic recoil. Then, all the gas was removed from the lung, and it was inflated again, this time with saline instead of with air. In this situation, surface tension forces were absent because there was no air–liquid interface. The elastic recoil was due only to the lung tissue itself. Note that there is no hysteresis with saline inflation. Whatever causes the hysteresis appears to be related to surface tension in the lung. The curve at left (saline inflation) therefore represents the elastic recoil due to only the lung tissue itself; the curve at right demonstrates the recoil due to both the lung tissue and the surface tension forces. The difference between the two curves is the recoil due to surface tension forces. The demonstration of the large role of surface tension forces in the recoil pressure of the lung led to consideration of how surface tension affects the alveoli. One traditional way of thinking about this has been to consider the alveolus to be a sphere hanging from the airway, as in Figure 32–9. The relationship between the pressure inside the alveolus and the wall tension of the alveolus would then be given by Laplace’s law (units in brackets): 2 × tension [dyn/cm] Pressure [dyn/cm ] = _______________ Radius [cm] 2

(3)

If two alveoli of different sizes are connected by a common airway (Figure 32–10) and the surface tension of the two alveoli is equal, then according to Laplace’s law, the pressure in the small alveolus is greater than that in the larger alveolus and the smaller alveolus will empty into the larger alveolus. If surface tension is independent of surface area, the smaller the alveolus on the right becomes, the higher the pressure in it. Thus, if the lung were composed of interconnected alveoli of different sizes (which it is) with a constant surface tension at the air–liquid interface, it would be inherently unstable, with a tendency for smaller alveoli to collapse into larger ones. This is usually not the case, which is fortunate because collapsed alveoli require very great distending pressures to reopen, partly because of the cohesive forces at the liquid–liquid interface of collapsed alveoli. At least two factors cause the alveoli to be more stable than this prediction based on constant surface

T

P1 r

P1 

(4)

where T is the wall tension, P the pressure inside the alveolus, and r the radius of the alveolus. The surface tension of most liquids (such as water) is constant and not dependent on the area of the air–liquid interface.

2r

T r P2 

This can be rearranged as follows: Pr T = __ 2

T P2

T 2r

FIGURE 32–10 Schematic representation of two alveoli of different sizes connected to a common airway. If the surface tension is the same in both alveoli, then the smaller alveolus will have a higher pressure and will empty into the larger alveolus. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

CHAPTER 32 Mechanics of the Respiratory System tension. The first factor is a substance called pulmonary surfactant, which is produced by specialized alveolar cells, and the second is the structural interdependence of the alveoli.

Pulmonary Surfactant Pulmonary surfactant decreases the elastic recoil due to surface tension, thereby increasing the compliance of the lungs above that predicted by an air–water interface and decreasing the inspiratory work of breathing. Pulmonary surfactant has a second major effect. It decreases the surface tension of smaller alveoli. This helps equalize alveolar pressures throughout the lung (so the end-expiratory pressure of all the alveoli is 0 cm H2O and the situation depicted in Figure 32–10 does not occur) and to stabilize alveoli. Pulmonary surfactant is a complex consisting of about 85–90% lipids and 10–15% proteins. The lipid portion is about 85% phospholipid, approximately 75% of which is dipalmitoyl phosphatidylcholine. This complex is produced by type II alveolar epithelial cells (described above). Pulmonary surfactant appears to be continuously produced in the lung, but it is also continuously cleared from the lung. Some pulmonary surfactant is taken back into the type II cells (reuptake), where it is recycled and secreted again, or it is degraded and used to synthesize other phospholipids. Surfactant is also cleared from the alveoli by alveolar macrophages, absorption into the lymphatics, or migration up to the small airways and the mucociliary escalator (discussed in Chapter 31). Type II alveolar epithelial cells may also help remove liquid from the alveolar surface by actively pumping sodium and water from the alveolar surface into the interstitium. The clinical consequences of a lack of functional pulmonary surfactant occur in several conditions. Surfactant is not produced by the fetal lung until about the fourth month of gestation, and it may not be fully functional until the seventh month or later. Prematurely born infants who do not have functional pulmonary surfactant experience great difficulty in inflating their lungs, especially on their first breaths. Even if their alveoli are inflated for them with positive-pressure ventilation, the tendency toward spontaneous collapse is great because their alveoli are much less stable without pulmonary surfactant. Therefore, the lack of functional pulmonary surfactant in a prematurely born neonate may be a major factor in the infant respiratory distress syndrome. Pulmonary surfactant may also be important in maintaining the stability of small airways. Alveolar hypoxia or hypoxemia (low oxygen in the arterial blood), or both, may lead to a decrease in surfactant production or an increase in surfactant destruction. This condition may be a contributing factor in the acute respiratory distress syndrome (also known as adult respiratory distress syndrome or “shock lung syndrome”) that can occur in patients after trauma or surgery. One approach to maintain patients with acute or infant respiratory distress syndrome is to ventilate their lungs with positive-pressure ventilators and to keep their alveolar pressure above atmospheric pressure during expiration (this is known as positive end-expiratory pressure [PEEP]). This process opposes the increased elastic recoil of

321

the alveoli and the tendency for spontaneous atelectasis to occur because of a lack of pulmonary surfactant. Exogenous pulmonary surfactant is now administered directly into the airway of neonates with infant respiratory distress syndrome. In summary, pulmonary surfactant helps decrease the work of inspiration by lowering the surface tension of the alveoli, thus reducing the elastic recoil of the lung and making the lung more compliant. Surfactant also helps stabilize the alveoli by lowering even further the surface tension of smaller alveoli, equalizing the pressure inside alveoli of different sizes.

Alveolar Interdependence A second factor tending to stabilize the alveoli is their mechanical interdependence, which was discussed at the beginning of this chapter. Alveoli do not hang from the airways like a “bunch of grapes” (the translation of the Latin word “acinus”), and they are not spheres. They are mechanically interdependent polygons with flat walls shared by adjacent alveoli. Alveoli are normally held open by the chest wall pulling on the outer surface of the lung, as shown in Figure 32–2. If an alveolus were to begin to collapse, it would increase the stresses on the walls of the adjacent alveoli, which would tend to hold it open. This process would oppose a tendency for isolated alveoli with a relative lack of pulmonary surfactant to collapse spontaneously. Conversely, if a whole subdivision of the lung (such as a lobule) has collapsed, as soon as the first alveolus is reinflated, it helps to pull other alveoli open by its mechanical interdependence with them. Thus, both pulmonary surfactant and the mechanical interdependence of the alveoli help stabilize the alveoli and oppose alveolar collapse (atelectasis).

MECHANICAL INTERACTION OF THE LUNG AND CHEST WALL The inward elastic recoil of the lung normally opposes the outward elastic recoil of the chest wall, and vice versa. If the integrity of the lung–chest wall system is disturbed by breaking the seal of the chest wall (e.g., by a penetrating knife wound), the inward elastic recoil of the lung is no longer opposed by the outward recoil of the chest wall, and their interdependence ceases. Lung volume decreases, and alveoli have a much greater tendency to collapse, especially if air moves in through the wound (causing a pneumothorax) until intrapleural pressure equalizes with atmospheric pressure and abolishes the transpulmonary pressure gradient. At this point, nothing is tending to hold the alveoli open and their elastic recoil is causing them to collapse. Similarly, the chest wall tends to expand because its outward recoil is no longer opposed by the inward recoil of the lung. When the lung–chest wall system is intact and the respiratory muscles are relaxed, the volume of gas left in the lungs is determined by the balance of these two forces. The volume of gas in the lungs at the end of a normal tidal expiration, when no respiratory muscles are actively contracting, is known as the

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functional residual capacity (FRC). For any given situation, the FRC will be that lung volume at which the outward recoil of the chest wall is equal and opposite to the inward recoil of the lungs. If the lung volume increases above the FRC, the increased inward elastic recoil of the lung exceeds the decreased outward elastic recoil of the chest wall. At high lung volumes (above about 70% of the total lung capacity [TLC]), the chest wall also has inward elastic recoil. Therefore, at high lung volumes, the elastic recoil of both the lung and chest wall are inward. At lung volumes below the FRC, the outward recoil of the chest wall is greater than the reduced inward recoil of the lungs. A change from the upright to the supine position decreases FRC. The reason for this decrease of about 30% is the effect of gravity on the mechanics of the chest wall, especially the diaphragm. When standing up or sitting, the contents of the abdomen are being pulled away from the diaphragm by gravity. When lying down, the abdominal contents are pushing inward against the relaxed diaphragm. This decreases the overall outward recoil of the chest wall and decreases the lung volume at which the outward recoil of the chest wall is equal and opposite to the inward recoil of the lungs.

AIRWAY RESISTANCE Several factors besides the elastic recoil of the lungs and the chest wall must be overcome to move air into or out of the lungs. These factors are primarily the frictional resistance of the lung and chest wall tissue, and the frictional resistance of the airways to the flow of air. Pulmonary tissue resistance is caused by the friction encountered as the lung tissues move against each other as the lung expands. The airway resistance plus the pulmonary tissue resistance is often referred to as the pulmonary resistance. Pulmonary tissue resistance normally contributes about 20% of the pulmonary resistance, with airway resistance responsible for the other 80%. Pulmonary tissue resistance can be increased in such conditions as pulmonary sarcoidosis and fibrosis. Because airway resistance is the major component of the total resistance and because it can increase tremendously both in healthy people and in those suffering from various diseases, the remainder of this chapter will concentrate on airway resistance.

LAMINAR, TURBULENT, AND TRANSITIONAL FLOW As was discussed in Chapter 22, the relationship among pressure, flow, and resistance is: Pressure difference = Flow × Resistance

(5)

The resistance to airflow is analogous to electrical resistance in that resistances in series are added directly: Rtot = R1 + R2 + …

(7)

Resistances in parallel are added as reciprocals: 1 1 __ ___ = __ + 1 +… Rtot R1 R2

(8)

Airflow, like that of other fluids, can occur as either laminar or turbulent flow, as was discussed in Chapter 26 (see Figure 26–6). When a fluid such as air is in laminar flow through rigid, smooth bore tubes, its behavior is governed by Poiseuille’s law, as was discussed in Chapter 22. Turbulent flow tends to occur if airflow is high, gas density is high, the tube radius is large, or all three conditions exist. True laminar flow probably occurs only in the smallest airways, where the linear velocity of airflow is extremely low. Linear velocity (cm/s) is equal to the flow (cm3/s) divided by the cross-sectional area. The sum of the cross-sectional areas of the smallest airways is very large, so the linear velocity of airflow is very low. The airflow in the trachea and larger airways is usually either turbulent or a mixture of laminar and turbulent flow.

DISTRIBUTION OF AIRWAY RESISTANCE About 25–40% of the total resistance to airflow is located in the upper airways: the nose, nasal turbinates, oropharynx, nasopharynx, and larynx. Resistance is higher when one breathes through the nose than when one breathes through the mouth. The vocal cords open slightly during normal inspirations and close slightly during expirations. During deep inspirations, they open widely. The muscles of the oropharynx also contract during normal inspiration; this dilates and stabilizes the upper airway. During deep forced inspirations, the development of negative pressure could cause the upper airway to be pulled inward and partly or completely obstruct airflow. Reflex contraction of these pharyngeal dilator muscles normally keeps the airway open. The component with the highest individual resistance of the tracheobronchial tree is obviously the smallest airway, which has the smallest radius. Nevertheless, because the smallest airways are arranged in parallel, their resistances add as reciprocals, so that the total resistance to airflow offered by the numerous small airways is extremely low during normal, quiet breathing. Therefore, the greatest resistance to airflow usually resides in the medium-sized bronchi.

Therefore, we have: Pressure difference [cm H O] Flow [L/s]

2 Resistance = _____________________

(6)

This means that resistance is a meaningful term only during flow. When airflow is considered, the units of resistance are usually cm H2O/[L/s].

CONTROL OF BRONCHIAL SMOOTH MUSCLE The smooth muscle of the airways from the trachea down to the alveolar ducts is under the control of efferent fibers of the

CHAPTER 32 Mechanics of the Respiratory System

Active control of the airways.

Constrict Parasympathetic stimulation Acetylcholine Histamine Leukotrienes Thromboxane A2 Serotonin α-Adrenergic agonists Decreased Pco2 in small airways Dilate Sympathetic stimulation (β2 receptors) Circulating β2 agonists Nitric oxide Increased Pco2 in small airways Decreased Po2 in small airways

100 Airway resistance (% maximum)

TABLE 32–2

323

75

50

25 RV

TLC

0 0

2

4

6

8

Lung volume (L)

autonomic nervous system (see Chapter 19). Stimulation of the cholinergic parasympathetic postganglionic nerves causes constriction of bronchial smooth muscle as well as increased glandular mucus secretion. The preganglionic fibers travel in the vagus nerve. Stimulation of the adrenergic sympathetic nerves causes dilation of bronchial and bronchiolar smooth muscle as well as inhibition of glandular secretion. This dilation of the airway smooth muscle is mediated by beta2 (β2) receptors, which predominate in the airways. Selective stimulation of the alpha (α) receptors with pharmacologic agents causes bronchoconstriction. Adrenergic transmitters carried in the blood may be as important as those released from the sympathetic nerves in causing bronchodilation. The bronchial smooth muscle is normally under greater parasympathetic tone than sympathetic tone. Inhalation of chemical irritants, smoke, or dust; stimulation of the arterial chemoreceptors; and substances such as histamine cause constriction of the airways. Decreased CO2 in the branches of the conducting system causes a local constriction of the smooth muscle of the nearby airways; increased CO2 or decreased O2 causes a local dilation. This may help balance ventilation and perfusion (see Chapter 35). Many other substances can have direct or indirect effects on airway smooth muscle (Table 32–2). Leukotrienes usually cause bronchoconstriction, as do some prostaglandins.

FIGURE 32–11 Relationship between lung volume and airway resistance. Total lung capacity (TLC) is at right; residual volume (RV) is at left. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

resistance, even with so many parallel pathways. To increase lung volume, a person breathing normally takes a “deep breath,” that is, makes a strong inspiratory effort. This effort causes intrapleural pressure to become much more negative than –7 or –10 cm H2O in a normal, quiet breath. The transmural pressure gradient across the wall becomes much more positive, and small airways are distended. A second reason for the decreased airway resistance at higher lung volumes is that the traction on the small airways increases. As shown in the schematic drawing in Figure 32–12, the small airways traveling through the lung form attachments to the walls of alveoli. As the alveoli expand during the course of a deep inspiration, the elastic recoil in their walls increases; this elastic recoil is transmitted to the attachments at the airway, pulling it open.

LUNG VOLUME AND AIRWAY RESISTANCE Airway resistance decreases with increasing lung volume, as shown in Figure 32–11. There are two reasons for this relationship; both mainly involve the small airways that, as described in this chapter, have little or no cartilaginous support. The small airways are therefore rather distensible and also compressible. Thus, the transmural pressure gradient across the wall of the small airways is an important determinant of the radius of the airways: since resistance is inversely proportional to the radius to the fourth power, changes in the radii of small airways can cause dramatic changes in airway

AIRWAY

Traction on airway by elastic recoil of alveolar septa

FIGURE 32–12 Representation of “traction” of the alveolar septa on a small distensible airway. Compare this figure with the picture of the alveolar duct in Figure 31–4. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

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DYNAMIC COMPRESSION OF AIRWAYS

pressure gradient would generate very high rates of airflow. However, the airways are not uniformly rigid and the smallest airways, which have no cartilaginous support and rely on the traction of alveolar septa to help keep them open, may be compressed or may even collapse. Whether or not they actually collapse depends on the transmural pressure gradient across the walls of the smallest airways. The situation during a normal passive expiration at the same lung volume (note the same alveolar elastic recoil pressure) is shown in the left part of Figure 32–13. The transmural pressure gradient across the smallest airways is +1 – (–8) cm H2O = +9 cm H2O tending to hold the airway open. During the forced expiration at right, the transmural pressure gradient is 30 – 25 cm H2O, or only 5 cm H2O holding the airway open. The airway may then be slightly compressed, and its resistance to airflow will be even greater than that during the passive expiration. This increased resistance during a forced expiration is called dynamic compression of airways. Consider what occurs during a maximal forced expiration. As the expiratory effort is increased to attain a lower lung volume, intrapleural pressure is getting more and more positive, and more and more dynamic compression will occur. Furthermore, as lung volume decreases, there will be less alveolar elastic recoil pressure and the difference between

Airway resistance is extremely high at low lung volumes, as shown in Figure 32–11. To achieve low lung volumes, a person must make a forced expiratory effort by contracting the muscles of expiration, mainly the abdominal and internal intercostal muscles. This effort generates a positive intrapleural pressure, which can be as high as 120 cm H2O during a maximal forced expiratory effort. (Maximal inspiratory intrapleural pressures can be as low as –80 cm H2O.) The effect of this high positive intrapleural pressure on the transmural pressure gradient during a forced expiration can be seen at right in Figure 32–13, a schematic drawing of a single alveolus and airway. The muscles of expiration are generating a positive intrapleural pressure of +25 cm H2O. Pressure in the alveolus is higher than intrapleural pressure because of the alveolar elastic recoil pressure of +10 cm H2O, which, together with intrapleural pressure, gives an alveolar pressure of +35 cm H2O. The alveolar elastic recoil pressure decreases at lower lung volumes because the alveolus is not as distended. In the figure, a gradient has been established from the alveolar pressure of +35 cm H2O to the atmospheric pressure of 0 cm H2O. If the airways were rigid and incompressible, the large expiratory

0

0

0.25

3

8

8

5

25

25

10

0.5 8

8

25

15

25

20 25

8

8

25

1

10

10 8

2

10

10

35 10

10 8

25

25

30

Contraction of internal intercostals and accessory muscles of expiration

10

10 25

Relaxed diaphragm pushed up by abdominal muscle contraction PASSIVE EXPIRATION

FORCED EXPIRATION

FIGURE 32–13 Schematic diagram illustrating dynamic compression of airways and the equal pressure point hypothesis during a forced expiration. Left: Passive (eupneic) expiration. Intrapleural pressure is –8 cm H2O, alveolar elastic recoil pressure is +10 cm H2O, and alveolar pressure is +2 cm H2O. Right: Forced expiration at the same lung volume. Intrapleural pressure is +25 cm H2O, alveolar elastic recoil pressure is +10 cm H2O, and alveolar pressure is +35 cm H2O. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

alveolar pressure and intrapleural pressure will decrease. At any instant during a forced expiration, there is a point along the airways where the pressure inside the airway is just equal to the pressure outside the airway. At that point (the “equal pressure point”), the transmural pressure gradient is 0 (note the arrows in Figure 32–13). Above that point, the transmural pressure gradient is negative: the pressure outside the airway is greater than the pressure inside it, and the airway will collapse if cartilaginous support or alveolar septal traction is insufficient to keep it open. As the forced expiratory effort continues, the equal pressure point is likely to move down the airway from larger to smaller airways. This movement happens because, as the muscular effort increases, intrapleural pressure increases and because, as lung volume decreases, alveolar elastic recoil pressure decreases. As the equal pressure point moves down the airway, dynamic compression increases and the airways begin to collapse. This airway closure can be demonstrated only at especially low lung volumes in healthy subjects, but the closing volume may occur at higher lung volumes in patients with high lung compliance as in emphysema. The closing volume will be discussed in Chapter 33. During a passive expiration, the pressure gradient for air˙ R) is simply alveolar pressure minus atmoflow (ΔP in ΔP = V spheric pressure. But if dynamic compression occurs, the effective pressure gradient is alveolar pressure minus intrapleural pressure (which equals the alveolar elastic recoil pressure) because intrapleural pressure is greater than atmospheric pressure and because intrapleural pressure can exert its effects on the compressible portion of the airways. Thus, during a forced expiration, when intrapleural pressure becomes positive and dynamic compression occurs, the effective driving pressure for airflow from the lung is the alveolar elastic recoil pressure. Alveolar elastic recoil is also important in opposing dynamic compression of the airways because of its role in the traction of the alveolar septa on small airways, as shown in Figure 32–12. The effects of alveolar elastic recoil on airflow during a forced expiration are illustrated in Figure 32–14.

ASSESSMENT OF AIRWAY RESISTANCE The resistance to airflow cannot be measured directly but must be calculated from the pressure gradient and airflow during a breath: ΔP R = ___ ˙ V

(9)

The above formula is an approximation because it presumes that all airflow is laminar, which is not true. But there is a second problem: how can the pressure gradient be determined? To know the pressure gradient, the alveolar pressure—which also cannot be measured directly—must be known. Alveolar pressure can be calculated using a body plethysmograph, an expensive piece of equipment described in the next chapter, but this procedure is not often done. Instead, airway resistance is usually assessed indirectly. The assessment of airway resis-

PA  Ppl ( Pel)

CHAPTER 32 Mechanics of the Respiratory System

Intrapleural pressure

325

Dynamic compression

Traction

Alveolar elastic recoil

Alveolar elastic recoil

Pel

Pel PA Pel

Pel

FIGURE 32–14 Representation of the effects of alveolar elastic recoil on airflow during a forced expiration. When dynamic compression occurs, alveolar elastic recoil helps to oppose it by traction on the small airways. The alveolar elastic recoil pressure becomes the effective driving pressure for airflow from the lung. PA, alveolar pressure; Ppl, intrapleural pressure; Pel, the alveolar elastic recoil pressure. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

tance during expiration will be emphasized because that factor is of interest in patients with lung disease.

Forced Vital Capacity One way of assessing expiratory airway resistance is to look at the results of a forced expiration into a spirometer, as shown in Figure 32–15. This measurement is called a forced vital capacity (FVC). The vital capacity (VC) is the volume of air a subject is able to expire after a maximal inspiration to the TLC. An FVC means that a maximal expiratory effort was made during this maneuver. In an FVC test, a person makes a maximal inspiration to the TLC. After a moment, he or she makes a maximal forced expiratory effort, blowing as much air as possible out of the lungs. At this point, only a residual volume (RV) of air is left in the lungs. (The lung volumes will be described in detail in the next chapter.) This procedure takes only a few seconds, as can be seen on the time scale. The part of the curve most sensitive to changes in expiratory airway resistance is the first second of expiration. The volume of air expired in the first second of expiration (the FEV1, or forced expiratory volume in 1 second), especially when expressed as a ratio with the total amount of air expired

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7

Volume (L)

6 5

Normal

4

FEV1 / FVC  80% FEV1  3.6 L

3

Obstruction

RV

FEV1 / FVC  50%

2

FVC  4.5 L FVC  3.0 L

FEV1  1.5 L

1 TLC

RV

0

1

2

3 4 Time (s)

5

6

FIGURE 32–15 Forced vital capacity (FVC) maneuver using a rolling seal spirometer. FVCs from a normal subject and from a patient with obstructive disease. FEV1, forced expiratory volume in the first second. Note that the total lung capacity (TLC) is at the bottom of the curves and the residual volumes (RVs) are at the top; volume therefore refers to the volume exhaled into the spirometer in the bottom trace. The time scale is from left to right. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

during the FVC, is a good index of expiratory airway resistance. In normal subjects, the FEV1/FVC is greater than 0.80; that is, at least 80% of the FVC is expired in the first second. A patient with an airway obstruction would be expected to have an FEV1/FVC far below 0.80, as shown in Figure 32–16, which shows FVC curves obtained from a commonly used rolling seal spirometer. Note that the TLC is at the bottom left, and the RVs are at the top right. The time scale is left to right. Note the calculations of the FEV1 to FVC ratios for a healthy person and for one with airway obstruction. Figure 32–15 clearly shows that elevated airway resistance takes time to overcome.

Flow–Volume Curves Flow–volume curves are also used to assess airway resistance. A family of flow–volume curves such as that depicted in Figure 32–16 is obtained by having a subject make repeated expiratory maneuvers with different degrees of effort. Flow rates are plotted against lung volume for expiratory efforts of different intensities. There are two interesting points about this family of curves. At high lung volumes, the airflow rate is effort-dependent, which can be seen in the left-hand portion of the curves. As the subject exhales with greater effort, flow rate increases. At low lung volumes, however, the expiratory efforts of different initial intensities all merge into the same effort-independent curve, as seen in the right-hand portion of the curve. This difference is because intrapleural pressures high enough to cause dynamic compression are necessary to attain very low lung volumes, no matter what the initial expiratory effort. Also, at low lung volumes there is less alveolar elastic recoil, so there is less traction on the same airways and a smaller pressure gradient for airflow. The maximal flow–volume curve is used as a diagnostic tool, as shown in Figure 32–17, because it helps distinguish between two major classes of pulmonary diseases—airway obstructive diseases and restrictive diseases, such as fibrosis.

Obstructive diseases interfere with airflow; restrictive diseases restrict the expansion of the lung. Figure 32–17 shows that both obstruction and restriction can cause a decrease in the maximal flow rate that the patient can attain, the peak expiratory flow (PEF; shown in Figure 32–16), but that this decrease occurs for different reasons. Restrictive lung diseases, which usually entail increased alveolar elastic recoil, may have decreased PEF because the TLC (and thus the VC) is decreased. The effort-independent part of the curve is similar to normal lungs. In fact, the FEV1/FVC is usually normal or even above normal since both the FEV1 and FVC are decreased because the lung has a low volume and because alveolar elastic recoil pressure may be increased. On the other hand, with obstructive diseases, the PEF and FEV1/FVC are both low. Obstructive diseases—such as asthma, bronchitis, and emphysema—are often associated with high lung volumes, which is helpful because the high volumes increase the alveolar elastic recoil pressure. The RV may be greatly increased if airway closure occurs at relatively high lung volumes. A second important feature of the flow–volume curve of a patient with obstructive disease is the effort-independent portion of the curve, which is depressed inward: flow rates are low for any relative volume. Flow–volume curves are very useful in assessing obstructions of the upper airways and the trachea. Flow–volume loops can help distinguish between fixed obstructions (those not affected by the inspiratory or expiratory effort) and variable obstructions (changes in the transmural pressure gradient caused by the inspiratory or expiratory effort result in changes in the cross-sectional area of the obstruction). If the obstruction is variable, flow–volume loops can demonstrate whether the obstruction is extrathoracic or intrathoracic (Figure 32–18). A fixed obstruction affects both expiratory and inspiratory airflow (Figure 32–18A). Both the expiratory and inspiratory flow–volume curves are truncated, with decreased peak expiratory and peak inspiratory flows. The flow–volume loop is unable to distinguish between a fixed extrathoracic and a fixed intrathoracic obstruction, which

CHAPTER 32 Mechanics of the Respiratory System 10

Peak expiratory flow

327

Maximal curve

Airflow (L/s)

Expiration

Effort independence

Effort dependence 5

Inspiration

0

RV

TLC

5

Maximal curve

10 Volume (L)

FIGURE 32–16 Flow–volume curves of varying intensities, demonstrating effort dependence at high lung volumes and effort independence at low lung volumes. Note that there is no effort independence in inspiration. The peak expiratory flow (PEF) is labeled for the maximal expiratory curve. TLC, total lung capacity; RV, residual volume. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

would usually be determined with a bronchoscope. Fixed obstructions can be caused by foreign bodies or by scarring that makes a region of the airway too stiff to be affected by the transmural pressure gradient. During a forced expiration, the cross-sectional area of a variable extrathoracic obstruction increases as the pressure inside the airway increases (Figure 32–18B). The expiratory flow–volume curve is therefore nearly normal or not affected.

However, during a forced inspiration, the pressure inside the upper airway decreases below atmospheric pressure, and unless the stability of the upper airway is maintained by reflex contraction of the pharyngeal muscles or by other structures, the cross-sectional area of the upper airway will decrease. Therefore, the inspiratory flow–volume curve is truncated with variable extrathoracic obstructions. Variable extrathoracic obstructions can be caused by tumors, fat deposits,

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SECTION VI Pulmonary Physiology

15 Normal

Airflow (L/s)

12 Restrictive disease 9

Obstructive disease

6

3 0 9

FIGURE 32–17

8

7

6

5 4 Lung volume (L)

3

2

1

0

Maximal expiratory flow–volume curves representative of obstructive and restrictive diseases. (Modified with

permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

Expiration

Flow

A.

Inspiration

Expiration

TLC

RV

Inspiration

Fixed (intra- or extrathoracic) expiration

Flow

B.

TLC Paw < Patm Inspiration

Inspiratory and expiratory flow–volume curves representing the patterns in: A) fixed intrathoracic or extrathoracic obstruction; B) variable extrathoracic obstruction; C) variable intrathoracic obstruction. TLC, total lung capacity; RV, residual volume; Paw, airway pressure; Patm, atmospheric pressure; Ppl, intrapleural pressure. (Modified with permission from Burrows B, Knudson RJ, Quan SF, Kettel LJ: Respiratory Disorders: A Pathophysiologic Approach,

Paw > Patm Expiration

Inspiration

Variable extrathoracic Expiration

C.

TLC Flow

FIGURE 32–18

Paw > Ppl

Paw < Ppl

Inspiration

Expiration

Inspiration

2nd ed. Copyright © 1983 by Year Book Medical Publishers, Chicago.)

RV

Variable intrathoracic

RV

CHAPTER 32 Mechanics of the Respiratory System weakened or flabby pharyngeal muscles (as in obstructive sleep apnea), paralyzed vocal cords, enlarged lymph nodes, or inflammation. During a forced expiration, positive intrapleural pressure decreases the transmural pressure gradient across a variable intrathoracic tracheal obstruction, decreasing its crosssectional area and decreasing the PEF (Figure 32–18C). During a forced inspiration, as large negative intrapleural pressures are generated, the transmural pressure gradient across the variable intrathoracic obstruction increases and its cross-sectional area increases. Thus, the inspiratory flow–volume curve is nearly normal or not affected. Variable intrathoracic obstructions of the trachea are most commonly caused by tumors.

CLINICAL CONSEQUENCES OF INCREASED AIRWAY RESISTANCE AND DECREASED ALVEOLAR COMPLIANCE As discussed at the beginning of this chapter, the lung has millions of small airways and hundreds of millions of alveoli. If we think of a pair of hypothetical alveoli supplied by the same airway, we can consider the time courses of their changes in volume in response to an abrupt increase in airway pressure (a “step” increase). If the resistances and compliances of the two units were equal, the two alveoli would fill with identical time courses to identical volumes. If the resistances were equal, but the compliance of one were half that of the other, then the two alveoli would fill with nearly identical time courses but the less compliant one would receive only half the volume received by the other. If the compliances of the two units were equal but one was supplied by an airway with twice the resistance to airflow of the one supplying the other, the two units would ultimately fill to the same volume. However, the one supplied by the airway with elevated resistance will fill more slowly than the other because of its elevated resistance. This difference means that at high breathing frequencies, the one that fills more quickly will receive a larger volume of air per breath; the one that fills more slowly will receive less ventilation per breath. Now let us extrapolate this two-unit situation to a lung with millions of airways supplying hundreds of millions of alveoli. In a patient with small airways disease, many alveoli may be supplied by airways with higher resistance to airflow than normal. These alveoli are sometimes referred to as “slow alveoli” or alveoli with long “time constants.” As the patient increases the breathing frequency, the slowest alveoli will not have enough time to fill. As the frequency increases, more and more slow alveoli will drop out. This can also be a problem during positive-pressure ventilation. There may be enough time for alveoli to fill because air is forced into them by the ventilator. However, because expiration is passive, there may not be enough time for the alveoli to empty, resulting in overinflation, especially of more compliant alveoli, causing lung injury.

329

THE WORK OF BREATHING The major points discussed in this chapter can be summarized by considering the work of breathing. The work done in breathing is proportional to the pressure change times the volume change. The volume change is the volume of air moved into and out of the lung—the tidal volume. The pressure change is the change in transpulmonary pressure necessary to overcome the elastic work of breathing and the resistive work of breathing. The elastic work of breathing is the work done to overcome the elastic recoil of the chest wall and the pulmonary parenchyma and the work done to overcome the surface tension of the alveoli. Restrictive diseases are those diseases in which the elastic work of breathing is increased. For example, the work of breathing is elevated in obese patients (who have decreased outward chest wall elastic recoil) and in patients with pulmonary fibrosis or a relative lack of pulmonary surfactant (who have increased elastic recoil of the alveoli). The resistive work of breathing is the work done to overcome the tissue resistance and the airway resistance. The tissue resistance may be elevated in conditions such as sarcoidosis, asbestosis, or silicosis. Elevated airway resistance is much more common and occurs in obstructive diseases such as asthma, bronchitis, and emphysema; upper airway obstruction; and accidental aspiration of foreign objects. Normally, most of the resistive work is that done to overcome airway resistance. The resistive work of breathing can be very great during a forced expiration, when dynamic compression occurs. This is especially true in patients who already have elevated airway resistance during normal, quiet breathing. For example, in patients with emphysema, a disease that attacks and obliterates alveolar walls, the work of breathing can be tremendous because of the destruction of the elastic tissue support of their small airways, which allows dynamic compression to occur unopposed. Also, the decreased elastic recoil of alveoli leads to a decreased pressure gradient for expiration.

CLINICAL CORRELATION A 26-year-old man comes to the emergency department because of sudden dyspnea (a feeling that breathing is difficult, also called “shortness of breath”) and pain in the upper part of the left side of his chest. He has no history of any medical problems. He is 183-cm (6′2″) tall and weighs about 63.5 kg (140 lb). Blood pressure is 125/80 mm Hg, heart rate is 90/min, and respiratory rate is 22/min (usually12–15/min in a healthy adult). There are no breath sounds on the left side of his chest, which is hyperresonant (louder and more hollow-sounding) to percussion (the physician tapping on the chest with his or her fingers). The patient has a pneumothorax. Air has entered the pleural space on the left side of his chest and he is unable to expand his left lung. Therefore, there are no breath sounds

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on the left side of his chest and it is hyperresonant to percussion. In this case, the pneumothorax is a primary spontaneous pneumothorax because it occurred suddenly, and is not attributable to an underlying pulmonary disease (secondary spontaneous pneumothorax) or trauma (traumatic pneumothorax). The inability to ventilate his left lung, combined with pain and anxiety, explains his high respiratory rate, as will be discussed in Chapters 33 and 38. Primary spontaneous pneumothorax is most common in tall, thin males between 10 and 30 years of age, although the reason for this is not known. It is believed to occur when overexpanded alveoli (“blebs”) rupture, perhaps as a result of a cough or sneeze. If the pneumothorax is mild and the patient is not in too much distress, it may resolve without treatment other than observation. More severe pneumothorax is treated by inserting a catheter or chest tube through the skin and intercostal muscles into the pleural space to allow removal of the air by external suction. A tension pneumothorax is a potentially life-threatening disorder that most commonly occurs as a result of trauma or lung injury. Air enters the pleural space on inspiration but cannot leave on expiration, progressively increasing intrapleural pressure above atmospheric. This can compress the structures on the affected side of the chest (e.g., blood vessels, heart, etc.) and eventually the structures on the other side of the chest as well.

CHAPTER SUMMARY ■ ■

■

■

■

■

A pressure gradient between the atmosphere and the alveoli must be established to move air into or out of the alveoli. During inspiration, alveoli expand passively in response to an increased transmural pressure gradient; during normal quiet expiration, the elastic recoil of the alveoli returns them to their original volume. The volume of gas in the lungs at the end of a normal tidal expiration (the FRC), when no respiratory muscles are actively contracting, is determined by the balance point of the inward recoil of the lungs and the outward recoil of the chest wall. At the FRC, intrapleural pressure is negative because the pleural liquid is between the opposing forces of the inward recoil of the lungs and the outward recoil of the chest wall. Alveoli are more compliant (and have less elastic recoil) at low volumes; alveoli are less compliant (and have more elastic recoil) at high volumes. Pulmonary surfactant increases alveolar compliance and helps prevent atelectasis by reducing surface tension in the alveoli.

■

■

During forced expiration, when intrapleural pressure becomes positive, small airways are compressed (dynamic compression) and may even collapse. The two main components of the work of breathing are the elastic recoil of the lungs and chest wall and the resistance to airflow.

STUDY QUESTIONS 1. In a normal healthy adult at the functional residual capacity A) alveolar pressure is greater than atmospheric pressure. B) alveolar pressure is less than atmospheric pressure. C) the inward recoil of the lungs is equal and opposite to the outward recoil of the chest wall. D) intrapleural pressure is positive. E) the alveolar transmural pressure gradient is negative. 2. Which of the following would be expected to cause increased static lung compliance (i.e., shift the pulmonary pressure– volume curve upward and to the left)? A) a relative lack of functional pulmonary surfactant B) diffuse interstitial alveolar fibrosis C) pulmonary vascular congestion D) emphysema E) diffuse alveolar collapse 3. The compliance of the lungs is A) greater at low lung volumes than it is at high lung volumes. B) in parallel with the compliance of the chest wall. C) increased in a person after surgical removal of one lobe of the lung. D) increased in a person with pulmonary interstitial fibrosis. E) less than the compliance of a single lobe of the lung. 4. During a forced expiration to the residual volume A) intrapleural pressure becomes more negative. B) alveolar elastic recoil is increasing. C) the outward recoil of the chest wall is increasing. D) intrapleural pressure is greater than alveolar pressure. E) airflow remains dependent on expiratory effort. 5. Which of the following will likely decrease the work of breathing? A) doubling the tidal volume at the same breathing frequency B) breathing through the mouth instead of the nose C) doubling the breathing frequency at the same tidal volume D) breathing through a 1-cm diameter, 3-ft long tube E) gaining 100 lb of body weight 6. The resistance to airflow in a normal healthy person would be greatest A) during a eupneic inspiration. B) during a eupneic expiration. C) during a forced inspiration. D) during a forced expiration. E) at the functional residual capacity.

33 C

Alveolar Ventilation Michael Levitzky

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■ ■ ■ ■

Define alveolar ventilation. Define the standard lung volumes. Predict the effects of alterations in lung and chest wall mechanics, due to normal or pathologic processes, on the lung volumes. Define anatomic dead space and relate the anatomic dead space and the tidal volume to alveolar ventilation. Calculate alveolar ventilation. Define and calculate physiologic and alveolar dead space. Predict the effects of alterations of alveolar ventilation on alveolar carbon dioxide and oxygen levels. Describe and explain the regional differences in alveolar ventilation found in the normal lung. Define the closing volume. Predict how changes in pulmonary mechanics affect the closing volume.

Alveolar ventilation is the exchange of gas between the alveoli and the external environment. It is the process by which oxygen is brought into the lungs from the atmosphere and by which the carbon dioxide carried into the lungs in the mixed venous blood is expelled from the body. Although alveolar ventilation is usually defined as the volume of fresh air entering the alveoli per minute, a similar volume of alveolar air leaving the body per minute is implicit in this definition.

THE LUNG VOLUMES The volume of gas in the lungs at any instant depends on the mechanics of the lungs and chest wall and the activity of the muscles of inspiration and expiration. The size of the lungs depends the height and weight or body surface area, as well as age and sex. Therefore, the lung volumes are usually compared with “predicted” lung volumes matched to age, sex, and body

Ch33_331-340.indd 331

size, and are normally expressed as the body temperature and ambient barometric pressure and saturated with water vapor (BTPS).

THE STANDARD LUNG VOLUMES AND CAPACITIES There are four standard lung volumes and four standard lung capacities, which consist of two or more of the standard lung volumes (Figure 33–1).

The Tidal Volume The tidal volume (VT) is the volume of air entering or leaving the nose or mouth per breath. During normal, quiet breathing (eupnea), the VT of a 70-kg adult is about 500 mL per breath, but this volume can increase substantially, for example, during exercise.

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SECTION VI Pulmonary Physiology

maximal inspiration

INSPIRATORY CAPACITY (IC) 3.0 L

(Modified with permission from Levitzky MG: Pulmonary

VITAL CAPACITY (VC) 4.5 L

TIDAL VOLUME (VT) 0.5 L

TOTAL LUNG CAPACITY (TLC) 6.0 L

FIGURE 33–1 The standard lung volumes and capacities. Typical values for a 70-kg adult are shown.

INSPIRATORY RESERVE VOLUME (IRV) 2.5 L

FUNCTIONAL RESIDUAL CAPACITY (FRC) 3.0 L

resting volume

EXPIRATORY RESERVE VOLUME (ERV) 1.5 L maximal expiration RESIDUAL VOLUME (RV) 1.5 L no air in lungs

Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

The Residual Volume The residual volume (RV) is the volume of gas remaining in the lungs after a maximal forced expiration. It is determined by the force generated by the muscles of expiration and the inward elastic recoil of the lungs as they oppose the outward elastic recoil of the chest wall. Dynamic compression of the airways during the forced expiratory effort may also be an important determinant of the RV as airway collapse occurs and traps gas in the alveoli. The RV of a healthy 70-kg adult is about 1.5 L, but it can be much greater in emphysema, a lung disease with increased compliance in which inward alveolar elastic recoil is diminished and airway collapse and gas trapping occur. The RV is important to a healthy person because it prevents the lungs from collapsing at very low lung volumes. Such collapsed alveoli would require great inspiratory efforts to reinflate.

The Expiratory Reserve Volume The expiratory reserve volume (ERV) is the volume of gas that is expelled from the lungs during a maximal forced expiration that starts at the end of a normal tidal expiration. It is therefore determined by the difference between the functional residual capacity (FRC, see below) and the RV. The ERV is about 1.5 L in a healthy 70-kg adult.

The Inspiratory Reserve Volume The inspiratory reserve volume (IRV) is the volume of gas that is inspired into the lungs during a maximal forced inspiration starting at the end of a normal tidal inspiration. It is determined by the strength of contraction of the inspiratory muscles, the inward elastic recoil of the lung and the chest wall, and the starting point, which is the FRC plus the VT . The IRV of a healthy 70-kg adult is about 2.5 L.

The Functional Residual Capacity The FRC is the volume of gas remaining in the lungs at the end of a normal tidal expiration. It represents the balance point

between the inward elastic recoil of the lungs and the outward elastic recoil of the chest wall, as discussed in Chapter 32. During exercise, the FRC may be lower than the relaxation volume because of active contraction of the expiratory muscles. The FRC, as seen in Figure 33–1, consists of the RV plus the ERV and is therefore about 3 L in a healthy 70-kg adult.

The Inspiratory Capacity The inspiratory capacity (IC) is the volume of air that is inhaled into the lungs during a maximal inspiratory effort that begins at the end of a normal tidal expiration (the FRC). It is therefore equal to the VT plus the IRV, as shown in Figure 33–1. The IC of a healthy 70-kg adult is about 3 L.

The Total Lung Capacity The total lung capacity (TLC) is the volume of air in the lungs after a maximal inspiratory effort. It is determined by the strength of contraction of the inspiratory muscles and the inward elastic recoil of the lungs and the chest wall. The TLC is the sum of all four lung volumes: the RV, the VT, the IRV, and the ERV. It is about 6 L in a healthy 70-kg adult.

The Vital Capacity The vital capacity (VC), discussed in Chapter 32, is the volume of air expelled from the lungs during a maximal forced expiration starting after a maximal forced inspiration. It is therefore equal to the TLC minus the RV, or about 4.5 L in a healthy 70-kg adult. The VC is also equal to the sum of the VT and the IRV and ERV. It is determined by the factors that determine the TLC and RV.

MEASUREMENT OF THE LUNG VOLUMES Measurement of the lung volumes is important clinically because many pathologic states can alter specific lung volumes or their

CHAPTER 33 Alveolar Ventilation relationships to one another. The lung volumes, however, can also change for normal physiologic reasons. Changing from a standing to a supine posture decreases the FRC because gravity is no longer pulling the abdominal contents away from the diaphragm. This decreases the outward elastic recoil of the chest wall, as noted in Chapter 32. Determination of the lung volumes can be useful diagnostically in differentiating between two major types of pulmonary disorders—the restrictive diseases and the obstructive diseases. Restrictive diseases such as alveolar fibrosis reduce the compliance of the lungs, increase elastic recoil, and lead to compressed lung volumes (Figure 33–2). The VT may even be decreased, with a corresponding increase in breathing frequency, to minimize the work of breathing. Obstructive diseases such as emphysema and chronic bronchitis cause increased resistance to airflow. Airways may become completely obstructed because of mucous plugs and because of the high intrapleural pressures generated to overcome the elevated airway resistance during a forced expiration. This is especially a problem in emphysema, in which destruction of alveolar septa leads to decreased elastic recoil of the alveoli and less radial traction, which normally help hold small airways open. For these reasons, the RV, the FRC, and the TLC may be greatly increased in obstructive diseases, as seen in Figure 33–2. The VC and ERV are usually decreased. The breathing frequency may be decreased to reduce the work expended overcoming the airway resistance, with a corresponding increase in the VT.

Spirometry The spirometer is a simple device for measuring gas volumes. As the person breathes in and out through a mouthpiece (a nose clip prevents airflow via the nose) and a tube connected to the spirometer, the volumes of gas entering and leaving the spirom-

333

eter can be determined. The spirometer can therefore measure only the lung volumes that the subject can exchange with it. As is the case with many pulmonary function tests, the subject must be conscious and cooperative and understand the instructions for performing the test. Figure 33–3 shows that the VT, IRV, ERV, IC, and VC can all be measured with a spirometer (as can the forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], and the FEV1/FVC, as discussed in Chapter 32). The RV, the FRC, and the TLC, however, cannot be determined with a spirometer because the subject cannot exhale all the gas in the lungs into the spirometer.

Measurement of Lung Volumes Not Measurable with Spirometry The lung volumes not measurable with spirometry can be determined by the nitrogen-washout technique, the heliumdilution technique, and body plethysmography. The FRC is usually determined, and RV (which is equal to FRC minus ERV) and the TLC (which is equal to VC plus RV) are then calculated from volumes obtained by spirometry.

Nitrogen-washout technique In the nitrogen-washout technique, the person breathes 100% oxygen through a one-way valve to wash all of the nitrogen out of the alveoli. The expired gas is collected and the volume of nitrogen washed out of the person’s lungs is calculated. The total volume of nitrogen in the person’s lungs at the beginning of the test can thus be determined. Nitrogen constitutes about 80% of the person’s initial lung volume, so multiplying the initial nitrogen volume by 1.25 gives the person’s initial lung volume. If the test starts at the end of a normal tidal expiration, the volume determined is the FRC.

IRV IC

VC VT

TLC IC

IRV

VT

ERV

VC

TLC

IC

IRV FRC VC

ERV

RV

VT TLC

FRC

ERV RV

FRC RV

normal

restrictive

obstructive

FIGURE 33–2 Illustration of typical alterations in the lung volumes and capacities in restrictive and obstructive diseases. The pattern shown for obstructive diseases is more characteristic for emphysema and asthma than for chronic bronchitis. IC, inspiratory capacity; TLC, total lung capacity; FRC, functional residual capacity; IRV, inspiratory reserve volume; VT, tidal volume; ERV, expiratory reserve volume; RV, residual volume; VC, vital capacity. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

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SECTION VI Pulmonary Physiology

SPIROMETER TRACE (SPIROGRAM) Maximal inspiration

volume (L)

Inspiratory reserve volume Inspiratory capacity

Vital capacity

FIGURE 33–3 Determination of the tidal volume, vital capacity, inspiratory capacity, inspiratory reserve volume, and expiratory reserve volume from a spirometer trace. (Modified with permission

Tidal volume

Expiratory reserve volume Maximal expiration

from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

Helium-dilution technique The helium-dilution technique makes use of the following relationship: if the total amount of a substance dissolved in a volume is known and its concentration can be measured, the volume in which it is dissolved can be determined. Helium is used for this test because it is not taken up by the pulmonary capillary blood, so the total amount of helium used in the test does not change during the test. The person breathes in and out of a spirometer filled with a mixture of helium and oxygen. When an equilibrium is reached, the concentration of helium is the same in the lungs as it is in the spirometer, and the test is stopped at the end of a normal tidal expiration, in other words, at the FRC. The calculated increase in the volume of distribution of helium therefore represents the lung volume. Since it may take several minutes for the helium concentration to equilibrate between the lungs and the spirometer, CO2 is absorbed from the system and oxygen is added to the spirometer at the rate at which it is used by the person. Both the nitrogen-washout and helium-dilution methods can be used on unconscious patients.

Body plethysmography A problem common to both the nitrogen-washout technique and the helium-dilution technique is that neither can measure trapped gas because nitrogen trapped in alveoli supplied by closed airways cannot be washed out and because the helium cannot enter alveoli supplied by closed airways. Furthermore, if the lungs have many alveoli served by airways with high resistance to airflow (the “slow alveoli” discussed at the end of Chapter 32), it may take a long time for all the nitrogen to wash out of the lungs or for the inspired and expired helium concentrations to equilibrate. In such patients, measurements of the lung volumes with a body plethysmograph are much more accurate because they do include trapped gas.

Time (s)

The body plethysmograph makes use of Boyle’s law: for a closed container at a constant temperature, the pressure times the volume of a gas mixture is constant. The body plethysmograph is an airtight chamber large enough that the patient can sit inside it and breathe through a mouthpiece and tubing. The patient breathes in for an instant against a closed airway and the pressures at the mouth and in the plethysmograph are monitored. As the patient breathes in against the closed airway, the chest expands and the pressure measured in the plethysmograph increases because the volume of air in the plethysmograph decreases by the amount the chest volume increased. The pressure measured at the mouth decreases as the patient breathes in against a closed airway. Boyle’s law is used to calculate the changes in volumes of the body plethysmograph and the lungs to determine the FRC.

ANATOMIC DEAD SPACE AND ALVEOLAR VENTILATION The volume of air entering and leaving the nose or mouth per minute, the minute volume, is not equal to the volume of air entering and leaving the alveoli per minute. Alveolar ventilation is less than the minute volume because the last part of each inspiration remains in the conducting airways and does not reach the alveoli. Similarly, the last part of each expiration remains in the conducting airways and is not expelled from the body. The anatomic dead space is illustrated in Figure 33–4. When a person breathes in a tidal volume of 500 mL, not all the air reaches the alveoli: the final 150 mL of the inspired air remains in the conducting airways. The volume of gas reaching the alveoli is equal to the volume inspired minus the volume of the anatomic dead space, in this case 500 – 150 mL, or 350 mL. During expiration, the first gas breathed out is inspired air that remained in the anatomic dead space; the last 150 mL is alveolar gas that

CHAPTER 33 Alveolar Ventilation

335

150 ml Tidal volume = 500 ml 350 ml

Volume in conducting airways left over from preceding breath

150 ml

Anatomic dead space = 150 ml

Conducting airways

150 ml

350 ml

FIGURE 33–4 Illustration of the anatomic dead space. Of a 500-mL tidal volume, 150 mL remains in the conducting airways and does not participate in gas exchange; only 350 mL enters the alveoli. (Reproduced with

Alveolar gas 150 ml

permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology, 11th ed. McGraw-Hill, 2008.)

remains in the anatomic dead space. Therefore, for any respiratory cycle, not all the tidal volume reaches the alveoli because the last part of each inspiration and each expiration remains in the dead space. The relationship for the VT breathed in and out through the nose or mouth, the dead space volume (VD), and the volume of gas entering and leaving the alveoli per breath (VA) is: VT = VD + VA

(2)

The alveolar ventilation (per minute) can be determined by multiplying both sides of the above equation by the breathing frequency (f) in breaths per minute: f (VA) = f (VT ) – f (VD )

For a healthy subject, the anatomic dead space can be estimated by referring to a table of standard values matched to sex, age, height, and weight or body surface area. The anatomic dead space is not measured clinically; a reasonable estimate of anatomic dead space is 1 mL of dead space per pound (2.2 kg) of ideal body weight.

(1)

or VA = VT – VD

Estimation of Anatomic Dead Space

(3)

Thus, for f = 12 breaths/min in the above example, we have: 4,200[mL/min] = 6,000[mL/min] – 1,800[mL/min] (4) . The alveolar ventilation (VA) in liters per minute is equal to . the minute volume (VE) minus . the volume wasted ventilating the dead space per minute (VD): . . . VA = VT – VD (5) . The dot over the letter V indicates per minute. The symbol VE is used because expired gas is usually collected. There is a difference between the volume of gas inspired and the volume of gas expired because as air is inspired, it is warmed to body temperature and humidified and also because normally less carbon dioxide is produced than oxygen is consumed.

MEASUREMENT OF ALVEOLAR VENTILATION Alveolar ventilation cannot be measured directly but must be determined from the VT, the breathing frequency, and the dead space ventilation, as noted in the previous section.

Physiologic Dead Space: The Bohr Equation The air in the anatomic dead space may not be the only inspired air that does not participate in gas exchange. The alveolar dead space is the volume of gas that enters unperfused alveoli per breath. Alveolar dead space is therefore alveoli that are ventilated but not perfused with pulmonary capillary blood. No gas exchange occurs in these alveoli for physiologic, rather than anatomic, reasons. A healthy person has little or no alveolar dead space, but a person with a low cardiac output might have significant alveolar dead space, for reasons explained in Chapter 34. The Bohr equation permits the determination of the sum of the anatomic and the alveolar dead space. The anatomic dead space plus the alveolar dead space is known as the physiologic dead space: Physiologic dead space = Anatomic dead space + Alveolar dead space

(6)

The Bohr equation makes use of a simple concept: any measurable volume of carbon dioxide found in the mixed expired gas must come from alveoli that are both ventilated and perfused because there are negligible amounts of carbon dioxide in inspired air. Inspired air remaining in the anatomic dead space or entering unperfused alveoli will leave the body as it entered (except for having been warmed to body temperature and humidified), contributing little or no carbon dioxide to the mixed expired air, as shown in the following Bohr equation:

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SECTION VI Pulmonary Physiology

50 End-tidal

FIGURE 33–5

Partial pressure of carbon dioxide at the mouth during a breath. During inspiration, the Pco2 rapidly decreases to near zero (0.3 mm Hg). The first expired gas comes from the anatomic dead space and therefore also has a Pco2 near zero. After exhalation of a mixture of gas from alveoli and anatomic dead space, the gas expired is a mixture from all ventilated alveoli. The slope of the alveolar plateau normally rises slightly because the alveolar Pco2 increases a few mm Hg between inspirations. The last alveolar gas expired before inspiration is called end-tidal. (Modified with permission

Pco2 (mm Hg)

40

30

20

10

0 0

1

2

3

5

Inspiration starts

Expiration starts

from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill

4

Time (s)

Medical, 2007.)

VDco Paco2 – PEco2 2 ____ = _________ Paco2 VT

(7)

where VDco2 is the dead space for CO2 (the physiologic dead space), VT the tidal volume, Paco2 the arterial partial pressure of carbon dioxide, and PEco2 the mixed expired partial pressure of carbon dioxide. The arterial Pco2 must be determined from an arterial blood sample; the Pco2 of the collected mixed expired gas can be determined with a CO2 meter. After the physiologic dead space is calculated using the Bohr equation, the estimated anatomic dead space can be subtracted from it to calculate the alveolar dead space. The CO2 meter can also used to estimate the mean alveolar Pco2 by analyzing the gas expelled at the end of a normal tidal expiration, the “end-tidal CO2” (Figure 33–5). In a person with significant alveolar dead space, however, the estimated alveolar Pco2 obtained in this fashion may not reflect the Pco2 of alveoli that are ventilated and perfused because some of this mixed end-tidal gas comes from unperfused alveoli. This gas dilutes the CO2 coming from alveoli that are both ventilated and perfused. There is, however, an equilibrium between the Pco2 of perfused alveoli and their end-capillary Pco2 (see Chapter 35 for detailed discussion), so that in patients without significant venous-to-arterial shunts, the arterial Pco2 represents the mean Pco2 of the perfused alveoli. If the arterial Pco2 is greater than the mixed alveolar Pco2 determined by sampling the end-tidal CO2, then the physiologic dead space is probably greater than the anatomic dead space, that is, a significant arterial–alveolar CO2 difference means that there is significant alveolar dead space; a person with no alveolar dead space has an arterial–end-tidal CO 2 difference of zero. As already noted, this difference is determined from the Pco2 from an arterial blood gas sample and from the end-tidal Pco2 . Young healthy people have no alveolar dead

space, so their physiologic dead space is equal to their anatomic dead space. Situations in which alveoli are ventilated but not perfused include those in which portions of the pulmonary vasculature have been occluded by blood clots or other material in the venous blood (pulmonary emboli), those in which there is low venous return leading to low right ventricular output (hemorrhage), and those in which alveolar pressure is high (positive-pressure ventilation with positive endexpiratory pressure). These will be discussed in greater detail in Chapter 34. The anatomic dead space can be altered by bronchoconstriction, which decreases VD; bronchodilation, which increases VD; or traction or compression of the airways, which increases and decreases VD, respectively.

ALVEOLAR VENTILATION & ALVEOLAR OXYGEN AND CARBON DIOXIDE LEVELS The levels of oxygen and carbon dioxide. in alveolar gas are determined .by the alveolar ventilation (VA), the oxygen consumption . (VO2) of the body, and the carbon dioxide production (VCO2 )of the body.

PARTIAL PRESSURES OF RESPIRATORY GASES According to Dalton’s law, in a gas mixture, the pressure exerted by each individual gas is independent of the pressures of other gases in the mixture. The partial pressure of a particular gas is equal to its fractional concentration times

CHAPTER 33 Alveolar Ventilation the total pressure of all the gases in the mixture. Thus, for any gas in a mixture (gas1), its partial pressure is given as follows: Pgas = Total gas (%) × Ptot 1

(8)

Oxygen constitutes 20.93% of dry atmospheric air. At a standard barometric pressure of 760 mm Hg, we have: PO2 = 0.2093 × 760 mm Hg = 159 mm Hg

(9)

Carbon dioxide constitutes only about 0.04% of dry atmospheric air, so we have: PCO2 = 0.0004 × 760 mm Hg = 0.3 mm Hg

PO2

PCO2

PN2

PH2O

Dry air

159

0.3

601

0

Inspired air

149

0.3

564

47

Alveolar air

104

40

569

47

Expired air

120

27

566

47

inspiration. Expired air is a mixture of about 350 mL of alveolar air and 150 mL of air from the dead space. Therefore, the Po2 of mixed expired air is higher than alveolar Po2 and lower than the inspired Po2, or approximately 120 mm Hg. Similarly, the Pco2 of mixed expired air is much higher than the inspired Pco2 but lower than the alveolar Pco2 , or about 27 mm Hg. The expected partial pressures of oxygen, carbon dioxide, nitrogen, and water vapor in dry air, inspired air, alveolar air, and expired air at an atmospheric pressure of 760 mm Hg are shown in Table 33–1.

(11)

where PB is the barometric pressure and PH2O the water vapor pressure. Then we have: 0.2093(760 – 47) mm Hg = 149 mm Hg

TABLE 33–1 Partial pressures in mm Hg of oxygen, carbon dioxide, nitrogen, and water vapor in dry air, inspired air, alveolar air, and expired air at a barometric pressure of 760 mm Hg.

(10)

As air is inspired through the upper airways, it is warmed and humidified, as discussed in Chapter 31. The partial pressure of water vapor is a relatively constant 47 mm Hg at body temperature, so the humidification of 1 L of dry gas in a closed container at 760 mm Hg would increase its total pressure to 760 + 47 mm Hg = 807 mm Hg. In the body, the gas will expand, according to Boyle’s law, so that 1 L of gas at 760 mm Hg is diluted by the added water vapor. The Po2 of inspired air, or PIo2 (saturated with water vapor at a standard barometric pressure), then is equal to the fractional concentration of inspired oxygen (FIo2) times the barometric pressure minus the water vapor pressure: PIo2 = FIo2 (PB – PH2O)

337

(12)

The Pco2 of inspired air (PIco2 ) is equal to FIco2 (PB – PH2O) or 0.0004(760 – 47) mm Hg = 0.29 mm Hg (rounded up to 0.3 mm Hg). Alveolar gas is composed of 2.5–3.0 L of gas already in the lungs at the FRC and approximately 350 mL per breath entering and leaving the alveoli. About 300 mL of oxygen is continuously diffusing from the alveoli into the pulmonary capillary blood per minute at rest and is being replaced by alveolar ventilation. Similarly, about 250 mL of carbon dioxide is diffusing from the mixed venous blood in the pulmonary capillaries into the alveoli per minute and is then removed by alveolar ventilation. (The Po2 and Pco2 of mixed venous blood are about 40 and 45–46 mm Hg, respectively.) Therefore, the partial pressures of oxygen and carbon dioxide in the alveolar air are determined by the alveolar ventilation, pulmonary capillary perfusion, oxygen consumption, and carbon dioxide production. Alveolar ventilation is normally adjusted by the respiratory control center in the brain to keep mean arterial and alveolar Pco2 at about 40 mm Hg (see Chapter 38). Mean alveolar Po2 is about 104 mm Hg (usually considered to be 100 mm Hg for convenience). The alveolar Po2 increases by 2–4 mm Hg with each normal tidal inspiration and decreases slowly until the next inspiration. Similarly, the alveolar Pco2 decreases 2–4 mm Hg with each inspiration and increases slowly until the next

ALVEOLAR VENTILATION AND CARBON DIOXIDE The concentration of carbon dioxide in the alveolar gas is, as already discussed, dependent on the alveolar ventilation and on the rate of carbon dioxide production by the body (and its delivery to the lung in the mixed venous blood). . The volume of carbon dioxide expired. per unit of time (VEco2 ) is equal to the alveolar ventilation (VA ) times the alveolar fractional concentration of CO2 (FAco2 ). No carbon dioxide comes from the dead space: . . VEco2 = VA FAco2 (13) Similarly, the fractional concentration of carbon dioxide in the alveoli is directly proportional to the carbon dioxide pro. duction by the body (Vco2) and inversely proportional to the alveolar ventilation: .

Vco . FAco2 ∝ ___ 2

VA

(14)

Since FAco2 (PB – PH2O) = PAco2 , we have: . V ___ PAco2 ∝ co. 2 VA

(15)

In healthy people, alveolar Pco2 is in equilibrium with arterial Pco2 (Paco2 ). Thus, if alveolar ventilation is doubled (and carbon dioxide production is unchanged), then the alveolar and arterial Pco2 are reduced by one half. If alveolar ventilation is cut in half, then alveolar and arterial Pco2 will double. This can be seen in the upper part of Figure 33–6.

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REGIONAL DISTRIBUTION OF ALVEOLAR VENTILATION

150

100 PACO2 (mm Hg) 50

0

2

4 6 Alveolar ventilation (L/min)

8

10

2

4 6 Alveolar ventilation (L/min)

8

10

150

100 PAO2 (mm Hg) 50

0

FIGURE 33–6 Predicted alveolar gas tensions for different levels of alveolar ventilation. (Modified with permission from Nunn JF: Applied Respiratory Physiology, 4th ed. 1993. Reprinted by permission of Elsevier Science Limited.)

ALVEOLAR VENTILATION AND OXYGEN As alveolar ventilation increases, the alveolar Po2 will also increase. Doubling alveolar ventilation, however, cannot double PAo2 in a person whose alveolar Po2 is already 104 mm Hg because the highest PAo2 one could possibly achieve breathing air at sea level is the inspired Po2 of about 149 mm Hg. The alveolar Po2 can be calculated by using the alveolar air equation: PAco PAo2 = PIo2 – ____ +F R

(16)

2

. Vco2 . ) and F a small where R is the respiratory exchange ratio ( ___ Vo2

correction factor. As already noted, PIo2 = FIo2(PB – PH2O). F is usually ignored. Therefore, we have: PA

co PAo2 = FIo2(PB – PH2O)– ____ R 2

(17)

As alveolar ventilation increases, the alveolar Pco2 decreases, bringing the alveolar Po2 closer to the inspired Po2, as can be seen in the lower part of Figure 33–6. Note that the alveolar Po2 obtained using the alveolar air equation is a calculated idealized average alveolar Po2. It represents what alveolar Po2 should be, not necessarily what it is.

As previously discussed, a 70-kg person has about 2.5–3.0 L of gas in the lungs at the FRC. Each breath brings about 350 mL of fresh gas into the alveoli and removes about 350 mL of alveolar air from the lung. Studies performed on healthy subjects standing or seated upright have shown that alveoli in the lower regions of the lungs receive more ventilation per unit volume than do those in the upper regions of the lung. The lower regions of the lung are relatively better ventilated than the upper regions of the lung. If a similar study is done on a subject lying on his or her left side, the regional differences in ventilation between the anatomic upper, middle, and lower regions of the lung disappear, although there is better relative ventilation of the left lung than of the right lung. The regional differences in ventilation are therefore mainly a result of the effects of gravity, with regions of the lung lower with respect to gravity (the “dependent” regions) relatively better ventilated than those regions above them (the “nondependent” regions). The explanation for these regional differences in ventilation is regional differences in intrapleural pressure. In Chapter 32, the intrapleural surface pressure was discussed as if it were uniform throughout the thorax, which is not the case. The intrapleural surface pressure is less negative in the lower, gravity-dependent regions of the thorax than it is in the upper, nondependent regions. There is a gradient of the intrapleural surface pressure such that for every centimeter of vertical displacement down the lung (from nondependent to dependent regions), the intrapleural surface pressure increases by about +0.2 to +0.5 cm H2O. This gradient is caused by gravity and by mechanical interactions between the lung and the chest wall. The influence of this gradient of intrapleural surface pressure on regional alveolar ventilation can be explained by predicting its effect on the transpulmonary pressure gradients in upper and lower regions of the lung. In the left side of Figure 33–7, alveolar pressure is assumed to be zero in both regions of the lung at the FRC, as discussed in Chapter 32. Since the intrapleural pressure is more negative in upper regions of the lung than it is in lower regions of the lung, the transpulmonary pressure (alveolar minus intrapleural) is greater in upper regions of the lung than it is in lower regions of the lung. Because the alveoli in upper regions of the lung are subjected to greater distending pressures than those in more dependent regions of the lung, they have greater volumes than the alveoli in more dependent regions. It is this difference in volume that leads to the difference in ventilation between alveoli located in dependent and nondependent regions of the lung. This can be seen on the hypothetical pressure–volume curve shown on the right side of Figure 33–7. This curve is similar to the pressure–volume curve for a whole lung shown in Figure 32–6, except that this curve is drawn with the pressure–volume characteristics of single alveoli in mind. The abscissa is the transpulmonary

CHAPTER 33 Alveolar Ventilation pressure (alveolar pressure minus intrapleural pressure). The ordinate is the volume of the alveolus expressed as a percent of its maximum. Because of the greater transpulmonary pressure, the alveolus in the upper region of the lung has a greater volume than the alveolus in a more gravity-dependent region of the lung. At the FRC, the alveolus in the upper part of the lung is on a less steep portion of the alveolar pressure–volume curve (i.e., it is less compliant) in Figure 33–7 than is the more compliant alveolus in the lower region of the lung. Therefore, any change in the transpulmonary pressure during a normal respiratory cycle will cause a greater change in volume in the alveolus in the lower, gravity-dependent region of the lung than it will in the alveolus in the nondependent region of the lung, as shown by the arrows in the figure. Because the alveoli in the lower parts of the lung have a greater change in volume per inspiration and per expiration, they are better ventilated than those alveoli in nondependent regions (during eupneic breathing from the FRC). A second effect of the intrapleural pressure gradient in a person seated upright is on regional static lung volume, as is evident from the above discussion. At the FRC, most of the alveolar air is in upper regions of the lung because those alveoli have larger volumes. Most of the ERV is also in upper portions of the lung. On the other hand, most of the IRV and IC are in lower regions of the lung. Even at low lung volumes, the upper alveoli are larger in volume than are the lower gravitydependent alveoli. They therefore constitute most of the RV. Patients with emphysema have greatly decreased alveolar elastic recoil, leading to high FRCs, extremely high RVs, and airway closure in dependent parts of the lung even at high lung

339

volumes, so they have relatively more ventilation of nondependent alveoli.

THE CLOSING VOLUME During a forced expiration, the lung volume at which airway closure begins to occur is known as the closing capacity; the volume of air exhaled from the time the first airways close until the subject reaches the RV and can exhale no more air is called the closing volume. (The terms are often used interchangeably.) Because people with emphysema have diminished alveolar elastic recoil to provide traction on the airways and help get air out of the alveoli during a forced expiration, they have very high closing capacities. That is, their airways begin to close at high lung volumes, trapping gas in the affected alveoli. They learn to breathe at higher lung volumes to optimize their elastic recoil. As discussed in Chapter 73, even healthy people lose alveolar elastic recoil as they age, resulting in higher closing capacities.

CLINICAL CORRELATION A 38-year-old man with an obvious curvature of the spine in the coronal and sagittal planes is seen by a pulmonologist because of dyspnea that has gotten worse during the last few months. He is 163-cm (5′4″) tall and weighs 61.2 kg (135 lb). Blood pressure is 135/95 mm Hg, heart rate is 80/min, and his respiratory rate is tachypnic at

FRC 100 Pleural pressure (cm H2O) 8.5

80

35 cm

1.5 40

Volume (%)

60

20

10

30 0 10 20 Transpulmonary pressure (cm H2O)

0 40

FIGURE 33–7 Effect of the pleural surface pressure gradient on the distribution of inspired gas at the functional residual capacity (FRC). (Modified with permission from Milic-Emili J: Pulmonary statics. In: Widdicombe JG, ed. MTP International Review of Sciences: Respiratory Physiology. London, England: Butterworth; 1974:105–137.)

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SECTION VI Pulmonary Physiology

25 breaths/min. His respiratory muscle strength appears to be normal. The pulmonologist orders pulmonary function tests and an arterial blood gas (with reference ranges in parenthesis) with the following results: TLC: 45% of predicted; VC: 40% of predicted; RV: 75% of predicted; FRC: 50% of predicted; FEV1: 40% of predicted; FVC: 40% of predicted; FEV1/FVC: 80% of predicted; arterial Po2: 75 mm Hg (80–100 mm Hg); arterial Pco2: 46 mm Hg (35–45 mm Hg); arterial pH: 7.38 (7.35–7.45). The patient has kyphoscoliosis that is a lateral curvature of the spine (scoliosis) as well as a sagittal curvature (kyphosis). It can be congenital; secondary to many disorders, including muscular dystrophy, poliomyelitis, spina bifida, and cerebral palsy; or it may be idiopathic (of unknown cause). Kyphoscoliosis results in decreased compliance of the rib cage with much less outward recoil of the chest wall at low thoracic volumes and much greater inward recoil at higher volumes. Kyphoscoliosis is therefore a restrictive disease. It is difficult for the patient to breathe in and, as a result, his inspiratory work of breathing is increased. It explains his increased resting respiratory rate (normally 12–15 breaths/min) because taking smaller tidal volumes at an increased breathing frequency decreases his work of breathing. The effects of the changes in the mechanics of his thorax can be seen in the lung volumes and capacities determined in this patient (see Figure 33–2). His FRC is low because, with less outward recoil of his chest wall, the balance point between the outward recoil of the chest wall and the inward recoil of his lungs occurs at a lower lung volume. His TLC is low because his ability to inhale maximally is severely impaired. His RV is also lower than predicted, but not as much as the TLC, because his ability to exhale is not as impaired. His VC, FVC, and FEV1 are all lower than predicted because his TLC is very low—he cannot exhale very much because he is unable to inhale very much. On the other hand, this patient does not have airway obstruction. Although both his FEV1 and FVC are low, the FEV1/FVC is within the normal range. The blood gases demonstrate that the increased work of breathing has resulted in decreased alveolar ventilation. His arterial Pco2 is high and his arterial Po2 is low. Treatment of patients with kyphoscoliosis is aimed at improving alveolar ventilation, for example, with noninvasive mechanical ventilation at night. Orthopedic surgery to help correct the problem may be effective in some patients.

CHAPTER SUMMARY ■

■ ■ ■

■

Alveolar ventilation is less than the volume of air entering or leaving the nose or mouth per minute (the minute volume) because the last part of each inspiration remains in the conducting airways (the anatomic dead space). Alveoli that are ventilated but not perfused constitute alveolar dead space. The physiologic dead space is the sum of the anatomic dead space and the alveolar dead space. At constant carbon dioxide production, alveolar Pco2 is approximately inversely proportional to alveolar ventilation; alveolar Po2 is calculated using the alveolar air equation. At or near the FRC, alveoli in lower regions of the upright lung are relatively better ventilated than those in upper regions of the lung.

STUDY QUESTIONS 1. Which of the following conditions are reasonable explanations for a functional residual capacity that is significantly less than predicted? A) third trimester of pregnancy B) pulmonary fibrosis C) obesity D) emphysema E) all of the above F) A, B, and C 2–5. An unconscious patient’s ventilation is maintained with positive-pressure ventilation with a tidal volume of 450 mL and a rate of 10 breaths/min. She weighs 100 lb. Her arterial Pco2 is 42 mm Hg, her end-tidal Pco2 is 35 mm Hg, and her mixed expired Pco2 is 28 mm Hg. 2. What is her minute volume? A) 350 mL/min B) 1,000 mL/min C) 3,500 mL/min D) 4,500 mL/min E) 5,500 mL/min 3. What is her alveolar ventilation? A) 350 mL/min B) 1,000 mL/min C) 3,500 mL/min D) 4,500 mL/min E) 5,500 mL/min 4. What is her physiologic dead space? A) 50 mL B) 100 mL C) 150 mL D) 200 mL E) 300 mL 5. What is her alveolar dead space? A) 50 mL B) 100 mL C) 150 mL D) 200 mL E) 300 mL

34 C

Pulmonary Perfusion Michael Levitzky

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■ ■

■

■ ■

Compare and contrast the bronchial circulation and the pulmonary circulation. Describe the anatomy of the pulmonary circulation, and explain its physiologic consequences. Compare and contrast the pulmonary circulation and the systemic circulation. Describe and explain the effects of lung volume on pulmonary vascular resistance. Describe and explain the effects of elevated intravascular pressures on pulmonary vascular resistance. List the neural and humoral factors that influence pulmonary vascular resistance. Describe the effect of gravity on pulmonary blood flow. Describe the interrelationships of alveolar pressure, pulmonary arterial pressure, and pulmonary venous pressure and their effects on the regional distribution of pulmonary blood flow. Predict the effects of alterations in alveolar pressure, pulmonary arterial and venous pressures, and body position on the regional distribution of pulmonary blood flow. Describe hypoxic pulmonary vasoconstriction and discuss its role in localized and widespread alveolar hypoxia. Describe the causes and consequences of pulmonary edema.

The lung receives blood flow via both the bronchial circulation and the pulmonary circulation. Bronchial blood flow constitutes a very small portion of the output of the left ventricle and supplies part of the tracheobronchial tree with systemic arterial blood. Pulmonary blood flow constitutes the entire output of the right ventricle and supplies the lung with the mixed venous blood draining all the tissues of the body. It is this blood that undergoes gas exchange with the alveolar air in the pulmonary capillaries. Because the right and left ventricles are arranged in series after birth, pulmonary blood flow is approximately equal to 100% of the output of the left ventricle (the cardiac output).

Ch34_341-352.indd 341

About 280 billion pulmonary capillaries supply the approximately 300–480 million alveoli, resulting in a potential surface area for gas exchange estimated to be 50–100 m2. As was shown in Figure 31—5, the alveoli are completely enveloped in pulmonary capillaries.

THE BRONCHIAL CIRCULATION The bronchial arteries supply arterial blood to the tracheobronchial tree and to other structures of the lung down to the level of the terminal bronchioles. They also provide blood flow

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342

SECTION VI Pulmonary Physiology

CONDUCTING AIRWAYS

ALVEOLI

PULMONARY ARTERY (Mean  15)

RIGHT

12

PULMONARY CAPILLARIES

8

PULMONARY VEINS

25/8 VENTRICLE 25/0

ATRIUM 5

ATRIUM 2

VENTRICLE 120/0 120/80

VEINS 15

SYSTEMIC CAPILLARIES

LEFT

AORTA (Mean  100)

30

TISSUES

FIGURE 34–1

Pressures, expressed in mm Hg, in the systemic and pulmonary circulations. (Modified with permission from Levitzky MG:

Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

to other thoracic structures. Lung structures distal to the terminal bronchioles, including the respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli, receive oxygen directly by diffusion from the alveolar air and nutrients from the mixed venous blood in the pulmonary circulation. The bronchial circulation may be important in the “air conditioning” of inspired air (discussed in Chapter 31). The blood flow in the bronchial circulation constitutes about 2% of the output of the left ventricle. Blood pressure in the bronchial arteries is the same as that in the other systemic arteries. This is much higher than the blood pressure in the pulmonary arteries (Figure 34–1). The venous drainage of the bronchial circulation is atypical. Although some of the bronchial venous blood enters the azygos and hemiazygos veins, a substantial portion of bronchial venous blood enters the pulmonary veins. The blood in the pulmonary veins has undergone gas exchange with the alveolar air—that is, the pulmonary veins contain “arterial” blood. Therefore, the bronchial venous blood entering the pulmonary venous blood is part of the normal anatomic right-to-left shunt, which will be discussed in Chapter 35.

THE PULMONARY CIRCULATION The walls of the vessels of the pulmonary circulation are much thinner than corresponding parts of the systemic circulation. This is particularly true of the main pulmonary artery and its

branches. The pulmonary artery rapidly subdivides into terminal branches that have thinner walls and greater internal diameters than do corresponding branches of the systemic arterial tree. There is much less vascular smooth muscle in the walls of the vessels of the pulmonary arterial tree, and there are no highly muscular vessels that correspond to the systemic arterioles. The pulmonary arterial tree rapidly subdivides over a short distance, ultimately branching into the approximately 280 billion pulmonary capillaries, where gas exchange occurs.

PULMONARY VASCULAR RESISTANCE The thin walls and small amount of smooth muscle found in the pulmonary arteries have important physiologic consequences. The pulmonary vessels offer much less resistance to blood flow than do the systemic arterial vessels. They are also much more distensible and compressible than systemic arterial vessels. These factors lead to much lower intravascular pressures than those found in the systemic arteries. The pulmonary vessels are located in the thorax and are subject to alveolar and intrapleural pressures that can change greatly, ranging from as low as −80 cm H2O during a maximal inspiratory effort to more than 100 cm H2O during a maximal forced expiration. Therefore, factors other than the tone of the

CHAPTER 34 Pulmonary Perfusion pulmonary vascular smooth muscle may have profound effects on pulmonary vascular resistance (PVR). PVR cannot be measured directly but an approximation can be calculated using the Poiseuille equation, as was discussed in Chapter 22. For the pulmonary circulation, the PVR is equal to the mean pulmonary artery pressure (Pa, the upstream pressure) minus the mean left atrial pressure (the downstream pressure), divided by pulmonary blood flow (the cardiac output). However, the mean left atrial pressure may not be the effective downstream pressure for the calculation of PVR under all lung conditions (see the section on zones of the lung later in this chapter). Because the right and left circulations are in series, the outputs of the right and left ventricles must be approximately equal to each other. (If they are not, blood and fluid will build up in the lungs or periphery.) If the two outputs are the same and the measured pressure drops across the systemic circulation and the pulmonary circulation are about 98 and 10 mm Hg, respectively (see Figure 34–1), then the PVR must be about one tenth that of the total peripheral resistance (TPR). TPR is sometimes called systemic vascular resistance (SVR).

DISTRIBUTION OF PULMONARY VASCULAR RESISTANCE The distribution of PVR can be estimated by the decrease in pressure across each of the three major components of the pulmonary vasculature: the pulmonary arteries, the pulmonary capillaries, and the pulmonary veins. In Figure 34–1, the resistance is fairly evenly distributed among the three components. At rest, about one third of the resistance to blood flow is located in the pulmonary arteries, about one third is located in the pulmonary capillaries, and about one third is located in the pulmonary veins. This is in contrast to the systemic circulation, in which about 70% of the resistance to blood flow is located in the systemic arteries, mostly in the highly muscular systemic arterioles.

CONSEQUENCES OF DIFFERENCES IN PRESSURE BETWEEN THE SYSTEMIC AND PULMONARY CIRCULATIONS The left ventricle must maintain a relatively high mean arterial pressure because such high pressures are necessary to overcome hydrostatic forces and pump blood to the brain. The apices of the lungs are a much shorter distance above the right ventricle, so such high pressures are unnecessary. The high arterial pressure in the systemic circulation allows the redistribution of left ventricular output and the control of blood flow to different tissues. In the pulmonary circulation, redistribution of right ventricular output is usually unnecessary because all alveolar–capillary units that are participating in gas exchange are performing the same function. The pressure is low and the small amount of smooth muscle in the pulmonary vessels (which is in large part responsible for the low pressure head) makes such local redistributions unlikely. An exception to this will be described in the section “Hypoxic Pulmonary Vasoconstriction.”

343

Another consequence of the pressure differences between the systemic and pulmonary circulations is that the workload and metabolic demand of the left ventricle is much greater than that of the right ventricle. The difference in wall thickness of the left and right ventricles of the adult is a reminder of the much greater workload of the left ventricle. The relatively small amounts of vascular smooth muscle, low intravascular pressures, and high distensibility of the pulmonary circulation lead to a much greater importance of extravascular effects (passive factors) on PVR. Gravity, body position, lung volume, alveolar and intrapleural pressures, intravascular pressures, and right ventricular output all can have profound effects on PVR without any alteration in the tone of the pulmonary vascular smooth muscle.

LUNG VOLUME AND PULMONARY VASCULAR RESISTANCE For distensible–compressible vessels, the transmural pressure gradient is an important determinant of the vessel diameter (see discussion of airway resistance in Chapter 32). As the transmural pressure gradient (which is equal to pressure inside minus pressure outside) increases, the vessel diameter increases and resistance decreases; as the transmural pressure decreases, the vessel diameter decreases and the resistance increases. Negative transmural pressure gradients lead to compression or even collapse of the vessel. Two different groups of pulmonary vessels must be considered when the effects of lung volume changes on PVR are analyzed—namely, the alveolar and extra-alveolar vessels (Figure 34–2).

ALVEOLUS

“alveolar”

“extraalveolar”

ALVEOLUS

During inspiration

FIGURE 34–2 Illustration of alveolar and extra-alveolar pulmonary vessels during an inspiration. The alveolar vessels (pulmonary capillaries) are exposed to the expanding alveoli and elongated. The extra-alveolar vessels, here shown exposed to the intrapleural pressure, expand as the intrapleural pressure becomes more negative and as radial traction increases during the inspiration. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

SECTION VI Pulmonary Physiology

Pulmonary vascular resistance

As lung volume increases during a normal negative-pressure inspiration, the alveoli increase in volume. While the alveoli expand, the vessels between them, mainly pulmonary capillaries, are elongated. As these vessels are stretched, their diameters decrease, just as stretching a rubber tube causes its diameter to narrow. Resistance to blood flow through the alveolar vessels increases as the alveoli expand because the alveolar vessels are longer and because their radii are smaller. At high lung volumes, then, the resistance to blood flow offered by the alveolar vessels increases; at low lung volumes, the resistance to blood flow offered by the alveolar vessels decreases. One group of the extra-alveolar vessels, the larger arteries and veins, is exposed to the intrapleural pressure. As lung volume is increased by making the intrapleural pressure more negative, the transmural pressure gradient of the larger arteries and veins increases and they distend. Another factor tending to decrease the resistance to blood flow offered by the extraalveolar vessels at higher lung volumes is radial traction by the connective tissue and alveolar septa holding the larger vessels in place in the lung. (Look at the small branch of the pulmonary artery at the bottom of Figure 31–4.) Thus, at high lung volumes (attained by normal negative-pressure breathing), the resistance to blood flow offered by the extra-alveolar vessels decreases. During a forced expiration to low lung volumes, however, intrapleural pressure becomes very positive. Extraalveolar vessels are compressed, and as the alveoli decrease in size, they exert less radial traction on the extra-alveolar vessels. The resistance to blood flow offered by the extra-alveolar vessels therefore increases (see left side of Figure 34–3). Because the alveolar and extra-alveolar vessels may be thought of as two groups of resistances in series with each

Stretching of pulmonary capillaries

Compression of extraalveolar vessels

FRC = Lowest PVR

other, the resistances of the alveolar and extra-alveolar vessels are additive at any lung volume. Thus, the effect of changes in lung volume on the total PVR gives the U-shaped curve seen in Figure 34–3. PVR is lowest near the functional residual capacity and increases at both high and low lung volumes. Also note that during mechanical positive-pressure ventilation, alveolar pressure (PA) and intrapleural pressure are positive during inspiration. In this case, both the alveolar and extraalveolar vessels are compressed as lung volume increases.

RECRUITMENT AND DISTENTION During exercise, cardiac output can increase several-fold without a correspondingly great increase in mean pulmonary artery pressure. Although the mean pulmonary artery pressure does increase, the increase is only a few millimeters of mercury, even if cardiac output has doubled or tripled. Since the pressure drop across the pulmonary circulation is proportional to the cardiac output times the PVR (i.e., ΔP = Q ˙ × R), this must indicate a decrease in PVR. Like the effects of lung volume on PVR, this decrease appears to be passive—that is, it is not a result of changes in the tone of pulmonary vascular smooth muscle caused by neural mechanisms or humoral agents. In fact, a decrease in PVR in response to increased blood flow or even an increase in perfusion pressure can be demonstrated in a vascularly isolated perfused lung, as was used to obtain the data summarized in Figure 34–4. (Note that the graph has blood pressure on the x-axis; blood flow has a similar effect.) Increasing the left atrial pressure also decreases PVR. There are two different mechanisms that can explain this decrease in PVR in response to elevated blood flow and

Pulmonary vascular resistance

344

Recruitment & distention of pulmonary capillaries

Lung volume Pulmonary blood flow

FIGURE 34–3

The effects of lung volume on pulmonary vascular resistance (PVR). PVR is lowest near the functional residual capacity (FRC) and increases at both high and low lung volumes because of the combined effects on the alveolar and extra-alveolar vessels. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture,

FIGURE 34–4 The effect of pulmonary blood flow (or blood pressure) on pulmonary vascular resistance. Increased pulmonary artery blood pressure or pulmonary blood flow decreases pulmonary vascular resistance. (Reproduced with permission from Kibble J, Halsey CR: The

Medical Physiology. New York: McGraw-Hill, 2009.)

Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

CHAPTER 34 Pulmonary Perfusion

Recruitment

345

Distention

FIGURE 34–5 Illustration of the mechanisms by which increased mean pulmonary artery pressure may decrease pulmonary vascular resistance. The upper figure shows a group of pulmonary capillaries, some of which are perfused. At left, the previously unperfused capillaries are recruited (opened) by the increased perfusion pressure. At right, the increased perfusion pressure has distended those vessels already open. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

perfusion pressure: recruitment and distention (Figure 34–5). As indicated in the diagram, at resting cardiac outputs, not all the pulmonary capillaries are perfused. A substantial number of capillaries are probably unperfused because of hydrostatic effects that will be discussed later in this chapter. Others may be unperfused because they have a relatively high critical opening pressure. That is, these vessels, because of their high vascular smooth muscle tone or other factors such as positive alveolar pressure, require a higher perfusion pressure than that solely necessary to overcome hydrostatic forces. Under normal circumstances, it is not likely that the critical opening pressures for pulmonary blood vessels are very great because they have so little smooth muscle. Increasing blood flow increases the mean pulmonary artery pressure, which opposes hydrostatic forces and exceeds the critical opening pressure in previously unopened vessels. This series of events opens new parallel pathways for blood flow, which lowers the PVR. This opening of new pathways is called recruitment. Note that decreasing the cardiac output or pulmonary artery pressure can result in a derecruitment of pulmonary capillaries. As perfusion pressure increases, the transmural pressure gradient of the pulmonary blood vessels increases, causing distention of the vessels. This increases their radii and decreases their resistance to blood flow. Both recruitment and distention cause the decreased PVR with elevated perfusion pressure or blood flow. Note that recruitment increases the surface area for gas exchange and

may decrease alveolar dead space. Derecruitment caused by low right ventricular output or high alveolar pressures decreases the surface area for gas exchange and may increase alveolar dead space.

CONTROL OF PULMONARY VASCULAR SMOOTH MUSCLE Pulmonary vascular smooth muscle is responsive to both neural and humoral influences. These produce active alterations in PVR, as opposed to the passive factors discussed in the previous section. A final passive factor, gravity, will be discussed later in this chapter. The main passive and active factors that influence PVR are summarized in Tables 34–1 and 34–2. The pulmonary vasculature is innervated by both sympathetic and parasympathetic fibers of the autonomic nervous system. The innervation of pulmonary vessels is relatively sparse in comparison with that of systemic vessels, and the autonomic nervous system has much less influence on the pulmonary vessels. There is relatively more innervation of the larger vessels and less of the smaller, more muscular vessels. There appears to be no innervation of vessels smaller than 30 μm in diameter, with little innervation of intrapulmonary veins and venules. Sympathetic stimulation of the innervation of the pulmonary vasculature may increase PVR or decrease the distensibility of

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TABLE 34–1 Passive influences on pulmonary vascular resistance. Cause

Effect on Pulmonary Vascular Resistance

Mechanism

Increased lung volume (above FRC)

Increases

Lengthening and compression of alveolar vessels

Decreased lung volume (below FRC)

Increases

Compression of and less traction on extra-alveolar vessels

Increased pulmonary artery pressure, increased left atrial pressure, increased pulmonary blood volume, increased cardiac output

Decreases

Recruitment and distention

Gravity, body position

Decreases in gravity-dependent regions of the lungs

Hydrostatic effects lead to recruitment and distention

Increased (more positive) interstitial pressure

Increases

Compression of vessels

Increased blood viscosity

Increases

Viscosity directly increases resistance

Increased alveolar pressure

Increases

Compression and derecruitment of alveolar vessels

Positive intrapleural pressure

Increases

Compression of extra-alveolar vessels; compression of vena cava decreases pulmonary blood flow and leads to derecruitment

Positive-pressure ventilation

FRC, functional residual capacity.

the larger vessels. Stimulation of the parasympathetic innervation of the pulmonary vessels generally causes vasodilation. The catecholamines epinephrine and norepinephrine both increase PVR when injected into the pulmonary circulation. Histamine, found in the lung in mast cells, is also a pulmonary vasoconstrictor. Certain prostaglandins and related substances, such as PGF2α, PGE2, and thromboxane,

TABLE 34–2 Active influences on pulmonary vascular resistance. Increase

Decrease

Stimulation of sympathetic innervation (may have greater effect by decreasing large-vessel distensibility)

Stimulation of parasympathetic innervation (if vascular tone is already elevated)

Norepinephrine, epinephrine

Acetylcholine

α-Adrenergic agonists

β-Adrenergic agonists

PGF2α, PGE2

PGE1

Thromboxane

Prostacyclin (PGI2)

Endothelin

Nitric oxide

Angiotensin

Bradykinin

Histamine (primarily a pulmonary venoconstrictor) Alveolar hypoxia Alveolar hypercapnia Low pH of mixed venous blood PG, prostaglandin.

are also pulmonary vasoconstrictors, as is endothelin. Alveolar hypoxia and hypercapnia also cause pulmonary vasoconstriction, as will be discussed later in this chapter. Acetylcholine, the β-adrenergic agonist isoproterenol, nitric oxide (NO), and certain prostaglandins, such as PGE1 and PGI2 (prostacyclin), are pulmonary vasodilators.

THE REGIONAL DISTRIBUTION OF PULMONARY BLOOD FLOW: THE ZONES OF THE LUNG Gravity is another important passive factor affecting local PVR and the relative perfusion of different regions of the lung. The interaction of the effects of gravity and extravascular pressures may have a profound influence on the relative perfusion of different areas of the lung.

THE REGIONAL DISTRIBUTION OF PULMONARY BLOOD FLOW If a radioactive substance such as the gas xenon (133Xe) is dissolved in saline and infused into the venous blood, it can be used to determine regional pulmonary blood flow. The greater the radioactivity measured over a specific region, the greater the blood flow. A pattern like that shown in Figure 34–6 is observed in a healthy person seated upright or standing up. There is greater blood flow per unit volume (per alveolus) to lower regions of the lung than to upper regions of the lung. Note that the test was made with the subject at the total lung capacity.

CHAPTER 34 Pulmonary Perfusion

THE INTERACTION OF GRAVITY AND EXTRAVASCULAR PRESSURE: THE ZONES OF THE LUNG

Blood flow/alveolus ( %)

150 TLC

100

50

rib 2

bottom 0 20

347

15 10 5 Lung distance (cm below rib 2)

0

FIGURE 34–6 Relative blood flow per alveolus (100% = perfusion of each alveolus if all were perfused equally) versus distance from the bottom of the lung in a human seated upright. Measurement of regional blood flow was determined using an intravenous injection of 133Xe. TLC, total lung capacity. (Modified with permission from Hughes JM, Glazier JB, Maloney JE, West JB. Effect of lung volume on the distribution of pulmonary blood flow in man. Respir Physiol. 1968;4(1):58–72.)

If the subject lies down, this pattern of regional perfusion is altered so that perfusion to the anatomically upper and lower portions of the lung is roughly evenly distributed, but blood flow per unit volume is still greater in the more gravitydependent regions of the lung. For example, if the subject were to lie down on the left side, the left lung would receive more blood flow per unit volume than would the right lung. Exercise, which increases the cardiac output, increases the blood flow per unit volume to all regions of the lung, but the perfusion gradient persists so that there is still relatively greater blood flow per unit volume in more gravity-dependent regions of the lung. The reason for this gradient of regional perfusion of the lung is gravity. The pressure at the bottom of a column of a liquid is proportional to the height of the column times the density of the liquid times gravity, so the intravascular pressures in more gravity-dependent portions of the lung are greater than those in upper regions. Because the pressures are greater in the more gravity-dependent regions of the lung, the resistance to blood flow is lower in lower regions of the lung owing to more recruitment or distention of vessels in these regions. It is therefore not only gravity, but also the characteristics of the pulmonary circulation that cause the increased blood flow to more gravity-dependent regions of the lung. After all, the same hydrostatic effects occur to an even greater extent in the systemic circulation, but the thick walls of the systemic arteries are not affected. There is also considerable heterogeneity in pulmonary blood flow at any vertical distance up the lung, that is, there may be significant variations in pulmonary blood flow within a given horizontal plane of the lung. These variations are caused by local factors and mechanical stresses.

When the pulmonary artery pressure is low, the uppermost regions of the lung receive no blood flow. Perfusion of the lung ceases at the point at which alveolar pressure (PA) is just equal to pulmonary artery pressure (Pa). Above this point, there is no perfusion because alveolar pressure exceeds pulmonary artery pressure, and the transmural pressure across capillary walls is negative. Below this point, perfusion per unit volume increases steadily with increased distance down the lung. Thus, under circumstances in which alveolar pressure is greater than pulmonary artery pressure in the upper parts of the lung, no blood flow occurs in that region, and the region is referred to as being in zone 1, as shown in Figure 34–7. (Note that in this figure blood flow is on the x-axis and that distance up the lung is on the y-axis.) Any zone 1, then, is alveoli that are ventilated but not perfused. It is alveolar dead space. Fortunately, during normal, quiet breathing in a person with a normal cardiac output, pulmonary artery pressure, even in the uppermost regions of the lung, is greater than alveolar pressure, so there is no zone 1. The lower portion of the lung in Figure 34–7 is said to be in zone 3. In this region, the pulmonary artery pressure and the pulmonary vein pressure (Pv) are both greater than alveolar pressure. The driving pressure (ΔP) for blood flow through the lung in this region is pulmonary artery pressure minus pulmonary vein pressure. Note that this driving pressure stays constant as one moves further down the lung in zone 3 because the hydrostatic pressure effects are the same for both the arteries and the veins.

Zone 1 PA>Pa>Pv

Pa

PA

Zone 2 Pa>PA>Pv Pv Distance

Zone 3 Pa>Pv>PA

Blood flow

FIGURE 34–7 The zones of the lung. The effects of gravity and alveolar pressure on the perfusion of the lung. Described in text. (Modified with permission from West, J.B., Dollery, C.T., Naimark, A.: Distribution of blood flow in isolated lung: Relation to vascular and alveolar pressures. J Appl Physiol 1964;19:713–724.)

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The middle portion of the lung in Figure 34–7 is in zone 2. In zone 2, pulmonary artery pressure is greater than alveolar pressure, so blood flow does occur. Nevertheless, because alveolar pressure is greater than pulmonary vein pressure, the effective driving pressure for blood flow is pulmonary artery pressure minus alveolar pressure in zone 2. (This is analogous to the situation described in Chapter 32: during a forced expiration, the driving pressure for airflow is equal to alveolar pressure minus intrapleural pressure.) Notice that in zone 2 (at right in Figure 34–7), the increase in blood flow per distance down the lung is greater than it is in zone 3. This is because the upstream driving pressure, the pulmonary artery pressure, increases according to the hydrostatic pressure increase, but the effective downstream pressure, alveolar pressure, is constant throughout the lung at any instant. To summarize: in zone 1, PA > Pa > Pv , and there is no blood flow; in zone 2, Pa > PA > Pv, and the effective driving pressure for blood flow is Pa – PA; in zone 3, Pa > Pv > PA, and the driving pressure for blood flow is Pa – Pv. It is important to realize that the boundaries between the zones are dependent on physiologic conditions—they are not fixed anatomic landmarks. Alveolar pressure changes during the course of each breath. During eupneic breathing these changes are only a few centimeters of water, but they may be much greater during speech, exercise, and other conditions. A patient on a positive-pressure ventilator with positive endexpiratory pressure (PEEP) may have substantial amounts of zone 1 because alveolar pressure is always high. After a hemorrhage or during general anesthesia, pulmonary blood flow and pulmonary artery pressure are low and zone 1 conditions are also likely. During exercise, cardiac output and pulmonary artery pressure increase and any existing zone 1 will be recruited to zone 2. The boundary between zones 2 and 3 will move upward as well. Changes in lung volume also affect the regional distribution of pulmonary blood flow and will therefore affect the boundaries between zones. Finally, changes in body position alter the orientation of the zones with respect to the anatomic locations in the lung, but the same relationships exist with respect to gravity and alveolar pressure.

smooth muscle cells to depolarize, allowing calcium to enter the cells. This, in turn, causes them to contract. The hypoxic pulmonary vasoconstriction response is graded—constriction begins to occur at alveolar Po2’s of approximately 100 mm Hg and increases until PAo2 decreases to about 20–30 mm Hg. If an area of the lung becomes hypoxic because of airway obstruction or if localized atelectasis occurs, any mixed venous blood flowing to that area will undergo little or no gas exchange (Figure 34–8) and will mix with blood draining well-ventilated areas of the lung as it enters the left atrium. This mixing will lower the overall arterial Po2. The hypoxic pulmonary vasoconstriction diverts mixed venous blood flow away from poorly ventilated areas of the lung by locally increasing vascular resistance, as shown in Figure 34–8C. Therefore, mixed venous blood is sent to better-ventilated areas of the lung (Figure 34–8D). The problem with hypoxic pulmonary vasoconstriction is that it is not a very strong response because there is so little smooth muscle in the pulmonary vasculature. Very high pulmonary artery pressures can interfere with hypoxic pulmonary vasoconstriction, as can other physiologic disturbances, such as alkalosis. In hypoxia of the whole lung, such as might be encountered at high altitude or in hypoventilation, hypoxic pulmonary vasoconstriction occurs throughout the lung. Even this may be useful in increasing gas exchange because greatly increasing the pulmonary artery pressure recruits previously unperfused pulmonary capillaries. This increases the surface area available for gas diffusion and improves the matching of ventilation and perfusion, as will be discussed in the next chapter. On the other hand, such a whole-lung hypoxic pulmonary vasoconstriction increases the workload on the right ventricle, and the high pulmonary artery pressure may overwhelm hypoxic pulmonary vasoconstriction in some parts of the lung, increase the capillary hydrostatic pressure in those vessels, and lead to pulmonary edema (see the next section of this chapter). Alveolar hypercapnia (increased carbon dioxide) also causes pulmonary vasoconstriction. Note that both hypoxic and hypercapnic pulmonary vasoconstriction are opposite to what occurs in the systemic circulation.

PULMONARY EDEMA HYPOXIC PULMONARY VASOCONSTRICTION Alveolar hypoxia (low alveolar Po2) or atelectasis (collapsed alveoli) causes an active vasoconstriction in the pulmonary circulation. The site of vascular smooth muscle constriction appears to be in the arterial (precapillary) vessels very close to the alveoli. The mechanism of hypoxic pulmonary vasoconstriction is not completely understood. The response occurs locally, that is, only in the area of the alveolar hypoxia. Connections to the central nervous system are not necessary. Hypoxia may act directly on pulmonary vascular smooth muscle to produce hypoxic pulmonary vasoconstriction. Hypoxia inhibits an outward potassium current, which causes pulmonary vascular

Pulmonary edema is the extravascular accumulation of fluid in the lung. This pathologic condition may be caused by one or more physiologic abnormalities, but the result is inevitably impaired gas transfer. As the edema fluid builds up, first in the interstitium and later in alveoli, diffusion of gases—particularly oxygen—decreases. The capillary endothelium is much more permeable to water and solutes than is the alveolar epithelium. Edema fluid therefore accumulates in the interstitium before it accumulates in the alveoli. As discussed in Chapter 26, the Starling equation describes the movement of liquid across the capillary endothelium: ˙ f = Kf [(Pc – Pis) – σ(πpl – πis)] Q

(1)

CHAPTER 34 Pulmonary Perfusion

O2 ⴝ 150 mm Hg CO2 ⴝ 0 mm Hg

O2 ⴝ 150 mm Hg CO2 ⴝ 0 mm Hg

O2 ⴝ 100 mm Hg CO2 ⴝ 40 mm Hg O2 ⴝ 40 mm Hg CO2 ⴝ 45 mm Hg

349

Decreased O2 Increased CO2 O2 ⴝ 40 mm Hg CO2 ⴝ 45 mm Hg

O2 ⴝ 100 mm Hg CO2 ⴝ 40 mm Hg

A

Decreased O2 Increased CO2

C O2 ⴝ 150 mm Hg CO2 ⴝ 0 mm Hg

O2 ⴝ 100 mm Hg CO2 ⴝ 40 mm Hg

Decreased O2 Increased CO2

Decreased O2 Increased CO2 O2 ⴝ 40 mm Hg CO2 ⴝ 45 mm Hg

Decreased O2 Increased CO2

B

D

FIGURE 34–8 Illustration of the physiologic function of hypoxic pulmonary vasoconstriction (HPV). A) Normal alveolar–capillary unit. B) Perfusion of a hypoventilated alveolus results in blood with a decreased Po and an increased Pco entering the left atrium. C) HPV 2 2 increases the resistance to blood flow to the hypoventilated alveolus. D) This diverts blood flow away from the hypoventilated alveolus to ˙/Q ˙ matching. HPV, hypoxic pulmonary vasoconstriction; V˙/Q ˙ = ventilation–perfusion ratio. better-ventilated alveoli, thus helping to maintainV (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

˙ f is the net flow of fluid, Kf the capillary filtration where Q coefficient (this describes the permeability characteristics of the membrane to fluids), Pc the capillary hydrostatic pressure, Pis the hydrostatic pressure of the interstitial fluid, σ the reflection coefficient (this describes the ability of the membrane to prevent extravasation of solute particles), πpl the colloid osmotic (oncotic) pressure of the plasma, and πis the colloid osmotic pressure of the interstitial fluid. The components of the Starling equation are very useful in understanding the potential causes of pulmonary edema, even though only the plasma colloid osmotic pressure (πpl) can be measured clinically.

CONDITIONS THAT MAY LEAD TO PULMONARY EDEMA Infections, circulating or inhaled toxins, oxygen toxicity, and other factors that destroy the integrity of the capillary endothelium and increase its permeability lead to localized or generalized pulmonary edema. The pulmonary capillary hydrostatic pressure is estimated to be about 10 mm Hg under normal conditions. If the capillary hydrostatic pressure increases dramatically, the filtration of fluid across the capillary endothelium will increase greatly, and enough fluid may leave the capillaries to exceed the lym-

phatic drainage. The pulmonary capillary hydrostatic pressure often increases as a result of problems in the left side of the circulation, such as infarction of the left ventricle, left ventricular failure, or mitral stenosis. As left atrial pressure and pulmonary venous pressure increase because of accumulating blood, the pulmonary capillary hydrostatic pressure also increases. Other causes of increased pulmonary capillary hydrostatic pressure include overzealous administration of intravenous fluids and diseases that occlude the pulmonary veins. The interstitial hydrostatic pressure of the lung is in the range of –5 to –7 mm Hg when a healthy person is at FRC. Conditions that would decrease (i.e., make it more negative) the interstitial pressure would increase the tendency for pulmonary edema to develop. These appear to be limited mainly to potential actions of the health care worker, such as rapid evacuation of chest fluids or treatment of a pneumothorax. Situations that increase alveolar surface tension, for example, when decreased amounts of pulmonary surfactant are present, could also make the interstitial hydrostatic pressure more negative and increase the tendency for the formation of pulmonary edema. Note that as fluid accumulates in the interstitium, the interstitial hydrostatic pressure increases, which helps limit further fluid extravasation. Any situation that permits more solute to leave the capillaries, such as a decreased reflection coefficient, will lead to more fluid movement out of the vascular space.

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Decreases in the colloid osmotic pressure of the plasma, which helps retain fluid in the capillaries, may lead to pulmonary edema. Plasma colloid osmotic pressure, normally in the range of 25–28 mm Hg, decreases with low plasma protein concentration or overadministration of certain intravenous solutions. On the other hand, increased colloid osmotic pressure in the interstitium will pull fluid from the capillaries. Any fluid that makes its way into the pulmonary interstitium must be removed by the lymphatic drainage of the lung. The volume of lymph flow from the human lung is capable of increasing as much as 10-fold under pathologic conditions. It is only when this large safety factor is overwhelmed that pulmonary edema occurs. Conditions that block the lymphatic drainage of the lung, such as tumors or scars, may predispose patients to pulmonary edema. Pulmonary edema can be associated with head injury, heroin overdose, and high altitude. The causes of the edema formation in these conditions are not known, although high-altitude pulmonary edema may be caused by high pulmonary artery pressures secondary to the hypoxic pulmonary vasoconstriction.

NONRESPIRATORY FUNCTIONS OF THE PULMONARY CIRCULATION The pulmonary circulation, strategically located between the systemic veins and arteries, is well suited for several functions not directly related to gas exchange. The entire cardiac output passes over the very large surface area of the pulmonary capillary bed, allowing the lungs to act as a site of blood filtration and storage, as well as for the metabolism of vasoactive constituents of the blood, as was discussed in Chapter 31. A typical adult male has a pulmonary blood volume of about 500 mL, which allows the pulmonary circulation to act as a reservoir for the left ventricle. If left ventricular output is transiently greater than systemic venous return, left ventricular output can be maintained for a few strokes by drawing on blood stored in the pulmonary circulation. Because virtually all mixed venous blood must pass through the pulmonary capillaries, the pulmonary circulation acts as a filter, protecting the systemic circulation from materials that enter the blood. The particles filtered, which may enter the circulation as a result of natural processes, trauma, or therapeutic measures, may include small fibrin or blood clots, fat cells, bone marrow, detached cancer cells, gas bubbles, agglutinated erythrocytes (especially in sickle cell disease), masses of platelets or leukocytes, and debris from stored blood or intravenous solutions. If these particles were to enter the arterial side of the systemic circulation, they might occlude vascular beds with no other source of blood flow. This occlusion would be particularly disastrous if it occurred in the blood supply to the central nervous system or the heart. The lung can perform this very valuable service because there are many more pulmonary capillaries present in the lung

than are necessary for gas exchange at rest: previously unopened capillaries will be recruited. Obviously, no gas exchange can occur distal to a particle embedded in and obstructing a capillary, so this mechanism is limited by the ability of the lung to remove such filtered material. If particles are experimentally suspended in venous blood and are then trapped in the pulmonary circulation, the diffusing capacity (see Chapter 35) usually decreases for 4–5 days and then returns to normal. The mechanisms for removal of material trapped in the pulmonary capillary bed include lytic enzymes in the vascular endothelium, ingestion by macrophages, and penetration to the lymphatic system. Patients on cardiopulmonary bypass do not have the benefit of this pulmonary capillary filtration, and blood administered to these patients must be filtered for them. The colloid osmotic pressure of the plasma proteins normally exceeds the pulmonary capillary hydrostatic pressure. This tends to pull fluid from the alveoli into the pulmonary capillaries and keep the alveolar surface free of liquids other than pulmonary surfactant. Water taken into the lungs is rapidly absorbed into the blood. This protects the gas exchange function of the lungs and opposes transudation of fluid from the capillaries to the alveoli. As noted in Chapter 31, type II alveolar epithelial cells may also actively pump sodium and water from the alveolar surface into the interstitium. Drugs or chemical substances that readily pass through the alveolar–capillary barrier by diffusion or by other means rapidly enter the systemic circulation. The lungs are frequently used as a route of administration of drugs and for anesthetic gases, such as halothane and nitrous oxide. Aerosolized drugs intended for the airways only, such as the bronchodilator isoproterenol and anti-inflammatory corticosteroids, may rapidly pass into the systemic circulation, where they may have clinically significant effects. The effects of isoproterenol, for example, could include cardiac stimulation and vasodilation.

CLINICAL CORRELATION A 60-year-old man who had a left ventricular myocardial infarction 3 months ago returns to the cardiologist because of dyspnea on exertion but not at rest, a cough productive of frothy fluid after exercise, and orthopnea (easier breathing in the upright than recumbent position). At rest, his heart rate is 105/min, blood pressure is 120/90 mm Hg, and his respiratory rate is increased at 20/min. His chest radiograph shows evidence of edema in gravity-dependent lung regions. The patient does not have dyspnea (the feeling of difficult breathing or “shortness of breath”) at rest and his blood pressure is within the normal range. His heart rate at rest is slightly above the normal range (50–100/min; tachycardia) and his respiratory rate is high (normally 12–15/min; tachypnea). He does have orthopnea.

CHAPTER 34 Pulmonary Perfusion ■

He had a left ventricular myocardial infarction 3 months ago and the damaged heart muscle has been replaced with scar tissue that cannot contract. Although his left ventricle can generate a sufficient stroke volume at rest, it cannot match the increased right ventricular output during exercise, leading to increased left atrial pressure. Because there are no valves between the left atrium and the pulmonary veins and capillaries, pulmonary capillary hydrostatic pressure increases. Filtration of fluid from the capillaries into the pulmonary interstitium increases sufficiently to exceed the ability of the pulmonary lymphatic drainage to remove it, resulting in interstitial edema and then alveolar edema. The dyspnea results from several factors. Pulmonary vascular congestion (excess blood in the pulmonary blood vessels) decreases the compliance of the lungs. Interstitial and alveolar edema increases the alveolar– capillary barrier for gas diffusion. This is particularly a problem for oxygen diffusion, as will be discussed in the next chapter. Stretch receptors in the pulmonary circulation respond to pulmonary vascular congestion and the arterial chemoreceptors respond to low arterial Po2, both contributing to the sensation of dyspnea, as will be discussed in Chapter 38. He breathes more easily in the upright position because the edema fluid collects in lower regions of the lungs, allowing better gas exchange in upper parts of the lungs.

CHAPTER SUMMARY ■

■

■ ■

Compared with the systemic arteries, the pulmonary arteries have much less vascular smooth muscle and therefore offer much less resistance to blood flow. Pulmonary arteries are more distensible, and because their intravascular pressures are lower, more compressible than systemic arteries. The vascular transmural pressure gradient is therefore an important determinant of PVR. Although pulmonary vascular smooth muscle can actively contract or relax in response to neural and humoral influences, passive factors play a more important role in determining PVR than they do in determining SVR. PVR is usually lowest at the functional residual capacity and increases at higher and at lower lung volumes. PVR usually decreases with increases in pulmonary blood flow, pulmonary artery pressure, left atrial pressure, or pulmonary capillary blood volume because of distention of already open blood vessels, recruitment of previously unopened vessels, or both.

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There is more blood flow in lower regions of the lung than in upper regions. The effects of pulmonary artery pressure, pulmonary vein pressure, and alveolar pressure on pulmonary blood flow are described as the zones of the lung. Alveolar hypoxia can cause constriction of precapillary pulmonary vessels, diverting blood flow away from poorly ventilated or unventilated alveoli.

STUDY QUESTIONS 1. Compared to the systemic circulation, the pulmonary circulation has A) greater arterial pressure. B) less distensible vessels. C) a more evenly distributed vascular resistance to blood flow among its arteries, capillaries, and veins. D) greater control of vascular resistance by the autonomic nervous system. E) greater total vascular resistance. 2. Which of the following would likely increase pulmonary vascular resistance? A) inhaling from the FRC to the TLC B) exhaling from the FRC to the RV C) breathing 10% O2–90% N2 for 10 minutes D) decreasing the cardiac output from 5 to 2.5 L/min E) all of the above 3. In zone 2 of the lung A) alveolar pressure > pulmonary arterial pressure > pulmonary venous pressure. B) pulmonary arterial pressure > alveolar pressure > pulmonary venous pressure. C) pulmonary arterial pressure > pulmonary venous pressure > alveolar pressure. D) the effective pressure gradient for blood flow is pulmonary arterial pressure minus pulmonary venous pressure. E) there is no blood flow. 4. Compared to the pulmonary circulation, the bronchial circulation has A) more total blood flow. B) higher mean arterial pressure. C) more distensible arteries. D) more even distribution of vascular resistance among the arteries, capillaries, and veins. E) lower arterial Po2. 5. Which of the following is least likely to cause pulmonary edema? A) mitral stenosis B) two liters of rapidly administered intravenous saline solution C) increased left atrial pressure D) rapid administration of very negative intrapleural pressure to alleviate a pneumothorax E) positive pressure ventilation

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35 C

Ventilation–Perfusion Relationships and Respiratory Gas Exchange Michael Levitzky

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■ ■

Predict the consequences of mismatched ventilation and perfusion. Explain the regional differences in the matching of ventilation and perfusion of the normal upright lung. Predict the consequences of the regional differences in the ventilation and perfusion of the normal upright lung. Define diffusion, and distinguish it from bulk flow. State Fick’s law for diffusion. Distinguish between perfusion limitation and diffusion limitation of gas transfer in the lung. Describe the diffusion of oxygen from the alveoli into the blood, and carbon dioxide from the blood to the alveoli. Define the diffusing capacity and discuss its measurement.

Alveolar ventilation and pulmonary perfusion have been discussed in the previous chapters in this section. The respiratory gases must diffuse through the alveolar–capillary barrier for gas exchange to occur. For optimal diffusion, the alveolar ventilation must be matched to the pulmonary perfusion.

VENTILATION–PERFUSION RELATIONSHIPS Alveolar ventilation brings oxygen into the lung and removes carbon dioxide from it. Similarly, the mixed venous blood brings carbon dioxide into the lung and takes up alveolar oxygen. The alveolar Po2 and Pco2 are thus determined by the relationship between alveolar ventilation and perfusion. Alterations in the ratio of ventilation to perfusion, called the V·a /Q· c for alveolar ventilation/pulmonary capillary blood flow (or just V· /Q· ), will result in changes in the alveolar Po2 and Pco2, as well as in gas delivery to or removal from the lung. Alveolar ventilation is normally about 4–6 L/min and pulmonary blood flow (which is equal to cardiac output) has a similar range, so the V· /Q· for the whole lung is in the range of

Ch35_353-362.indd 353

0.8–1.2. However, ventilation and perfusion must be matched on the alveolar–capillary level for optimal gas exchange to occur and the V· /Q· for the whole lung is really of interest only as an approximation of the situation in all the alveolar– capillary units of the lung.

CONSEQUENCES OF HIGH AND LOW VENTILATION–PERFUSION RATIOS Oxygen is delivered to the alveolus by alveolar ventilation, is removed from the alveolus as it diffuses into the pulmonary capillary blood, and is carried away by blood flow. Similarly, carbon dioxide is delivered to the alveolus in the mixed venous blood and diffuses into the alveolus in the pulmonary capillary. It is removed from the alveolus by alveolar ventilation. As will be discussed later in this chapter, at resting cardiac outputs, the diffusion of both oxygen and carbon dioxide is normally limited by pulmonary perfusion. The alveolar partial pressures of both oxygen and carbon dioxide are therefore determined by the V· /Q· . If the V· /Q· in an alveolar–capillary unit increases, the delivery of oxygen relative to its removal will increase, as will the removal of carbon dioxide relative to its delivery. Alveolar

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SECTION VI Pulmonary Physiology O2  150 mm Hg CO2  0 mm Hg B.

O2  150 mm Hg CO2  0 mm Hg

A.

O2  40 mm Hg CO2  45 mm Hg

C.

O2  100 mm Hg CO2  40 mm Hg

O2  150 mm Hg CO2  0 mm Hg

O2  40 mm Hg

O2  40 mm Hg

O2  40 mm Hg

O2  100 mm Hg

CO2  45 mm Hg

CO2  45 mm Hg

CO2  45 mm Hg

CO2  40 mm Hg

Mixed venous blood 0

Decreasing VA/QC

Normal

Increasing VA/QC



Inspired air

· · · · The effect of changes in the ventilation–perfusion ratio on the alveolar PO2 and PCO2. A) Normal VA / QC. B) VA / QC = 0. · · C) VA / QC is infinite. Curved arrows denote direction of blood flow. (Modified with permission from West JB. Ventilation/Blood Flow and Gas Exchange. 5th ed.

FIGURE 35–1

Oxford: Blackwell; 1990.)

Units B and C represent the two extremes of a continuum of ventilation–perfusion ratios. The V· /Q· ratio of a particular alveolar–capillary unit can fall anywhere along this continuum, as shown at the bottom of Figure 35–1. The alveolar Po2 and Pco2 of such units will therefore fall between the two extremes shown in the figure: units with low V· /Q· ratios will have relatively low Po2 and high Pco2; units with high V·/Q· ratios will have relatively high Po2 and low Pco2. This is demonstrated graphi-

• •

Shunt [V/Q = 0] Alveolar PO2 = Venous PO2 = 40 50

• •

Decreasing V/Q

40 Alveolar PCO2 (mm Hg)

Po2 will therefore increase, and alveolar Pco2 will decrease. If the V·/Q· in an alveolar–capillary unit decreases, the removal of oxygen relative to its delivery will increase and the delivery of carbon dioxide relative to its removal will increase. Alveolar Po2 will therefore decrease, and alveolar Pco2 will increase. Figure 35–1 shows the consequences of alterations in the relationship of ventilation and perfusion on hypothetical alveolar– capillary units. Unit A has a normal V·/Q· . Inspired air enters the alveolus with a Po2 of about 150 mm Hg and a Pco2 of nearly 0 mm Hg. Mixed venous blood enters the pulmonary capillary with a Po2 of about 40 mm Hg and a Pco2 of about 45 mm Hg. This results in an alveolar Po2 of about 100 mm Hg and an alveolar Pco2 of 40 mm Hg. The partial pressure gradient for oxygen diffusion from alveolus to pulmonary capillary is thus about 100 – 40, or 60 mm Hg; the partial pressure gradient for CO2 diffusion from pulmonary capillary to alveolus is about 45 – 40, or 5 mm Hg. The airway supplying unit B has become completely occluded. Its V· /Q· is zero. As time goes on, the air trapped in the alveolus equilibrates by diffusion with the gas dissolved in the mixed venous blood entering the alveolar–capillary unit. No gas exchange can occur, and any blood perfusing this alveolus will leave it exactly as it entered it. Unit B is therefore acting as a right-to-left shunt. The blood flow to unit C is blocked by a pulmonary embolus, and unit C is therefore completely unperfused. It has an infinite V·/Q· . Because no oxygen can diffuse from the alveolus into pulmonary capillary blood and because no carbon dioxide can enter the alveolus from the blood, the Po2 of the alveolus is approximately 150 mm Hg and its Pco2 is approximately zero; that is, the gas composition of this unperfused alveolus is the same as that of inspired air. Unit C is alveolar dead space. If unit C were unperfused because its alveolar pressure exceeded its precapillary pressure (rather than because of an embolus), then it would also correspond to part of zone 1, as discussed in Chapter 34.

Normal values PO2 = 100 PCO2 = 40

30 Increasing • • V/Q

20

10

• •

Deadspace [V/Q = ∞] Alveolar PO2 = inspired PO2 = 150

0 0 10 20 30 40 50 60 70 80 90 100 110120 130 140 150

Alveolar PO2 (mm Hg)

FIGURE 35–2 The ventilation–perfusion ratio line on an · · O2–CO2 diagram. Unit with a VA / QC of zero has the PO2 and PCO2 of · · mixed venous blood; a unit with an infinite VA / QC has the PO2 and PCO2 of inspired air. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

CHAPTER 35 Ventilation–Perfusion Relationships and Respiratory Gas Exchange cally in an O2–CO2 diagram such as that seen in Figure 35–2. The diagram shows the results of mathematical calculations of alveolar Po2 and Pco2 for V· /Q· ratios between zero (for mixed venous blood) and infinity (for inspired air). The resulting curve is known as the ventilation–perfusion ratio line. This simple O2–CO2 diagram can be modified to include correction lines for other factors, such as the respiratory exchange ratios of the alveoli and the blood or the dead space. The position of the V· /Q· ratio line is altered if the partial pressures of the inspired gas or mixed venous blood are altered.

TESTING FOR MISMATCHED VENTILATION & PERFUSION Several methods can demonstrate the presence or location of areas of the lung with mismatched ventilation and perfusion. These methods include calculations of the physiologic shunt, and the physiologic dead space, differences between the alveolar and arterial Po2 and Pco2, and lung scans after inhaled and intravenously administered 133Xe or 99mTc.

Physiologic Shunts and the Shunt Equation A right-to-left shunt is the mixing of venous blood that has not been oxygenated (or not fully oxygenated) into the arterial blood. The physiologic shunt, which corresponds to the physiologic dead space, consists of the anatomic shunts plus the intrapulmonary shunts. The intrapulmonary shunts can be absolute shunts, or they can be “shuntlike states,” that is, areas of low ventilation–perfusion ratios in which alveoli are underventilated and/or overperfused. Anatomic shunts consist of systemic venous blood entering the left ventricle without having entered the pulmonary vasculature. In a healthy adult, about 2–5% of the cardiac output, including venous blood from the bronchial veins, the thebesian veins, and the pleural veins, enters the left side of the circulation directly without passing through the pulmonary capillaries. Pathologic anatomic shunts such as right-to-left intracardiac shunts can also occur. Mixed venous blood perfusing pulmonary capillaries associated with totally unventilated or collapsed alveoli constitutes an absolute shunt (like the anatomic shunts) because no gas exchange occurs as the blood passes through the lung. Alveolar– capillary units with low V·a / Q·c also act to lower the arterial oxygen content because blood draining these units has a lower Po2 than blood from units with well-matched ventilation and perfusion. Increasing the percentage of inspired oxygen (FIO2) does not significantly increase the arterial Po2 of patients with absolute intrapulmonary shunts or “shuntlike areas” because the pulmonary capillary blood that flows to unventilated or very poorly ventilated alveoli is not exposed to alveolar air. The shunt equation conceptually divides all alveolar– capillary units into two groups: those with well-matched ventilation and perfusion and those with ventilation– perfusion ratios of zero. Thus, the shunt equation combines

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the areas of absolute shunt (including the anatomic shunts) and the shuntlike areas into a single conceptual group. The resulting ratio of shunt flow to the cardiac output, often referred to as the venous admixture, is the part of the cardiac output that would have to be perfusing absolutely unventilated alveoli to cause the systemic arterial oxygen content obtained from a patient. A much larger portion of the cardiac output could be overperfusing poorly ventilated alveoli and yields the same ratio: Q· s _______ Ccʹ –Ca __ = o2 o2 Q· t Ccʹo2 –C –V o2

(1)

where Q·t represents the total pulmonary blood flow per minute (i.e., the cardiac output), Q· S represents the amount of blood flow per minute entering the systemic arterial blood without receiving any oxygen (the “shunt flow”), Cao2 equals oxygen content of arterial blood (see Chapter 36) in milliliters of oxygen per 100 mL of blood, and C–V o and Ccʹo equal the oxygen content of the mixed venous blood and the end-capillary oxygen content (the oxygen content in the blood at the end of the ventilated and perfused pulmonary capillaries), respectively. The shunt fraction is usually multiplied by 100% so that the shunt flow is expressed as a percentage of the cardiac output. The arterial and mixed venous oxygen contents can be determined if blood samples are obtained from a systemic artery and from the pulmonary artery (for mixed venous blood), but the oxygen content of the blood at the end of the pulmonary capillaries with well-matched ventilation and perfusion is, of course, impossible to measure directly. This must be calculated from the alveolar air equation and the patient’s hemoglobin concentration. 2

2

Physiologic Dead Space The use of the Bohr equation to determine the physiologic dead space was discussed in Chapter 33. If the anatomic dead space is subtracted from the physiologic dead space, the result (if there is a difference) is alveolar dead space, or areas of infinite V· /Q·. Alveolar dead space also results in an arterial– alveolar CO2 difference (or arterial–end-tidal CO2 difference), that is, the end-tidal Pco2 is normally equal to the arterial Pco2. An arterial Pco2 greater than the end-tidal Pco2 usually indicates the presence of alveolar dead space.

ALVEOLAR–ARTERIAL OXYGEN DIFFERENCE The alveolar and arterial Po2 are often treated as though they are equal. However, the arterial Po2 is usually a few mm Hg less than the alveolar Do2. This normal alveolar–arterial oxygen difference, the (A –a)Do2, is caused by the normal anatomic shunt, some degree of ventilation–perfusion mismatch (see later in this chapter), and diffusion limitation in some parts of the lung. Of these, V· /Q· mismatch is usually the most important, with a small contribution from shunts and very little from diffusion

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TABLE 35–1 Causes of increased alveolar–arterial oxygen difference. Increased right-to-left shunt Anatomic Intrapulmonary

average alveolar Po2 that represents what alveolar Po2 should be, not necessarily what it is.

REGIONAL DIFFERENCES IN VENTILATION–PERFUSION RATIOS AND THEIR CONSEQUENCES

Increased ventilation–perfusion mismatch Impaired diffusion Increased inspired partial pressure of oxygen Decreased mixed venous partial pressure of oxygen Shift of oxyhemoglobin dissociation curve Adapted with permission from Marshall BE, Wyche MQ, Jr. Hypoxemia during and after anesthesia. Anesthesiology. 1972;37(2):178–209.

limitation. Larger-than-normal differences between the alveolar and arterial Po2 may indicate significant ventilation–perfusion mismatch; however, increased alveolar–arterial oxygen differences (Table 35–1) can also be caused by anatomic or intrapulmonary shunts, diffusion block, low mixed venous Po2, breathing higher-than-normal oxygen concentrations, or shifts of the oxyhemoglobin dissociation curve (also see Table 37–7). The alveolar–arterial Po2 difference is normally about 5–15 mm Hg in a young healthy person breathing room air at sea level. It increases with age because of the progressive decrease in arterial Po2 that occurs with aging (Chapter 73). The normal alveolar–arterial Po2 difference increases by about 20 mm Hg between the ages of 20 and 70. Note that the “alveolar” Po2 used in determining the alveolar–arterial oxygen difference is the PAo calculated using the alveolar air equation. As noted in Chapter 33, it is an idealized 2

The regional variations in ventilation in the normal upright lung were discussed in Chapter 33. They are summarized on the left side of Figure 35–3. The right side of Figure 35–3 shows that the more gravity-dependent regions of the lung also receive more blood flow per unit volume than do the upper regions of the lung, as discussed in Chapter 34.

REGIONAL DIFFERENCES IN THE VENTILATION–PERFUSION RATIOS IN THE UPRIGHT LUNG Simplified graphs of the gradients of ventilation and perfusion from the bottom to the top of normal upright lungs are shown plotted on the same axes in Figure 35–4. The ventilation– perfusion ratio was then calculated for several locations. Figure 35–4 shows that even though the lower regions of the lung receive both better ventilation and better perfusion than do the upper portions of the lung, the gradient of perfusion from the bottom of the lung to the top is greater than the gradient of ventilation. Because of this, the ventilation–perfusion

Ventilation Intrapleural pressure more negative Greater transmural pressure gradient Alveoli larger, less compliant Less ventilation

FIGURE 35–3

Summary of regional differences in ventilation (left) and perfusion (right) in the normal upright lung. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

Intrapleural pressure less negative Smaller transmural pressure gradient Alveoli smaller, more compliant More ventilation

Perfusion Lower intravascular pressures Less recruitment, distention Higher resistance Less blood flow

Greater vascular pressures More recruitment, distention Lower resistance Greater blood flow

CHAPTER 35 Ventilation–Perfusion Relationships and Respiratory Gas Exchange

3.0 • •

V/Q Perfusion

V/Q ratio

Ventilation or perfusion

2.0

• •

Ventilation

1.0 • •

Low V/Q at lung bases

physiologic P(A–a)O2 gradient

0 Base

Distance up the lung (from base to apex)

Apex

FIGURE 35–4 Distribution of ventilation and perfusion and ventilation–perfusion ratio down the upright lung. (Reproduced with permission from Kibble J, Halsey CR: The Big Picture, Medical Physiology. New York: McGraw-Hill, 2009.)

ratio is relatively low in more gravity-dependent regions of the lung and higher in upper regions of the lung. The effects of the regional differences in V· /Q· on the alveolar Po2 and Pco2 can be predicted from Figure 35–2: the upper regions should have a relatively high Po2 and a low Pco2; the lower regions should have a relatively low Po2 and a high Pco2. This means that the oxygen content of the blood draining the upper regions is higher and the carbon dioxide content is lower than that of the blood draining the lower regions. However, these contents are based on milliliters of blood (see Chapter 36), and there is much less blood flow to the uppermost sections than there is to the bottom sections. Therefore, even though the uppermost sections have the highest V·/Q· and Po2 and the lowest Pco2, there is more gas exchange in the more basal sections.

DIFFUSION OF GASES Diffusion of a gas occurs when there is a net movement of molecules from an area in which that particular gas exerts a high partial pressure to an area in which it exerts a lower partial pressure. Movement of a gas by diffusion is therefore different from the movement of gases through the conducting airways, which occurs by “bulk flow” (mass movement or convection). In bulk flow, gas movement results from differences in total pressure, and molecules of different gases move together along the total pressure gradient. In diffusion, each of the different gases moves according to its own individual partial pressure gradient. Gas transfer during diffusion occurs by random molecular movement. It is therefore dependent on temperature because molecular movement increases at higher

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temperatures. Gases move in both directions during diffusion, but the area of higher partial pressure, because of its greater number of molecules per unit volume, has proportionately more random “departures.” Thus, the net movement of gas is dependent on the partial pressure difference between the two areas. In a static situation, diffusion continues until no partial pressure differences exist for any gases in the two areas; in the lungs, oxygen and carbon dioxide continuously enter and leave the alveoli, so such an equilibrium does not take place.

FICK’S LAW FOR DIFFUSION Oxygen is brought into the alveoli by bulk flow through the conducting airways. When air flows through the conducting airways during inspiration, the linear velocity of the bulk flow decreases as the air approaches the alveoli. This is because the total cross-sectional area increases dramatically in the distal portions of the tracheobronchial tree. By the time the air reaches the alveoli, bulk flow probably ceases, and further gas movement occurs by diffusion. Oxygen then moves through the gas phase in the alveoli according to its own partial pressure gradient. The distance from the alveolar duct to the alveolar–capillary interface is usually less than 1 mm. Oxygen then diffuses through the alveolar–capillary interface. It must first, therefore, move from the gas phase to the liquid phase, according to Henry’s law, which states that the amount of a gas absorbed by a liquid with which it does not combine chemically is directly proportional to the partial pressure of the gas to which the liquid is exposed and the solubility of the gas in the liquid. Oxygen must dissolve in and diffuse through the thin layer of pulmonary surfactant, the alveolar epithelium, the interstitium, and the capillary endothelium, as was shown in Figure 31–6 (step 2, near the arrow). It must then diffuse through the plasma (step 3), where some remains dissolved and the majority enters the erythrocyte and combines with hemoglobin (step 4). The blood then carries the oxygen out of the lung by bulk flow and distributes it to the other tissues of the body, as was shown in Figure 31–1. At the tissues, oxygen diffuses from the erythrocyte through the plasma, capillary endothelium, interstitium, tissue cell membrane, and cell interior and into the mitochondrial membrane. The process is almost entirely reversed for carbon dioxide. The factors that determine the rate of diffusion of gas through the alveolar–capillary barrier are described by Fick’s law for diffusion, shown as follows in a simplified form: AD(P1 – P2) V·gas = _________ T

(2)

where V· gas is the volume of gas diffusing through the tissue barrier per time (mL/min), A the surface area of the barrier available for diffusion, D the diffusion coefficient, or diffusivity, of the particular gas in the barrier, T the thickness of the barrier or the diffusion distance, and P1 – P2 the partial pressure difference of the gas across the barrier. That is, the volume of gas per unit of time moving across the alveolar–capillary barrier is directly proportional to the area of

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the barrier, the diffusivity, and the difference in concentration between the two sides, but is inversely proportional to the barrier thickness. The surface area of the blood–gas barrier is believed to be at least 70 m2 in a healthy average-sized adult at rest. That is, about 70 m2 of the potential surface area is both ventilated and perfused at rest. If more capillaries are recruited, as in exercise, the surface area available for diffusion increases; if venous return decreases, for example, because of hemorrhage, or if alveolar pressure is increased by positive-pressure ventilation, then capillaries may be derecruited and the surface area available for diffusion may decrease. The thickness of the alveolar–capillary diffusion barrier is only about 0.2–0.5 μm. This barrier thickness can increase in interstitial fibrosis or interstitial edema, thus interfering with diffusion. Diffusion probably increases at higher lung volumes because as alveoli are stretched, the diffusion distance decreases slightly (and also because small airways subject to closure may be open at higher lung volumes). The diffusivity, or diffusion constant, for a gas is directly proportional to the solubility of the gas in the diffusion barrier and is inversely proportional to the square root of the molecular weight (MW) of the gas: Solubility √MW

____ D α _______

through the alveolar–capillary barrier before carbon dioxide retention due to diffusion impairment occurs. The factors that limit the movement of a gas through the alveolar–capillary barrier, as described by Fick’s law for diffusion, can be arbitrarily divided into three components: the diffusion coefficient, the surface area and thickness of the alveolar–capillary membrane, and the partial pressure gradient across the barrier for each particular gas. The diffusion coefficient, as discussed in the previous section, is dependent on the physical properties of the gases and the alveolar– capillary membrane. The surface area and thickness of the membrane are physical properties of the barrier, but they can be altered by changes in the pulmonary capillary blood volume, the cardiac output or the pulmonary artery pressure, or changes in lung volume. The partial pressure gradient of a gas (across the barrier) is the final major determinant of its rate of diffusion. The partial pressure of a gas in the mixed venous blood and in the pulmonary capillaries is just as important a factor as its alveolar partial pressure in determining its rate of diffusion.

Diffusion Limitation An erythrocyte and its attendant plasma spend an average of about 0.75–1.2 seconds inside the pulmonary capillaries at resting cardiac outputs. Figure 35–5 shows the calculated change with time in the partial pressures in the blood of three gases: oxygen, carbon monoxide, and nitrous oxide. These are shown in comparison to the alveolar partial pressures for each gas, as indicated by the dotted line. This alveolar partial pressure is different for each of the three gases, and it depends on its concentration in the inspired gas mixture and on how rap-

(3)

Because oxygen is less dense than carbon dioxide, it should diffuse 1.2 times as fast as carbon dioxide, but the solubility of carbon dioxide in the liquid phase is about 24 times that of oxygen, so carbon dioxide diffuses 20 times more rapidly through the alveolar–capillary barrier than does oxygen. For this reason, patients develop problems in oxygen diffusion

Alveolar partial pressure

FIGURE 35–5 Calculated changes in the partial pressures of carbon monoxide, nitrous oxide, and oxygen in the blood as it passes through a functional pulmonary capillary. There are no units on the ordinate because the scale is different for each of the three gases, depending on the alveolar partial pressure of each gas. The abscissa is in seconds, indicating the time the blood has spent in the capillary. At resting cardiac outputs, blood spends an average of 0.75 of a second in a pulmonary capillary. The alveolar partial pressure of each gas is indicated by the dotted line. Note that the partial pressures of nitrous oxide and oxygen equilibrate rapidly with their alveolar partial pressure. (Modified with permission from Comroe JH: The

Partial pressure in plasma

N2O

O2

CO 0

0

0.25

0.50 Time in capillary (s)

0.75

Lung; Clinical Physiology and Pulmonary Function Tests, 2nd ed. Chicago: Year Book Medical Publishers, 1962.)

Enter capillary

Leave capillary

CHAPTER 35 Ventilation–Perfusion Relationships and Respiratory Gas Exchange idly it is removed by the pulmonary capillary blood. The schematic is drawn as though all three gases were administered simultaneously, but this is not necessarily the case. Consider each gas as though it were acting independently of the others. The partial pressure of carbon monoxide in the pulmonary capillary blood rises very slowly compared with that of the other two gases in the figure if a low inspired concentration of carbon monoxide is used for a very short time. However, if the content of carbon monoxide (in milliliters of carbon monoxide per milliliter of blood) were measured simultaneously, it would be rising very rapidly. The reason for this rapid rise is that carbon monoxide combines chemically with the hemoglobin in the erythrocytes. The affinity of carbon monoxide for hemoglobin is about 210 times that of oxygen for hemoglobin. The carbon monoxide that is chemically combined with hemoglobin does not contribute to the partial pressure of carbon monoxide in the blood because it is no longer physically dissolved in it. Therefore, the partial pressure of carbon monoxide in the pulmonary capillary blood does not come close to the partial pressure of carbon monoxide in the alveoli during the time that the blood is exposed to the alveolar carbon monoxide. The partial pressure gradient across the alveolar–capillary barrier for carbon monoxide is thus well maintained for the entire time the blood spends in the pulmonary capillary. The diffusion of carbon monoxide is therefore limited only by its diffusivity in the barrier and by the surface area and thickness of the barrier. Carbon monoxide transfer from the alveolus to the pulmonary capillary blood is referred to as diffusion-limited rather than perfusion-limited.

Perfusion Limitation The partial pressure of nitrous oxide in the pulmonary capillary blood equilibrates very rapidly with the partial pressure of nitrous oxide in the alveolus because nitrous oxide moves through the alveolar–capillary barrier very easily and because it does not combine chemically with the hemoglobin in the erythrocytes. After only about 0.1 of a second of exposure of the pulmonary capillary blood to the alveolar nitrous oxide, the partial pressure gradient across the alveolar–capillary barrier has been abolished. From this point on, no further nitrous oxide transfer occurs from the alveolus to the blood in the capillary that has already equilibrated with the alveolar nitrous oxide partial pressure; during the last 0.6–0.7 of a second, no net diffusion occurs between the alveolus and the blood as it travels through the pulmonary capillary. Blood just entering the capillary at the arterial end will not be equilibrated with the alveolar partial pressure of nitrous oxide, so nitrous oxide can diffuse into the blood at the arterial end. The transfer of nitrous oxide is therefore perfusion-limited. Nitrous oxide transfer from a particular alveolus to one of its pulmonary capillaries can be increased by increasing the cardiac output and thus reducing the amount of time the blood stays in the pulmonary capillary after equilibration with the alveolar partial pressure of nitrous oxide has occurred. (Because increasing the cardiac output may recruit previously unperfused capillaries, the total

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diffusion of both carbon monoxide and nitrous oxide may increase as the surface area for diffusion increases.)

Diffusion of Oxygen As can be seen in Figure 35–5, the time course for oxygen transfer falls between those for carbon monoxide and nitrous oxide. The partial pressure of oxygen rises fairly rapidly (it starts at the Po2 of the mixed venous blood, about 40 mm Hg, rather than at zero), and equilibration with the alveolar Po2 of about 100 mm Hg occurs within about 0.25 of a second, or about one third of the time the blood is in the pulmonary capillary at typical resting cardiac outputs. Oxygen moves easily through the alveolar– capillary barrier and into the erythrocytes, where it combines chemically with hemoglobin. The partial pressure of oxygen rises more rapidly than the partial pressure of carbon monoxide. Nonetheless, the oxygen chemically bound to hemoglobin (and therefore no longer physically dissolved) exerts no partial pressure, so the partial pressure gradient across the alveolar– capillary membrane is initially well maintained and oxygen transfer occurs. The chemical combination of oxygen and hemoglobin, however, occurs rapidly (within hundredths of a second), and at the normal alveolar partial pressure of oxygen, the hemoglobin becomes nearly saturated with oxygen very quickly, as will be discussed in the next chapter. As this happens, the partial pressure of oxygen in the blood rises rapidly to that in the alveolus, and from that point, no further oxygen transfer from the alveolus to the equilibrated blood can occur. Therefore, under the conditions of normal alveolar Po2 and resting cardiac output, oxygen transfer from alveolus to pulmonary capillary is perfusion-limited. During exercise, blood moves through the pulmonary capillary much more rapidly than it does at resting cardiac outputs. In fact, the blood may stay in the pulmonary capillary an average of only about 0.25 of a second during strenuous exercise. Oxygen transfer into the blood per time will be greatly increased because there is little or no perfusion limitation of oxygen transfer. (Indeed, that part of the blood that stays in the capillary less than the average may be subjected to diffusion limitation of oxygen transfer.) Of course, total oxygen transfer is also increased during exercise because of recruitment of previously unperfused capillaries, which increases the surface area for diffusion, and because of better matching of ventilation and perfusion. A person with an abnormal alveolar–capillary barrier due to a fibrotic thickening or interstitial edema may approach diffusion limitation of oxygen transfer at rest and may have a serious diffusion limitation of oxygen transfer during strenuous exercise. A person with an extremely abnormal alveolar–capillary barrier might have diffusion limitation of oxygen transfer even at rest.

Diffusion of Carbon Dioxide The equilibration of the partial pressure of carbon dioxide in the pulmonary capillary blood with that of the alveolus in a healthy person with a mixed venous partial pressure of carbon dioxide of 45 mm Hg and an alveolar partial pressure of

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carbon dioxide of 40 mm Hg is about 0.25 of a second, or about the same as that for oxygen. This may seem surprising, considering that the diffusivity of carbon dioxide is about 20 times that of oxygen, but the partial pressure gradient is normally only about 5 mm Hg for carbon dioxide, whereas it is about 60 mm Hg for oxygen. Carbon dioxide transfer is therefore also normally perfusion-limited, although it may be diffusion-limited in a person with an abnormal alveolar– capillary barrier.

MEASUREMENT OF DIFFUSING CAPACITY It is often useful to determine the diffusion characteristics of a patient’s lungs during their assessment in the pulmonary function laboratory. It may be particularly important to determine whether an apparent impairment in diffusion is a result of perfusion limitation or diffusion limitation. The diffusing capacity is the rate at which oxygen or carbon monoxide is absorbed from the alveolar gas into the pulmonary capillaries (in milliliters per minute) per unit of partial pressure gradient (in millimeters of mercury). It is usually measured with very low concentrations of carbon monoxide because carbon monoxide transfer from alveolus to capillary is diffusion-limited as was discussed previously in this chapter. The mean partial pressure of oxygen or carbon monoxide is, as already discussed, affected by their chemical reactions with hemoglobin, as well as by their transfer through the alveolar– capillary barrier. For this reason, the diffusing capacity of the lung is influenced by both the diffusing capacity of the membrane and the reaction with hemoglobin. The amount of hemoglobin in the lung is dependent on the hemoglobin concentration in the blood and the amount of blood in the pulmonary capillaries—the pulmonary capillary blood volume. Diffusion through the alveolus is normally very rapid and usually can be disregarded, although it could be a major factor in a person with pulmonary edema. Several different methods are used clinically to measure the carbon monoxide diffusing capacity (the DLCO) and involve both single-breath and steady-state techniques, sometimes during exercise. The DLCO is decreased in diseases associated with interstitial or alveolar fibrosis, such as sarcoidosis, scleroderma, and asbestosis, or with conditions causing interstitial or alveolar pulmonary edema, as indicated in Table 35–2. It is also decreased in conditions causing a decrease in the surface area available for diffusion, such as emphysema, tumors, a low cardiac output, or a low pulmonary capillary blood volume, as well as in conditions leading to ventilation–perfusion mismatch, which effectively decreases the surface area available for diffusion. The carbon monoxide diffusing capacity can be very useful in assessing patients with chronic obstructive pulmonary disease (COPD). A low DLCO distinguishes patients whose disorder is primarily emphysema from those whose disorder is primarily chronic bronchitis. The DLCO can also be helpful in assessing patients with restrictive diseases.

TABLE 35–2 Conditions that decrease the diffusing capacity. Thickening of the barrier Interstitial or alveolar edema Interstitial or alveolar fibrosis Sarcoidosis Scleroderma Decreased surface area Emphysema Tumors Low cardiac output Low pulmonary capillary blood volume Decreased uptake by erythrocytes Anemia Low pulmonary capillary blood volume Ventilation–perfusion mismatch Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.

CLINICAL CORRELATION A 40-year-old man with a broken leg in a cast because of a skiing injury and no history of respiratory problems suddenly has difficulty breathing and complains of chest pain. He is brought to the hospital. In the emergency department, his breathing is observed to be rapid and shallow. His heart rate is 120/min and his arterial blood pressure is 80/60 mm Hg. His respiratory rate is 25/min. A chest x-ray and an electrocardiogram (ECG) are performed on the patient to help determine the cause of his chest pain and dyspnea. The ECG shows no abnormalities indicative of myocardial ischemia (insufficient blood flow to the heart muscle) or myocardial infarction (injury of the heart muscle) such as ST segment or T-wave abnormalities (see Chapter 23). The chest x-ray shows no abnormalities indicative of pneumonia, atelectasis (collapsed alveoli), or pneumothorax (air between the inside of the chest wall and the outside of the lung). An arterial blood sample is obtained from the patient while he was breathing room air to determine his arterial blood gases (arterial Po2, arterial Pco2, and arterial pH). His arterial Po2 was 70 mm Hg (normal >90); his arterial Pco2 was 30 mm Hg (normal range is 35–45); his pH was 7.50 (normal range is 7.35–7.45). The patient has a pulmonary embolus, most likely as a result of blood clotting in his immobilized leg. Flow of venous blood in the broken leg is impaired by the cast and the lack of muscle contraction to enhance venous return from his leg to his heart. Stasis (low or absent flow) of blood often leads to clotting (thrombosis). When thrombosis occurs in nonsuperficial veins such as those in the leg, it is called deep venous thrombosis (DVT). The thrombus can break loose and be carried to the right side of the heart and enter the pulmonary arterial tree,

CHAPTER 35 Ventilation–Perfusion Relationships and Respiratory Gas Exchange

where it can block blood flow to part of the lung. This is called a pulmonary embolus, in this case a thromboembolus. Pulmonary emboli can be life-threatening if they occlude a significant fraction of the pulmonary vascular bed. The region of the lung with occluded blood flow creates alveolar dead space (ventilated but not perfused) that contributes nothing to gas exchange. The patient’s end-tidal Pco2 decreases because it contains air coming from unperfused alveoli that contribute no carbon dioxide to the exhaled air. The arterial Pco2 is therefore greater than the end-tidal (“alveolar”) Pco2. The diffusing capacity of the patient is decreased because of decreased surface area for gas exchange. Occlusion of pulmonary vessels is likely to increase pulmonary vascular resistance, increase pulmonary artery pressure, and increase right ventricular work. Blood flow to the left side of the patient’s heart decreases, which explains his low systemic blood pressure. His tachycardia is likely a result of the response of his baroreceptor reflex to his low blood pressure, and the pain and anxiety he is experiencing. His tachypnea is explained by the influence of receptors in his lungs (which will be described in Chapter 38) and the pain and anxiety. The tachypnea resulted in hyperventilation causing his arterial Pco2 to decrease below the normal range and his arterial pH to exceed the normal range (see discussion of uncompensated respiratory alkalosis in Chapter 37). His low arterial Po2 is a result of the occlusion of pulmonary vessels forcing blood flow to poorly ventilated alveoli. Treatment of patients with pulmonary emboli (sometimes called pulmonary embolism) depends on the severity of the disorder. Anticoagulants are used to prevent further clotting, thrombolytic drugs are used to break clots down, intravenous catheters with deployable filters can be used to remove the emboli, and large life-threatening emboli may be removed surgically (embolectomy).

CHAPTER SUMMARY ■ ■

■

■

Ventilation and perfusion must be matched on the alveolar– capillary level for optimal gas exchange. Ventilation–perfusion ratios close to 1.0 result in alveolar Po2 of approximately 100 mm Hg and Pco2 close to 40 mm Hg; ventilation–perfusion ratios greater than 1.0 increase the Po2 and decrease the Pco2; ventilation–perfusion ratios less than 1.0 decrease the Po2 and increase the Pco2. Alveolar dead space and intrapulmonary shunt represent the two extremes of ventilation–perfusion ratios, infinite and zero, respectively. The ventilation–perfusion ratios in lower regions of the normal upright lung are lower than 1.0, resulting in lower Po2 and higher Pco2; the ventilation–perfusion ratios in upper parts of the lung are greater than 1.0, resulting in higher Po2 and lower

■

■

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Pco2; nonetheless, there is normally more gas exchange in lower regions of the lung because they receive more blood flow. The volume of gas per unit of time moving across the alveolar–capillary barrier is directly proportional to the area of the barrier, the diffusivity of the gas in the barrier, and the difference in concentration of the gas between the two sides of the barrier, but is inversely proportional to the barrier thickness. If the partial pressure of a gas in the plasma equilibrates with the alveolar partial pressure of the gas within the amount of time the blood is in the pulmonary capillary, its transfer is perfusion-limited; if equilibration does not occur within the time the blood is in the capillary, its transfer is diffusion-limited.

STUDY QUESTIONS 1. An otherwise normal person is brought to the emergency department after having accidentally aspirated a foreign body into the right main-stem bronchus, partially occluding it. Which of the following is/are likely to occur? A) The right lung’s alveolar Po2 will be lower and its alveolar Pco will be higher than those of the left lung. 2 B) The calculated shunt fraction will increase. C) Blood flow to the right lung will decrease. D) The arterial Po2 will decrease. E) All of the above. 2. A healthy person lies down on her right side and breathes normally. Her right lung, in comparison to her left lung, will be expected to have a A) lower alveolar Po2 and a higher alveolar Pco2. B) lower blood flow per unit volume. C) less ventilation per unit volume. D) higher ventilation–perfusion ratio. E) larger alveoli. 3. Which of the following conditions or circumstances is expected to increase the diffusing capacity (DL) of the lungs? A) changing from the supine to the upright position B) exercise C) emphysema D) anemia E) low cardiac output due to blood loss F) diffuse interstitial fibrosis of the lungs 4. If the pulmonary capillary partial pressure of a gas equilibrates with that in the alveolus before the blood leaves the capillary (assume the gas is diffusing from the alveolus to the pulmonary capillary) A) its transfer is said to be perfusion-limited. B) its transfer is said to be diffusion-limited. C) increasing the cardiac output will not increase the amount of the gas diffusing across the alveolar–capillary barrier. D) increasing the alveolar partial pressure of the gas will not increase the amount of the gas diffusing across the alveolar–capillary barrier. E) recruiting additional pulmonary capillaries will not increase the amount of the gas diffusing across the alveolar–capillary barrier.

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36 C

Transport of Oxygen and Carbon Dioxide Michael Levitzky

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■

■ ■ ■ ■

State the relationship between the partial pressure of oxygen in the blood and the amount of oxygen physically dissolved in the blood. Describe the chemical combination of oxygen with hemoglobin and the oxyhemoglobin dissociation curve. Define hemoglobin saturation, oxygen-carrying capacity, and oxygen content. State the physiologic consequences of the shape of the oxyhemoglobin dissociation curve. List the physiologic factors that can influence the oxyhemoglobin dissociation curve, and predict their effects on oxygen transport by the blood. State the relationship between the partial pressure of carbon dioxide in the blood and the amount of carbon dioxide physically dissolved in the blood. Describe the transport of carbon dioxide as carbamino compounds with blood proteins. Explain how most of the carbon dioxide in the blood is transported as bicarbonate. Describe the carbon dioxide dissociation curve for whole blood.

TRANSPORT OF OXYGEN BY THE BLOOD Oxygen is transported both physically dissolved in blood and chemically combined to the hemoglobin in the erythrocytes. Much more oxygen is normally transported combined with hemoglobin than is physically dissolved in the blood. Without hemoglobin, the cardiovascular system could not supply sufficient oxygen to meet tissue demands.

PHYSICALLY DISSOLVED At a temperature of 37°C, 1 mL of plasma contains 0.00003mL O2/(mm Hg Po2). Whole blood contains a similar amount of dissolved oxygen per milliliter because oxygen dissolves in the fluid of the erythrocytes in about the same amount. Therefore,

Ch36_363-374.indd 363

normal arterial blood with a Po2 of approximately 100 mm Hg contains only about 0.003 mL O2/mL of blood, or 0.3 mL O2/100 mL of blood. (Blood oxygen content is conventionally expressed in milliliters of oxygen per 100 mL of blood, also called volume percent.) The physically dissolved oxygen in the blood therefore cannot meet the metabolic demand for oxygen, even at rest.

CHEMICALLY COMBINED WITH HEMOGLOBIN The Structure of Hemoglobin Hemoglobin is a complex molecule with a tetrameric structure consisting of four linked polypeptide chains (globin), each of which is attached to a protoporphyrin (heme) group. Each heme group has a ferrous (Fe2+) iron atom at its center 363

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and can bind a molecule of oxygen (or carbon monoxide), so the tetrameric hemoglobin molecule can combine chemically with four oxygen molecules (or eight oxygen atoms). Variations in the amino acid sequences of the four globin subunits may have important physiologic consequences. Normal adult hemoglobin (HbA) consists of two alpha (α) chains, each of which has 141 amino acids, and two beta (β) chains, each of which has 146 amino acids. Fetal hemoglobin (HbF), which consists of two α chains and two gamma (γ) chains, has a higher affinity for oxygen than does HbA. Synthesis of β chains normally begins about 6 weeks before birth, and HbA usually replaces almost all the HbF by the time an infant is 4 months old. Other, abnormal hemoglobin molecules may be produced by genetic substitution of a single amino acid for the normal one in an α or β chain or (rarely) by alterations in the structure of heme groups. These alterations may produce changes in the affinity of the hemoglobin for oxygen, change the physical properties of hemoglobin, or alter the interaction of hemoglobin and other substances that affect its combination with oxygen, such as 2,3-bisphosphoglycerate (2,3-BPG) (discussed later in this chapter). More than 120 abnormal variants of normal HbA have been demonstrated in patients. The best known of these, hemoglobin S, is present in sickle cell disease. Hemoglobin S tends to polymerize and crystallize in the cytosol of the erythrocyte when it is not combined with oxygen. This polymerization and crystallization decreases the solubility of hemoglobin S within the erythrocyte and changes the shape of the cell from the normal biconcave disk to a crescent or “sickle” shape. A sickled cell is more fragile than a normal cell. In addition, the cells have a tendency to stick to one another, which increases blood viscosity and also favors thrombosis or blockage of blood vessels.

Chemical Reaction of Oxygen and Hemoglobin Hemoglobin rapidly combines reversibly with oxygen. It is the reversibility of the reaction that allows oxygen to be released to the tissues; if the reaction did not proceed easily in both directions, hemoglobin would be of little use in delivering oxygen to satisfy metabolic needs. The reaction is very fast, with a half-time of 0.01 of a second or less. Each gram of hemoglobin is capable of combining with about 1.39 mL of oxygen under optimal conditions, but under normal circumstances, some hemoglobin exists in forms such as methemoglobin (in which the iron atom is in the ferric state) or is combined with carbon monoxide, in which case the hemoglobin cannot bind oxygen. For this reason, the oxygen-carrying capacity of hemoglobin is conventionally considered to be 1.34 mL O2/(g Hb), that is, each gram of hemoglobin, when fully saturated with oxygen, binds 1.34 mL of oxygen. Therefore, a person with 15 g Hb/ 100 mL of blood has an oxygen-carrying capacity of 20.1 mL O2/100 mL of blood: 1.34 mL O 20.1 mL O2 (1) 15 g Hb __________ × ________2 = __________ 100 mL blood

g Hb

100 mL blood

The reaction of hemoglobin and oxygen is conventionally written as follows: Hb + O2 Deoxyhemoglobin

HbO2 Oxyhemoglobin

(2)

HEMOGLOBIN AND THE PHYSIOLOGIC IMPLICATIONS OF THE OXYHEMOGLOBIN DISSOCIATION CURVE The equilibrium point of the reversible reaction of hemoglobin and oxygen is dependent on how much oxygen the hemoglobin in blood is exposed to. This corresponds directly to the partial pressure of oxygen (Po2) in the plasma under the conditions in the body. Thus, the Po2 of the plasma determines the amount of oxygen that binds to the hemoglobin in the erythrocytes.

THE OXYHEMOGLOBIN DISSOCIATION CURVE One way to express the proportion of oxygen that is bound to hemoglobin is as percent saturation. This is equal to the content of oxygen in the blood (minus that part physically dissolved) divided by the oxygen-carrying capacity of the hemoglobin in the blood times 100%: O bound to Hb O2 capacity of Hb

2 % Hb saturation = _____________ × 100%

(3)

Note that the oxygen-carrying capacity of an individual depends on the amount of hemoglobin in the blood. The blood oxygen content also depends on the amount of hemoglobin present (as well as on the Po2). Both content and capacity are expressed as milliliters of oxygen per 100 mL of blood. On the other hand, the percent hemoglobin saturation expresses only a percentage and not an amount or volume of oxygen; “percent saturation” is not interchangeable with “oxygen content.” For example, two patients might have the same percent of hemoglobin saturation, but if one has a lower blood hemoglobin concentration because of anemia, he or she will have a lower blood oxygen content. The relationship between the Po2 of the plasma and the percent of hemoglobin saturation can be expressed graphically as the oxyhemoglobin dissociation curve. An oxyhemoglobin dissociation curve for normal blood is shown in Figure 36–1. The oxyhemoglobin dissociation curve is really a plot of how the availability of one of the reactants, oxygen (expressed as the Po2 of the plasma), affects the reversible chemical reaction of oxygen and hemoglobin. The product, oxyhemoglobin, is expressed as percent saturation—really a percentage of the maximum for any given amount of hemoglobin. As can be seen in Figure 36–1, the relationship between Po2 and HbO2 is not linear; it is a sigmoid (S-shaped) curve, steep at the lower Po2 and nearly flat when the Po2 is above 70 mm Hg.

CHAPTER 36 Transport of Oxygen and Carbon Dioxide

365

Hemoglobin saturation ( %)

100

80

60 50% 40

20 0 20

0

40

60

80

100

120

140

160

P50 Partial pressure of oxygen (mm Hg)

FIGURE 36–1 A typical “normal” adult oxyhemoglobin dissociation curve for blood at 37°C with a pH of 7.40 and a PCO2 of 40 mm Hg. The P50 is the partial pressure of oxygen at which hemoglobin is 50% saturated with oxygen. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

It is this S shape that is responsible for several very important physiologic properties of the reaction of oxygen and hemoglobin. The reason that the curve is S-shaped and not linear is that it is actually a plot of four reactions rather than one, that is, each of the four subunits of hemoglobin can combine with one molecule of oxygen. The reactions of the four subunits of hemoglobin with oxygen do not occur simultaneously. Instead they occur sequentially in four steps, with an interaction between the subunits occurring in such a way that during the successive combinations of the subunits with oxygen, each combination facilitates the next. Similarly, dissociation of oxygen from hemoglobin subunits facilitates further dissociations. The dissociation curve for a single monomer of hemoglobin is far different from that for the tetramer (see Figure 36–4C).

Loading Oxygen in the Lung Mixed venous blood entering the pulmonary capillaries normally has a Po2 of about 40 mm Hg. At a Po2 of 40 mm Hg, hemoglobin is about 75% saturated with oxygen, as seen in Figure 36–1. Assuming a blood hemoglobin concentration of 15 g Hb/100 mL of blood, this corresponds to 15.08 mL O2/100 mL of blood bound to hemoglobin plus an additional 0.12 mL O2/100 mL of blood physically dissolved, or a total oxygen content of approximately 15.2 mL O2/100 mL of blood. Oxygen-carrying capacity is given as follows: 1.34 mL O 20.1 mL O2 15 g Hg __________ × ________2 = __________ 100 mL blood g Hb 100 mL blood

(4)

Oxygen bound to hemoglobin at a Po2 of 40 mm Hg (37°C, pH 7.4) is given as follows: 20.1 mL O2 __________ × 100 mL blood Capacity

75% % saturation

15.08 mL O2 = ___________ 100 mL blood Content

(5)

Oxygen physically dissolved at a Po2 of 40 mm Hg is given as follows: 0.003 mL O2 0.12 mL O2 ______________________ × 40 mm Hg = __________ (6) 100 mL blood Po2 (in mm Hg) 100 mL blood

Total blood oxygen content at a Po2 of 40 mm Hg (37°C, pH 7.4) is given as follows: 15.08 mL O2 __________ 100 mL blood Bound to Hb

0.12 mL O2 __________ 100 mL blood

+

=

Physically dissolved

15.2 mL O2 __________ 100 mL blood (7) Total

As the blood passes through the pulmonary capillaries, it equilibrates with the alveolar Po2 of about 100 mm Hg. At a Po2 of 100 mm Hg, hemoglobin is about 97.4% saturated with oxygen, as seen in Figure 36–1. This corresponds to 19.58 mL O2/100 mL of blood bound to hemoglobin plus 0.3 mL O2/100 mL of blood physically dissolved, or a total oxygen content of 19.88 mL O2/100 mL of blood. Oxygen bound to hemoglobin at a Po2 of 100 mm Hg (37°C, pH 7.4) is given as follows: 20.1 mL O2 ___________ × 100 mL blood Capacity

97.4%

19.58 mL O 100 mL blood

2 = __________

% saturation

(8)

Content

Oxygen physically dissolved at a Po2 of 100 mm Hg is given as follows: 0.003 mL O2 0.3 mL O2 ______________________ × 100 mm Hg = __________ (9) 100 mL blood Po2 (in mm Hg) 100 mL blood

Total blood oxygen content at a Po2 of 100 mm Hg (37°C, pH 7.4) is given as follows: 19.58 mL O2 __________ 100 mL blood Bound to Hb

+

0.3 mL O2 __________ 100 mL blood Physically dissolved

=

19.88 mL O2 __________ 100 mL blood (10) Total

Thus, in passing through the lungs, each 100 mL of blood has loaded (19.88 – 15.20) mL O2, or 4.68 mL O2. Assuming a

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cardiac output of 5 L/min, this means that approximately 234 mL O2 is loaded into the blood per minute: 46.8 mL O2 ________ 234 mL O 5 L blood ________ _______ × = min 2 min liter blood

(11)

Note that the oxyhemoglobin dissociation curve is relatively flat when Po2 is greater than approximately 70 mm Hg. This is very important physiologically because it means that there is only a small decrease in the oxygen content of blood equilibrated with a Po2 of 70 mm Hg instead of 100 mm Hg. In fact, the curve shows that at a Po2 of 70 mm Hg, hemoglobin is still approximately 94.1% saturated with oxygen. This constitutes an important safety factor because a patient with a relatively low alveolar or arterial Po2 of 70 mm Hg (owing to hypoventilation or intrapulmonary shunt, for example) is still able to load adequate oxygen into the blood. A quick calculation shows that at 70 mm Hg, the total blood oxygen content is approximately 19.12 mL O2/100 mL of blood compared with the 19.88 mL O2/100 mL of blood at a Po2 of 100 mm Hg. These calculations show that Po2 is often a more sensitive diagnostic indicator of the status of a patient’s respiratory system than the arterial oxygen content. Of course, the oxygen content is more important physiologically to the patient. Because hemoglobin is approximately 97.4% saturated at a Po2 of 100 mm Hg, increasing the alveolar Po2 above 100 mm Hg can add little additional oxygen to hemoglobin (only about 0.52 mL O2/100 mL of blood at a hemoglobin concentration of 15 g/100 mL of blood). Hemoglobin is fully saturated with oxygen at a Po2 of about 250 mm Hg.

Unloading Oxygen at the Tissues As blood passes from the arteries into the systemic capillaries, it is exposed to lower Po2 and oxygen is released by the hemoglobin. The Po2 in the capillaries varies from tissue to tissue, being very low in some (e.g., myocardium) and relatively higher in others (e.g., renal cortex). As can be seen in Figure 36–1, the oxyhemoglobin dissociation curve is very steep in the range of 40–10 mm Hg. This means that a small decrease in Po2 can result in a substantial further dissociation of oxygen and hemoglobin, unloading more oxygen for use by the tissues. At a Po2 of 40 mm Hg, hemoglobin is about 75% saturated with oxygen, with a total blood oxygen content of 15.2 mL O2/100 mL of blood (at 15 g Hb/100 mL of blood). At a Po2 of 20 mm Hg, hemoglobin is only 32% saturated with oxygen. The total blood oxygen content is only 6.49 mL O2/100 mL of blood, a decrease of 8.71 mL O2/100 mL of blood for only a 20-mm Hg decrease in Po2. The unloading of oxygen at the tissues is also facilitated by other physiologic factors that can alter the shape and position of the oxyhemoglobin dissociation curve. These include the pH, Pco2, temperature of the blood, and concentration of 2,3-BPG in the erythrocytes.

INFLUENCES ON THE OXYHEMOGLOBIN DISSOCIATION CURVE Figure 36–2 shows the influence of alterations in temperature, pH, Pco2, and 2,3-BPG on the oxyhemoglobin dissociation

curve. High temperature, low pH, high Pco2, and elevated levels of 2,3-BPG all shift the oxyhemoglobin dissociation curve to the right; that is, for any particular Po2, there is less oxygen chemically combined with hemoglobin at higher temperatures, lower pH, higher Pco2, and elevated levels of 2,3-BPG. The rightward shift represents a decreased affinity of hemoglobin for oxygen. The effects of blood pH and Pco2 on the oxyhemoglobin dissociation curve are shown in Figure 36–2A and B. Low pH and high Pco2 both shift the curve to the right. High pH and low Pco2 both shift the curve to the left. These two effects often occur together. The influence of pH (and Pco2) on the oxyhemoglobin dissociation curve is referred to as the Bohr effect. The Bohr effect will be discussed in greater detail at the end of this chapter. Figure 36–2C shows the effects of blood temperature on the oxyhemoglobin dissociation curve. High temperatures shift the curve to the right; low temperatures shift the curve to the left. At very low blood temperatures, hemoglobin has such a high affinity for oxygen that it does not release the oxygen, even at very low Po2. 2,3-BPG (also called 2,3-diphosphoglycerate, or 2,3-DPG) is produced by erythrocytes during their normal glycolysis and is present in fairly high concentrations within red blood cells (about 15 mmol/(g Hb)). 2,3-BPG binds to the hemoglobin in erythrocytes, which decreases the affinity of hemoglobin for oxygen. Higher concentrations of 2,3-BPG therefore shift the oxyhemoglobin dissociation curve to the right, as shown in Figure 36–2D. It has been demonstrated that more 2,3-BPG is produced during chronic hypoxic conditions, thus shifting the dissociation curve to the right and allowing more oxygen to be released from hemoglobin at a particular Po2. Very low levels of 2,3-BPG shift the curve far to the left, as shown in the figure. This means that blood deficient in 2,3-BPG does not unload much oxygen. Blood stored in blood banks for as little as 1 week has been shown to have very low levels of 2,3-BPG. Use of banked blood in patients may result in decreased oxygen unloading to the tissues unless steps are taken to restore the normal levels of 2,3-BPG. As blood enters metabolically active tissues, it is exposed to an environment different from that found in the arterial tree. The Pco2 is higher, the pH is lower, and the temperature is also higher than that of the arterial blood. The curve shown in Figure 36–1 is for blood at 37°C, with a pH of 7.4 and a Pco2 of 40 mm Hg. Blood in metabolically active tissues and therefore the venous blood draining them are no longer subject to these conditions because they have been exposed to a different environment. Because low pH, high Pco2, increased 2,3-BPG, and higher temperature all shift the oxyhemoglobin dissociation curve to the right, they all can help unload oxygen from hemoglobin at the tissues. On the other hand, as the venous blood returns to the lung and CO2 leaves the blood (which increases the pH), the affinity of hemoglobin for oxygen increases as the curve shifts back to the left, as shown in Figure 36–3. Note that the effects of pH, Pco2, and temperature shown in Figure 36–2 have a more profound effect on enhancing the unloading of oxygen at the tissues than they do interfering with its loading at the lungs.

CHAPTER 36 Transport of Oxygen and Carbon Dioxide 100

100

Hemoglobin saturation (%)

 pH

60

40

20

80

60

40

20

0 A.

20

40

60 PO (mm Hg) 2

80

0

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0 C.

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80

100

80

100

100

PCO  20 mm Hg 2 PCO  40 mm Hg 2

40

PCO2  80 mm Hg 20 0

0 B.

20

40

60 80 100 PO (mm Hg) 2

120

140

160

60

40

20

0

FIGURE 36–2

No

60

No 2 ,3

80

rm al 2 ,3Add BP ed G 2,3 -B PG

-BPG

80 Hemoglobin saturation (%)

Hemoglobin saturation ( %)

37° 43°



 pH

pH

Hemoglobin saturation ( %)

80

7.4 0 7.2 0

7.6 0

20°

0

367

0 D.

20

40

60 PO (mm Hg) 2

The effects of pH (A), PCO2 (B), temperature (C), and 2,3-BPG (D) on the oxyhemoglobin dissociation curve. (Modified with

permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

A convenient way to discuss shifts in the oxyhemoglobin dissociation curve is the P50, shown in Figures 36–1 and 36–3. The P50 is the Po2 at which 50% of the hemoglobin present in the blood is in the deoxyhemoglobin state and 50% is in the oxyhemoglobin state. At a temperature of 37°C, a pH of 7.4, and a Pco2 of 40 mm Hg, normal human blood has a P50 of 26 or 27 mm Hg. If the oxyhemoglobin dissociation curve is shifted to the right, the P50 increases. If it is shifted to the left, the P50 decreases.

Other Factors Affecting Oxygen Transport Most forms of anemia (low blood hemoglobin concentration or low number of red blood cells) do not affect the oxyhemoglobin dissociation curve if the association of oxygen and hemoglobin is expressed as percent saturation. For

example, anemia secondary to erythrocyte loss does not affect the combination of oxygen and hemoglobin for the remaining erythrocytes. It is the amount of hemoglobin that decreases, not the percent saturation or even the arterial Po2. The arterial content of oxygen, however, in milliliters of oxygen per 100 mL of blood, is reduced, as shown in Figure 36–4A, because the decreased amount of hemoglobin per 100 mL of blood decreases the oxygen-carrying capacity of the blood. Carbon monoxide has a much greater affinity for hemoglobin than does oxygen, as discussed in Chapter 35. It can therefore effectively block the combination of oxygen with hemoglobin because oxygen cannot be bound to iron atoms already combined with carbon monoxide. Carbon monoxide has a second deleterious effect: it shifts the oxyhemoglobin dissociation curve to the left. Thus, carbon monoxide can

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SECTION VI Pulmonary Physiology a

100

Hemoglobin saturation (%)

80

v-

60 50% 40

20

0

0

20

40 P50

60 PO2 (mm Hg)

80

100

FIGURE 36–3 Oxyhemoglobin dissociation curves for arterial and venous blood. The venous curve is shifted to the right because the pH is lower and the PCO2 (and possibly the temperature) is higher. The rightward shift results in a higher P50 for venous blood. a, arterial point (P 2 = 100mm Hg); –v, mixed venous point (P 2 = 40mm Hg). O

O

(Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

prevent the loading of oxygen into the blood in the lungs and can also interfere with the unloading of oxygen at the tissues. This can be seen in Figure 36–4A. Carbon monoxide is particularly dangerous for several reasons. A person breathing very low concentrations of carbon monoxide can slowly reach life-threatening levels of carboxyhemoglobin (COHb) in the blood because carbon monoxide has such a high affinity for hemoglobin. The effect is cumulative. What is worse is that a person breathing carbon monoxide is not aware of doing so—the gas is colorless, odorless, and tasteless and does not elicit any reflex coughing or sneezing, increase in ventilation, or feeling of difficulty in breathing. Smoking and living in urban areas cause small amounts of COHb to be present in the blood of healthy adults. A nonsmoker who lives in a rural area may have only about 1% COHb; a smoker who lives in an urban area may have 5–8% COHb in the blood. Hemoglobin within erythrocytes can rapidly scavenge nitric oxide (NO). NO can react with oxyhemoglobin to form methemoglobin and nitrate or react with deoxyhemoglobin to form a hemoglobin–NO complex. In addition, hemoglobin may act as a carrier for NO, in the form of S-nitrosothiol, on the cysteine residues on the β-globin chain. This is called s-nitrosohemoglobin (SNO-Hb). When hemoglobin binds oxygen, the formation of this S-nitrosothiol is enhanced; when hemoglobin releases oxygen, NO could be released. Thus, in regions where the Po2 is low, NO—a potent vasodilator—could be released. Methemoglobin is hemoglobin with iron in the ferric (Fe3+) state. It can be caused by nitrite poisoning or by toxic reactions

to oxidant drugs, or it can be found congenitally in patients with hemoglobin M. Iron atoms in the Fe3+ state will not combine with oxygen. As already discussed in this chapter, variants of the normal HbA may have different affinities for oxygen. HbF in red blood cells has a dissociation curve to the left of that for HbA, as shown in Figure 36–4B. Fetal Po2 is much lower than in the adult; the curve is located properly for its operating range. Furthermore, HbF’s greater affinity for oxygen relative to the maternal hemoglobin promotes transport of oxygen across the placenta by maintaining the diffusion gradient. The shape of the HbF curve in blood appears to be a result of the fact that 2,3-BPG has little effect on the affinity of HbF for oxygen. Myoglobin (Mb), a heme protein that occurs naturally in muscle cells, consists of a single polypeptide chain attached to a heme group. It can therefore combine chemically with a single molecule of oxygen and is similar structurally to a single subunit of hemoglobin. As can be seen in Figure 36–4C, the hyperbolic dissociation curve of Mb (which is similar to that of a single hemoglobin subunit) is far to the left of that of normal HbA; that is, at lower Po2, much more oxygen remains bound to Mb. Mb can therefore store oxygen in skeletal muscle. As blood passes through the muscle, oxygen leaves hemoglobin and binds to Mb. It can be released from the Mb when conditions within muscle cause lower tissue Po2. Cyanosis is not really an influence on the transport of oxygen but rather is a sign of poor transport of oxygen. It occurs when more than 5 g Hb/100 mL of arterial blood is in the deoxy state. It is a bluish purple discoloration of the skin, nail beds, and mucous membranes, and its presence is indicative of an abnormally high concentration of deoxyhemoglobin in the arterial blood. Its absence, however, does not exclude hypoxemia because an anemic patient with hypoxemia may not have sufficient hemoglobin to appear cyanotic.

TRANSPORT OF CARBON DIOXIDE BY THE BLOOD Carbon dioxide is carried in the blood in physical solution, chemically combined to amino acids in blood proteins, and as bicarbonate ions. About 200–250 mL of carbon dioxide is produced by the tissue metabolism each minute in a resting 70-kg person and must be carried by the venous blood to the lung for removal from the body. At a cardiac output of 5 L/min, each 100 mL of blood passing through the lungs must therefore unload 4–5 mL of carbon dioxide.

PHYSICALLY DISSOLVED Carbon dioxide is about 20 times more soluble in the plasma (and inside the erythrocytes) compared to oxygen. As a result, about 5–10% of the total carbon dioxide transported by the blood is carried in physical solution.

CHAPTER 36 Transport of Oxygen and Carbon Dioxide

369

100

20

12

60

50% CO Hb 8

Anemia (6 g Hb/100 mL blood)

Hb su bu nit Hb A

80 Mb

16

Saturation (%)

O2 bound to hemoglobin, mL O2/100 mL

Normal blood

40

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Hemoglobin saturation (%)

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PO2 (mm Hg)

About 0.0006mL CO2/(mm Hg Pco2) will dissolve in 1 mL of plasma at 37°C. One hundred milliliters of plasma or whole blood at a Pco2 of 40 mm Hg, therefore, contains about 2.4 mL CO2 in physical solution. Figure 36–5 shows that the total CO2 content of whole blood is about 48 mL CO2/100 mL of blood at 40 mm Hg, so approximately 5% of the carbon dioxide carried in the arterial blood is in physical solution. Similarly, multiplying 0.06mL CO2/100mL of blood/ (mm Hg Pco2) times a venous Pco2 of 45 mm Hg shows that about 2.7 mL CO2 is physically dissolved in the mixed venous blood. The total carbon dioxide content of venous blood is about 52.5 mL CO2/100 mL of blood; a little more than 5% of the total carbon dioxide content of venous blood is in physical solution.

FIGURE 36–4 Other physiologic factors influencing oxygen transport and storage. A) The effects of carbon monoxide and anemia on the carriage of oxygen by hemoglobin. Note that the ordinate is expressed as the volume of oxygen bound to hemoglobin in milliliters of oxygen per 100 mL of blood. B) A comparison of the oxyhemoglobin dissociation curves for normal adult hemoglobin (HbA) and fetal hemoglobin (HbF). C) Dissociation curves for normal HbA, a single monomeric subunit of hemoglobin (Hb subunit), and myoglobin (Mb). (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

CARBAMINO COMPOUNDS Carbon dioxide can combine chemically with the terminal amine groups in blood proteins, forming carbamino compounds. The reaction occurs rapidly; no enzymes are necessary. Note that a hydrogen ion is released when a carbamino compound is formed: H

H R

+ CO2

N H

Terminal amine group

R

N

+ H+ COO– Carbamino compound

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FIGURE 36–5 Carbon dioxide dissociation curves for whole blood (37°C) at different oxyhemoglobin saturations. Note that the ordinate is whole blood CO2 content in milliliters of CO2 per 100 mL of blood. a, arterial point; –v, mixed venous point. (Modified with permission from Levitzky MG:

Whole blood carbon dioxide content, mL CO2 /100 mL blood

70

60 v50

%H 97.5

bO 2

a 40

30

20

10

Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

Because the protein found in greatest concentration in the blood is the globin of hemoglobin, most of the carbon dioxide transported in this manner is bound to amino acids of hemoglobin. Deoxyhemoglobin can bind more carbon dioxide as carbamino groups than can oxyhemoglobin. Therefore, as the hemoglobin in the venous blood enters the lung and combines with oxygen, it releases carbon dioxide from its terminal amine groups. About 5–10% of the total carbon dioxide content of blood is in the form of carbamino compounds.

BICARBONATE The remaining 80–90% of the carbon dioxide transported by the blood is carried as bicarbonate ions. This is made possible by the following reaction: CO2 + H2O Carbonic anhydrase H2CO3

HbO 2 0% HbO 2 70%

H+ + HCO3– (12)

Carbon dioxide can combine with water to form carbonic acid, which then dissociates into a hydrogen ion and a bicarbonate ion. Very little carbonic acid is formed by the association of water and carbon dioxide without the presence of the enzyme carbonic anhydrase because the reaction occurs so slowly. Carbonic anhydrase, which is present in high concentration in erythrocytes (but not in plasma), makes the reaction proceed about 13,000 times faster. (Note that the product of the carbonic anhydrase reaction is actually not carbonic acid, but a bicarbonate ion and a proton—see Chapter 47.) Hemoglobin also plays an integral role in the transport of carbon dioxide because it can accept the hydrogen ion liberated by the

0 0

10

20

30

40 50 PCO (mm Hg) 2

60

70

80

dissociation of carbonic acid, thus allowing the reaction to continue. This will be discussed in detail in the last section of this chapter.

THE CARBON DIOXIDE DISSOCIATION CURVE The carbon dioxide dissociation curve for whole blood is shown in Figure 36–5. Within the normal physiologic range of Pco2, the curve is nearly a straight line, with no steep or flat portions. The carbon dioxide dissociation curve for whole blood is shifted to the right at greater levels of oxyhemoglobin and shifted to the left at greater levels of deoxyhemoglobin. This is known as the Haldane effect. The Haldane effect allows the blood to load more carbon dioxide at the tissues, where there is more deoxyhemoglobin, and unload more carbon dioxide in the lungs, where there is more oxyhemoglobin. The Bohr and Haldane effects are both explained by the fact that deoxyhemoglobin is a weaker acid than oxyhemoglobin; that is, deoxyhemoglobin more readily accepts the hydrogen ion liberated by the dissociation of carbonic acid, thus permitting more carbon dioxide to be transported in the form of bicarbonate ion. This is referred to as the isohydric shift. Conversely, the association of hydrogen ions with the amino acids of hemoglobin lowers the affinity of hemoglobin for oxygen, thus shifting the oxyhemoglobin dissociation curve to the right at low pH or high Pco2. The following relationship can therefore be written: H+Hb + O2

H+ + HbO2

(13)

CHAPTER 36 Transport of Oxygen and Carbon Dioxide

371

A. IN THE TISSUES TISSUE

ERYTHROCYTE

PLASMA Dissolved CO2

CO2

CAPILLARY WALL

H2O

CO2

Dissolved

H2O  CO2 Carbonic anhydrase

CO2

H2CO3 HCO3 

Cl

HCO3  H Cl H  HbO2

O2

O2  HHb

O2

HHb  CO2 Carbamino compounds

B. IN THE LUNG ALVEOLUS

ERYTHROCYTE

PLASMA Dissolved CO2

CAPILLARY WALL

CO2

H2O

CO2

Dissolved

H2O  CO2 Carbonic anhydrase

CO2

H2CO3 HCO3 Cl

HCO3  H Cl H  HbO2

O2

O2

O2  HHb

HHb  CO2 Carbamino compounds

FIGURE 36–6 Schematic representation of uptake and release of carbon dioxide and oxygen at the tissues (A) and in the lung (B). Note that small amounts of carbon dioxide can form carbamino compounds with blood proteins other than hemoglobin and may also be hydrated in trivial amounts in the plasma to form carbonic acid and then bicarbonate (not shown in diagram). The circles represent the bicarbonate–chloride exchange carrier protein. (Modified with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.)

These effects can be seen in the schematic diagrams of oxygen and carbon dioxide transport shown in Figure 36–6. At the tissues, the Po2 is decreased and the Pco2 is increased. Carbon dioxide dissolves in the plasma, and some diffuses into the erythrocyte. Some of this carbon dioxide dissolves in the cytosol, some forms carbamino compounds with hemoglobin, and some is hydrated by carbonic anhydrase to form carbonic acid. At low Po2, there are substantial amounts of

deoxyhemoglobin in the erythrocytes and the deoxyhemoglobin is able to accept the hydrogen ions liberated by the dissociation of carbonic acid and the formation of carbamino compounds. The hydrogen ions released by the dissociation of carbonic acid and the formation of carbamino compounds bind to specific amino acid residues on the globin chains and facilitate the release of oxygen from hemoglobin (the Bohr effect). Bicarbonate ions diffuse out of the erythrocyte

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SECTION VI Pulmonary Physiology

through the cell membrane much more readily than do hydrogen ions. Because more bicarbonate ions than hydrogen ions leave the erythrocyte, electrical neutrality is maintained by the exchange of chloride ions for bicarbonate ions by the bicarbonate–chloride carrier protein. This is the “chloride shift.” Small amounts of water also move into the cell to maintain the osmotic equilibrium. At the lung, the Po2 is increased and the Pco2 is decreased. As oxygen combines with hemoglobin, the hydrogen ions that were taken up when it was in the deoxyhemoglobin state are released. They combine with bicarbonate ions, forming carbonic acid. This breaks down into carbon dioxide and water. At the same time, carbon dioxide is also released from the carbamino compounds. Carbon dioxide then diffuses out of the red blood cells and plasma and into the alveoli. A chloride shift opposite in direction to that in the tissues also occurs to maintain electrical neutrality.

CLINICAL CORRELATION An 18-year-old man is brought by ambulance to the emergency department about 35 minutes after being shot in the leg. He is conscious, although disoriented and in pain, and appears pale. Heart rate is 150/min and his arterial blood pressure is 80/60 mm Hg. He is breathing spontaneously with a high respiratory rate of 26/min. During the trip to hospital, the wound was stabilized and he received 2 L of normal saline (0.9% NaCl in water) solution intravenously. In the emergency department, he continues to lose blood while the physicians attempt to stop the hemorrhage. As his arterial blood pressure continues to decrease to 60/45 mm Hg, he is given 2 additional liters of saline. His hematocrit decreases to 21% (normal range 40–50%), corresponding to a hemoglobin concentration of 7 g/100 mL of blood (normal range 13–18 g/100 mL blood). His respiratory rate increases to 40/min. Results of blood gas analysis (see Chapter 37) from an arterial blood sample show an arterial Po2 of 95 mm Hg, an arterial Pco2 of 28 mm Hg (normal range 35–45 mm Hg), and an arterial pH of 7.30 (normal range 7.35–7.45) despite the hypocapnia. He becomes agitated and loses consciousness. He is intubated (a tube inserted into trachea) and mechanically ventilated via the endotracheal tube. The patient’s decreased blood volume led to decreased venous return, decreased cardiac output, and decreased systemic blood pressure. Decreased firing of the baroreceptors in the carotid sinuses and aortic arch decreased parasympathetic stimulation of the heart and increased sympathetic stimulation of the heart, arterioles, and the veins. This resulted in increased heart rate and myocardial contractility; increased arteriolar tone; and decreased venous compliance to enhance venous return, cardiac

output, and blood pressure. However, all of these responses were not sufficient to increase his blood pressure or his cardiac output to normal levels, as he continued to lose blood. The decreased cardiac output and increased vascular resistance to most vascular beds resulted in decreased tissue perfusion (including his skin, explaining his pale appearance). This ischemia resulted in production of lactic acid causing hydrogen ion stimulation of the arterial chemoreceptors (see Chapters 37 and 38), which explains his tachypnea (high respiratory rate). He was hyperventilating in compensation as demonstrated by the hypocapnia. As he continued to lose blood, his blood pressure was no longer sufficient to provide adequate cerebral blood flow and he lost consciousness and showed signs of circulatory shock. Administration of normal saline temporarily increased blood volume, but diluted his erythrocytes, decreasing his hematocrit, hemoglobin concentration, oxygen-carrying capacity, and arterial oxygen content, even if his alveolar and arterial partial pressures of oxygen were normal. Mixed venous Po2 would decrease as tissues extracted as much oxygen as possible from the arterial blood. Renal and endocrine responses to hemorrhage also would occur, as will be discussed in Sections 7 and 9. In the emergency department, his treatment would be aimed at stopping blood loss and restoring cardiac output and blood pressure with matched packed red blood cells (red blood cells after most of the plasma and other cells have been removed from whole blood) to restore his oxygen carrying capacity.

CHAPTER SUMMARY ■

■

■

■

■

Blood normally carries a small amount of oxygen physically dissolved in the plasma and a large amount chemically combined to hemoglobin: only the physically dissolved oxygen contributes to the partial pressure, but the partial pressure of oxygen determines how much combines chemically with hemoglobin. The oxyhemoglobin dissociation curve describes the reversible reaction of oxygen and hemoglobin to form oxyhemoglobin; it is relatively flat at a Po2 above approximately 70 mm Hg and is very steep at a Po2 in the range of 20–40 mm Hg. Decreased pH, increased Pco2, increased temperature, and increased 2,3-BPG concentration of the blood all shift the oxyhemoglobin dissociation curve to the right. Blood normally carries small amounts of carbon dioxide physically dissolved in the plasma and chemically combined to blood proteins as carbamino compounds and a large amount in the form of bicarbonate ions. Deoxyhemoglobin favors the formation of carbamino compounds, and it promotes the transport of carbon dioxide as bicarbonate ions by buffering hydrogen ions formed by the dissociation of carbonic acid.

CHAPTER 36 Transport of Oxygen and Carbon Dioxide

STUDY QUESTIONS 1. An otherwise healthy person has lost enough blood to decrease the hemoglobin concentration from 15 to 12 g/100 mL blood. Which of the following would be expected to decrease? A) arterial Po2 B) blood oxygen-carrying capacity C) arterial hemoglobin saturation D) arterial oxygen content E) B and D. 2. A woman’s hemoglobin concentration is 10 g of hemoglobin per 100 mL of blood. If her hemoglobin is 90% saturated with oxygen at an arterial Po2 of 80 mm Hg, what is her total arterial oxygen content, including physically dissolved oxygen? A) 10.72 mL O2/100 mL blood B) 10.96 mL O2/100 mL blood C) 12.06 mL O2/100 mL blood D) 12.30 mL O2/100 mL blood E) 13.40 mL O2/100 mL blood

3. Which of the following should increase the P50 of the oxyhemoglobin dissociation curve? A) hypercapnia B) acidosis C) increased blood levels of 2,3-BPG D) increased body temperature E) all of the above 4. Most of the carbon dioxide in the blood is transported A) as bicarbonate. B) as carbamino compounds. C) physically dissolved in the plasma. D) physically dissolved inside erythrocytes.

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37 C

Acid–Base Regulation and Causes of Hypoxia Michael Levitzky

H A

P

T

E

R

O B J E C T I V E S ■ ■ ■ ■ ■ ■ ■

Define acids, bases, and buffers. List the buffer systems available in the human body. State the normal ranges of arterial pH, PCO2, and bicarbonate concentration, and define alkalosis and acidosis. List the potential causes of respiratory acidosis and alkalosis and metabolic acidosis and alkalosis. Discuss the respiratory mechanisms that help compensate for acidosis and alkalosis. Evaluate blood gas data to determine acid–base status. Classify and explain the causes of tissue hypoxia.

The respiratory and renal systems maintain the balance of acids and bases in the body. This chapter will introduce the major concepts of the respiratory system’s contribution to acid–base balance; Chapter 47 addresses the renal system contribution to acid–base balance and includes a more detailed discussion of the basic chemistry of acid–base physiology, buffers, and the chemistry of the CO2–bicarbonate system.

INTRODUCTION TO ACID–BASE CHEMISTRY An acid can be simply defined as a substance that can donate a hydrogen ion (a proton) to another substance and a base as a substance that can accept a hydrogen ion from another substance. A strong acid is a substance that is completely or almost completely dissociated into a hydrogen ion and its corresponding or conjugate base in dilute aqueous solution; a weak acid is only slightly ionized in aqueous solution. In general, a strong acid has a weak conjugate base and a weak acid has a strong conjugate base. The strength of an acid or a base should not be confused with its concentration. A buffer is a mixture of substances in aqueous solution (usually a combination of a weak acid and its conjugate base) that can resist changes in hydrogen ion concentration when

Ch37_375-384.indd 375

strong acids or bases are added; that is, the changes in hydrogen ion concentration that occur when a strong acid or base is added to a buffer system are much smaller than those that would occur if the same amount of acid or base were added to pure water or another nonbuffer solution. The hydrogen ion activity of pure water is about 1.0 × 10–7 mol/L. By convention, solutions with hydrogen ion activities above 10–7 mol/L are considered to be acid; those with hydrogen ion activities below 10–7 are considered to be alkaline. The range of hydrogen ion concentrations or activities in the body is normally from about 10–1 for gastric acid to about 10–8 for the most alkaline pancreatic secretion. This wide range of hydrogen ion activities necessitates the use of the more convenient pH scale. The pH of a solution is the negative logarithm of its hydrogen ion activity. With the exception of the highly concentrated gastric acid, in most instances in the body, the hydrogen ion activity is about equal to the hydrogen ion concentration. The pH of arterial blood is normally close to 7.40, with a normal range considered to be about 7.35–7.45. An arterial pH (pHa) less than 7.35 is considered acidemia; a pHa greater than 7.45 is considered alkalemia. The underlying condition characterized by hydrogen ion retention or by loss of bicarbonate or other bases is referred to as acidosis; the underlying condition characterized by hydrogen ion loss or retention of

375

11/29/10 4:40:09 PM

376

SECTION VI Pulmonary Physiology

TABLE 37–1 The pH scale. pH

Concentration (nmol/L)

6.90

126

7.00

100

7.10

79

7.20

63

7.30

50

7.40

40

7.50

32

7.60

25

7.70

20

7.80

16

Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.

base is referred to as alkalosis. Under pathologic conditions, the extremes of arterial blood pH have been noted to range as high as 7.8 and as low as 6.9. These correspond to hydrogen ion concentrations as seen in Table 37–1 (hydrogen ion concentrations are expressed as nanomoles [10–9 mol/L] for convenience). Note that the pH scale is “inverted” by the negative sign and is also logarithmic as it is defined. An increase in pH represents a decrease in hydrogen ion concentration. In fact, an increase of only 0.3 pH units indicates that the hydrogen ion concentration was cut in half. Hydrogen ions are the most reactive cations in body fluids, and they interact with negatively charged regions of other molecules, such as those of body proteins. Interactions of hydrogen ions with negatively charged functional groups of proteins can lead to marked changes in protein structural conformations with resulting alterations in the behavior of the proteins. An example of this was already seen in Chapter 36, where hemoglobin was noted to combine with less oxygen at a lower pH (the Bohr effect). Alterations in the structural conformations and charges of protein enzymes affect their activities, with resulting alterations in the functions of body tissues. Extreme changes in the hydrogen ion concentration of the body can result in loss of organ system function and may be fatal. Under normal circumstances, cellular metabolism is the main source of acids in the body. These acids are the waste products of substances ingested as foodstuffs. The greatest source of hydrogen ions is the carbon dioxide produced as one of the end products of the oxidation of glucose and fatty acids during aerobic metabolism. The hydration of carbon dioxide results in the formation of carbonic acid, which then can dissociate into a hydrogen ion and a bicarbonate ion, as discussed in Chapter 36. This process is reversed in the pulmonary capillaries, and CO2 then diffuses through the alveolar–capillary barrier into the alveoli, from which it is removed by alveolar

ventilation. Carbonic acid is therefore said to be a volatile acid because it can be converted into a gas and then removed from an open system such as the body. Very great amounts of carbon dioxide can be removed from the lungs by alveolar ventilation: under normal circumstances, about 15,000–25,000 mmol of carbon dioxide is removed via the lungs daily. A much smaller quantity of fixed or nonvolatile acids is also normally produced during the course of the metabolism of foodstuffs. The fixed acids produced by the body include sulfuric acid, which originates from the oxidation of sulfurcontaining amino acids such as cysteine; phosphoric acid from the oxidation of phospholipids and phosphoproteins; hydrochloric acid, which is produced during the conversion of ingested ammonium chloride to urea and by other reactions; and lactic acid from the anaerobic metabolism of glucose. Other fixed acids may be ingested accidentally or formed in abnormally large quantities by disease processes, such as the acetoacetic and butyric acid formed during diabetic ketoacidosis (see Chapter 66). About 70 mEq of fixed acids is normally removed from the body each day (about 1 mEq/kg/body weight per day); the range is 50–100 mEq. A vegetarian diet may produce significantly less fixed acid and may even result in no net production of fixed acids. The removal of fixed acids is accomplished mainly by the kidneys, as will be discussed in Chapter 47. Some may also be removed via the gastrointestinal tract. Fixed acids normally represent only about 0.2% of the total body acid production. The body contains a variety of substances that can act as buffers in the physiologic pH range. These include bicarbonate, phosphate, and proteins in the blood, the interstitial fluid, and inside cells (discussed in greater detail in Chapter 47). The isohydric principle states that all the buffer pairs in a homogeneous solution are in equilibrium with the same hydrogen ion concentration. For this reason, all the buffer pairs in the plasma behave similarly, so that the detailed analysis of a single buffer pair, like the bicarbonate buffer system, can reveal a great deal about the chemistry of all the plasma buffers. The main buffers of the blood are bicarbonate, phosphate, and proteins. The bicarbonate buffer system consists of the buffer pair of the weak acid, carbonic acid, and its conjugate base, bicarbonate. The ability of the bicarbonate system to function as a buffer of fixed acids in the body is largely due to the ability of the lungs to remove carbon dioxide from the body. In a closed system, bicarbonate would not be nearly as effective. At a temperature of 37°C, about 0.03 mmol of carbon dioxide per mm Hg of Pco2 will dissolve in a liter of plasma. (Note that the solubility of CO2 was expressed as milliliters of CO2 per 100 mL of plasma in Chapter 36.) Therefore, the carbon dioxide dissolved in the plasma, expressed as millimoles per liter, is equal to 0.03 x Pco2 . At body temperature in the plasma, the equilibrium of the reaction is such that there is roughly 1,000 times more carbon dioxide physically dissolved in the plasma than there is in the form of carbonic acid. The dissolved carbon dioxide is in equilibrium with the carbonic acid, though, so both the dissolved carbon dioxide and the carbonic

CHAPTER 37 Acid–Base Regulation and Causes of Hypoxia acid are considered as the undissociated HA in the Henderson–Hasselbalch equation (see Chapter 47) for the bicarbonate system: [HCO3–]p

pH = pK + log ___________ [CO + H CO ] 2

2

(1)

3

where [HCO3−]p stands for plasma bicarbonate concentration. The concentration of carbonic acid is negligible, so we have: [HCO3–]p

pH = pK′ + log _______ 0.03 P

(2)

co2

where pK′ is the pK of the HCO3−–CO2 system in blood. The pK′ of this system at physiologic pH values and at 37°C is 6.1. Therefore, at a pHa of 7.40 and an arterial Pco2 of 40 mm Hg, we have: [HCO3–]p

7.40 = 6.1 + log _________

(3)

1.2 mmol/L

Therefore, the arterial plasma bicarbonate concentration is about 24 mmol/L (the normal range is 23–28 mmol/L) because the logarithm of 20 is equal to 1.3. Note that the term total CO2 refers to the dissolved carbon dioxide (including carbonic acid) plus the carbon dioxide present as bicarbonate. A useful way to display the interrelationships among the variables of pH, Pco2, and bicarbonate concentration of the plasma, as expressed by the Henderson–Hasselbalch equation, is the pH–bicarbonate diagram shown in Figure 37–1. As can be seen from Figure 37–1, pH is on the abscissa of the pH–bicarbonate diagram, and the plasma bicarbonate concentration in millimoles per liter is on the ordinate. For

100 40

80

70

[H ] (nmol/L) 50 40

60

30

20

16

ba

r

A

iso ba

B

Hg

m m 

40 m

m

60

 CO 2



CO 2

r

ba

C

P

CO 2

P

25

r

iso Hg

mm 80

30 P

[HCO3]p (mmol/L)

Hg

ba

r

iso

35

20

D



P CO

E

15 10 7.0

m

7.1

7.2

7.3

7.4 pH

Hg

iso

0m

2

2

7.5

Normal buffer line

7.6

7.7

FIGURE 37–1

2

Acid–Base Chemistry, 6th ed. 1974.)

each value of pH and bicarbonate ion concentration, there is a single corresponding Pco2 on the graph. Conversely, for any particular pH and Pco2, only one bicarbonate ion concentration will satisfy the Henderson–Hasselbalch equation. If the Pco2 is held constant, for example, at 40 mm Hg, an isobar line can be constructed, connecting the resulting points as the pH is varied. The representative isobars shown in Figure 37–1 give an indication of the potential alterations of acid–base status when alveolar ventilation is increased or decreased. If everything else remains constant, hypoventilation leads to acidosis; hyperventilation leads to alkalosis. The bicarbonate buffer system is a poor buffer for carbonic acid. The presence of hemoglobin makes blood a much better buffer. The buffer value of plasma in the presence of hemoglobin is four to five times that of plasma separated from erythrocytes. Therefore, the slope of the normal in vivo buffer line shown in Figures 37–1 is mainly determined by the nonbicarbonate buffers present in the body. The phosphate buffer system mainly consists of the buffer pair of the dihydrogen phosphate (H2PO4−) and the monohydrogen phosphate (HPO42−) anions. Although several potential buffering groups are found on proteins, only one large group has pK in the pH range encountered in the blood. These are the imidazole groups in the histidine residues of the peptide chains. The protein present in the greatest quantity in the blood is hemoglobin. As already noted, deoxyhemoglobin is a weaker acid than is oxyhemoglobin. Thus, as oxygen leaves hemoglobin in the tissue capillaries, the imidazole group removes hydrogen ions from the erythrocyte interior, allowing more carbon dioxide to be transported as bicarbonate. This process is reversed in the lungs. The bicarbonate buffer system is the major buffer found in the interstitial fluid, including the lymph. The phosphate buffer pair is also found in the interstitial fluid. The volume of the interstitial compartment is much larger than that of the plasma, so the interstitial fluid may play an important role in buffering. The extracellular portion of bone contains very large deposits of calcium and phosphate salts, mainly in the form of hydroxyapatite. In an otherwise healthy adult, where bone growth and resorption are in a steady state, bone salts can buffer hydrogen ions in chronic acidosis. Chronic buffering of hydrogen ions by the bone salts may therefore lead to demineralization of bone. The intracellular proteins and organic phosphates of most cells can function to buffer both fixed acids and carbonic acid. Of course, buffering by the hemoglobin in erythrocytes is intracellular.

7.8

The pH–bicarbonate diagram with PCO isobars. 2 Note the hydrogen ion concentration in nanomoles per liter at the top of the figure corresponding to the pH values on the abscissa. Points A to E correspond to different pH values and bicarbonate concentrations all falling on the same PCO isobar. (Modified with

permission of the University of Chicago Press from Davenport HW: The ABC of

377

ACIDOSIS AND ALKALOSIS Acid–base disorders can be divided into four major categories: respiratory acidosis, respiratory alkalosis, metabolic acidosis, and metabolic alkalosis. These primary acid–base disorders may occur singly (“simple”) or in combination (“mixed”) or may be altered by compensatory mechanisms.

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SECTION VI Pulmonary Physiology

RESPIRATORY ACIDOSIS

TABLE 37–2 Common causes of respiratory acidosis.

The arterial Pco2 is normally maintained at or near 40 mm Hg (normal range is 35–45 mm Hg) by the mechanisms that regulate breathing. Sensors exposed to the arterial blood and to the cerebrospinal fluid provide the central controllers of breathing with the information necessary to regulate the arterial Pco2 at or near 40 mm Hg (see Chapter 38). Any short-term alterations (i.e., those which occur without renal compensation) in alveolar ventilation that result in an increase in alveolar and therefore also in arterial Pco2 tend to lower the pHa, resulting in respiratory acidosis. This can be appreciated by examining the Pco2 = 60 and 80 mm Hg isobars in Figure 37–1. The pHa at any Paco2 depends on the bicarbonate and other buffers present in the blood. Pure changes in arterial Pco2 caused by changes in ventilation travel along the normal in vivo buffer line (Figures 37–1 and 37–2). Pure uncompensated respiratory acidosis would correspond with point C in Figure 37–2 (at the intersection of an elevated Pco2 isobar and the normal buffer line). In respiratory acidosis, the ratio of bicarbonate to CO2 decreases. Yet, as can be seen at point C in Figure 37–2, in uncompensated primary (simple) respiratory acidosis, the absolute plasma bicarbonate concentration does increase somewhat because of the buffering of some of the hydrogen ions liberated by the dissociation of carbonic acid by nonbicarbonate buffers. Any impairment of alveolar ventilation can cause respiratory acidosis. As shown in Table 37–2, depression of the respiratory centers in the medulla (see Chapter 38) by anesthetic agents, narcotics, hypoxia, central nervous system disease or trauma, or even greatly increased PaCo2 itself results in hypoventilation and respiratory acidosis. Interference with the neural transmission to the respiratory muscles by disease

Metabolic alkalosis and respiratory acidosis F 35

[HCO3]p (mmol/L)

D

25

20

15

Uncompensated metabolic alkalosis

Metabolic alkalosis Uncompensated E respiratory acidosis Metabolic alkalosis C and respiratory alkalosis Metabolic acidosis A and respiratory acidosis Normal buffer line I Metabolic G acidosis B Uncompensated Uncompensated metabolic acidosis respiratory alkalosis Metabolic acidosis H and respiratory alkalosis

10 7.0

7.1

FIGURE 37–2

7.2

7.3

7.4 pH

7.5

7.6

7.7

7.8

Acid–base paths in vivo. (Modified with permission of

the University of Chicago Press from Davenport HW: The ABC of Acid–Base Chemistry, 6th ed. 1974.)

Neuromuscular disorders Spinal cord injury Phrenic nerve injury Poliomyelitis, Guillain–Barré syndrome, etc. Botulism, tetanus Myasthenia gravis Administration of curarelike drugs Diseases affecting the respiratory muscles Chest wall restriction Kyphoscoliosis Extreme obesity Lung restriction Pulmonary fibrosis Sarcoidosis Pneumothorax, pleural effusions, etc. Pulmonary parenchymal diseases Pneumonia, etc. Pulmonary edema Airway obstruction Chronic obstructive pulmonary disease Upper airway obstruction Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.

processes, drugs or toxins, or dysfunctions or deformities of the respiratory muscles or the chest wall can result in respiratory acidosis. Restrictive, obstructive, and obliterative diseases of the lungs can also result in respiratory acidosis.

RESPIRATORY ALKALOSIS

40

30

Depression of the respiratory control centers Anesthetics Sedatives Opiates Brain injury or disease Severe hypercapnia, hypoxia

Alveolar ventilation in excess of that needed to keep pace with body’s carbon dioxide production results in alveolar and arterial Pco2 below 35 mm Hg. Such hyperventilation leads to respiratory alkalosis. Uncompensated primary respiratory alkalosis results in movement to a lower Pco2 isobar along the normal buffer line, as seen at point B in Figure 37–2. The decreased Paco2 shifts the equilibrium of the series of reactions describing carbon dioxide hydration and carbonic acid dissociation to the left. This results in a decreased arterial hydrogen ion concentration, increased pH, and a decreased plasma bicarbonate concentration. The ratio of bicarbonate to carbon dioxide increases. The causes of respiratory alkalosis include anything leading to hyperventilation. As shown in Table 37–3, hyperventilation syndrome, a psychological dysfunction of unknown cause, results in chronic or recurrent episodes of hyperventilation and respiratory alkalosis. Drugs, hormones (such as progesterone), toxic substances, central nervous system diseases or disorders,

CHAPTER 37 Acid–Base Regulation and Causes of Hypoxia

TABLE 37–3 Common causes of respiratory alkalosis.

379

TABLE 37–4 Common causes of metabolic acidosis.

Central nervous system Anxiety Hyperventilation syndrome Inflammation (encephalitis, meningitis) Cerebrovascular disease Tumors

Ingested drugs or toxic substances Methanol Ethanol Salicylates Ethylene glycol Ammonium chloride

Drugs or hormones Salicylates Progesterone

Loss of bicarbonate ions Diarrhea Pancreatic fistulas Renal dysfunction

Bacteremias, fever Pulmonary diseases Acute asthma Pulmonary vascular diseases (pulmonary embolism) Overventilation with mechanical ventilators Hypoxia; high altitude Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.

bacteremias, fever, overventilation by mechanical ventilators (or the clinician), or ascent to high altitude may all result in respiratory alkalosis.

Lactic acidosis Hypoxemia Anemia, carbon monoxide Shock (hypovolemic, cardiogenic, septic, etc.) Severe exercise Acute respiratory distress syndrome (ARDS) Ketoacidosis Diabetes mellitus Alcoholism Starvation Inability to excrete hydrogen ions Renal dysfunction Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.

METABOLIC ACIDOSIS Metabolic acidosis may be thought of as nonrespiratory acidosis. It can be caused by the ingestion, infusion, or production of a fixed acid; decreased renal excretion of hydrogen ions; the movement of hydrogen ions from the intracellular to the extracellular compartment; or the loss of bicarbonate or other bases from the extracellular compartment. As can be seen in Figure 37–2, primary uncompensated metabolic acidosis results in a downward movement along the Pco2 = 40 mm Hg isobar to point G, that is, a net loss of buffer establishes a new blood–buffer line lower than and parallel to the normal blood–buffer line. Pco2 is unchanged, hydrogen ion concentration is increased, and the ratio of bicarbonate concentration to CO2 is decreased. As shown in Table 37–4, ingestion of methyl alcohol or salicylates can cause metabolic acidosis by increasing the fixed acids in the blood. (Salicylate poisoning—for example, aspirin overdose—causes both metabolic acidosis and later respiratory alkalosis.) Diarrhea can cause significant bicarbonate losses, resulting in metabolic acidosis. Renal dysfunction can lead to an inability to excrete hydrogen ions, as well as an inability to reabsorb bicarbonate ions, as will be discussed in the next section. True “metabolic” acidosis may be caused by an accumulation of lactic acid in severe hypoxemia or shock and by diabetic ketoacidosis.

METABOLIC ALKALOSIS Metabolic, or nonrespiratory, alkalosis occurs when there is an excessive loss of fixed acids from the body, or it may occur

as a consequence of the ingestion, infusion, or excessive renal reabsorption of bases such as bicarbonate. Figure 37–2 shows that primary uncompensated metabolic alkalosis results in an upward movement along the Pco2 = 40 mm Hg isobar to point D, that is, a net gain of buffer establishes a new blood–buffer line higher than and parallel to the normal blood–buffer line. Pco2 is unchanged, hydrogen ion concentration is decreased, and the ratio of bicarbonate concentration to carbon dioxide is increased. As shown in Table 37–5, loss of gastric juice by vomiting results in a loss of hydrogen ions and may cause metabolic alkalosis. Excessive ingestion of bicarbonate or other bases (e.g., stomach antacids) or overinfusion of bicarbonate by the clinician may cause metabolic alkalosis. In addition,

TABLE 37–5 Common causes of metabolic alkalosis. Loss of hydrogen ions Vomiting Gastric fistulas Diuretic therapy Treatment with or overproduction of steroids (aldosterone or other mineralocorticoids) Ingestion or administration of excess bicarbonate or other bases Intravenous bicarbonate Ingestion of bicarbonate or other bases (e.g., antacids) Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.

380

SECTION VI Pulmonary Physiology

diuretic therapy, treatment with steroids (or the overproduction of endogenous steroids), and conditions leading to severe potassium depletion may also cause metabolic alkalosis.

mechanism or the breathing apparatus itself. Compensation for acidosis or alkalosis in these conditions must therefore come from outside the respiratory system. The respiratory compensatory mechanism can operate very rapidly (within minutes) to partially correct metabolic acidosis or alkalosis.

COMPENSATORY MECHANISMS Uncompensated primary acid–base disturbances, such as those indicated by points B–D and G in Figure 37–2, seldom occur because respiratory and renal compensatory mechanisms are called into play to offset these disturbances. The two main compensatory mechanisms are functions of the respiratory and renal systems.

RESPIRATORY COMPENSATORY MECHANISMS The respiratory system can compensate for metabolic acidosis or alkalosis by altering alveolar ventilation. As discussed in Chapter 33, if carbon dioxide production is constant, the alveolar Pco2 is inversely proportional to the alveolar ventilation. In metabolic acidosis, the increased blood hydrogen ion concentration stimulates chemoreceptors, which, in turn, increase alveolar ventilation, thus decreasing arterial Pco2. This causes an increase in pHa, returning it toward normal. (The mechanisms by which ventilation is regulated are discussed in detail in Chapter 38.) These events can be better understood by looking at Figure 37–2. Point G represents uncompensated metabolic acidosis. As the respiratory compensation for the metabolic acidosis occurs, in the form of an increase in ventilation, the arterial Pco2 decreases. The point representing blood pHa, Paco2, and bicarbonate concentration would then move a short distance along the lower-than-normal buffer line (from point G toward point H) until a new lower Paco2 is attained. This returns the pHa toward normal; complete compensation does not occur. The respiratory compensation for metabolic acidosis occurs almost simultaneously with the development of the acidosis. The blood pH, Pco2, and bicarbonate concentration point does not really move first from the normal (point A) to point G and then move a short distance along line GH; instead, the compensation begins to occur as the acidosis develops, so the point takes an intermediate pathway between the two lines. The respiratory compensation for metabolic alkalosis is to decrease alveolar ventilation, thus increasing Paco2. This decreases pHa toward normal, as can be seen in Figure 37–2. Point D represents uncompensated metabolic alkalosis; respiratory compensation would move the blood pHa, PaCo2, and bicarbonate concentration point a short distance along the new higher-than-normal blood–buffer line toward point F. Again the compensation occurs as the alkalosis develops, with the point moving along an intermediate course. Under most circumstances, the cause of respiratory acidosis or alkalosis is a dysfunction in the ventilatory control

RENAL COMPENSATORY MECHANISMS The kidneys can compensate for respiratory acidosis and metabolic acidosis of nonrenal origin by excreting fixed acids and by retaining filtered bicarbonate. They can also compensate for respiratory alkalosis or metabolic alkalosis of nonrenal origin by decreasing hydrogen ion excretion and by decreasing the retention of filtered bicarbonate. These mechanisms are discussed in Chapter 47. Renal compensatory mechanisms for acid–base disturbances operate much more slowly than respiratory compensatory mechanisms. For example, the renal compensatory responses to sustained respiratory acidosis or alkalosis may take 3–6 days. The kidneys help regulate acid–base balance by altering the excretion of fixed acids and the retention of the filtered bicarbonate; the respiratory system helps regulate body acid–base balance by adjusting alveolar ventilation to alter alveolar Pco2. For these reasons, the Henderson–Hasselbalch equation is in effect: Kidneys

pH = Constant + ______ Lungs

(4)

CLINICAL INTERPRETATION OF ARTERIAL BLOOD GASES Samples of arterial blood are usually analyzed clinically to determine the “arterial blood gases”: the arterial Po2, Pco2, and pH. The plasma bicarbonate can then be calculated from the pH and Pco2 by using the Henderson–Hasselbalch equation. This can be done directly, or by using a nomogram, or by graphical analysis such as the pH–bicarbonate diagram (the “Davenport plot,” after its popularizer), the pH– Pco2 diagram (the “Siggaard-Andersen”), or the composite acid–base diagram. Blood gas analyzers perform these calculations automatically. Table 37–6 summarizes the changes in pHa, Paco2, and plasma bicarbonate concentration that occur in simple, mixed, and partially compensated acid–base disturbances. It contains the same information shown in Figure 37–2, depicted differently. A thorough understanding of the patterns shown in Table 37–6 coupled with knowledge of a patient’s Pco2 and other clinical findings can reveal a great deal about the underlying pathophysiologic processes in progress. A simple approach to interpreting a blood gas set is to first look at the pH to determine whether the predominant problem is acidosis or alkalosis. (Note that an acidemia could represent more than one cause of acidosis, an acidosis with some compensation, or even an acidosis and a separate underlying

CHAPTER 37 Acid–Base Regulation and Causes of Hypoxia

TABLE 37–6 Acid–base disturbances. pH

PCO2

HCO3−

Uncompensated respiratory acidosis

↓↓

↑↑

↑

Uncompensated respiratory alkalosis

↑↑

↓↓

↓

Uncompensated metabolic acidosis

↓↓

↔

↓↓

Uncompensated metabolic alkalosis

↑↑

↔

↑↑

Partially compensated respiratory acidosis

↓

↑↑

↑↑

Partially compensated respiratory alkalosis

↑

↓↓

↓↓

Partially compensated metabolic acidosis

↓

↓↓

↓↓

Partially compensated metabolic alkalosis

↑

↑↑

↑↑

Respiratory and metabolic acidosis

↓↓

↑↑

↓

Respiratory and metabolic alkalosis

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Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.

alkalosis. Similarly, an alkalemia could represent more than one cause of alkalosis, an alkalosis with some compensation, or even an alkalosis and a separate underlying acidosis.) After evaluating the pH, look at the arterial Pco2 to see if it explains the pH. For example, if the pH is low and the Pco2 is increased, then the primary problem is respiratory acidosis. If the pH is low and the Pco2 is near 40 mm Hg, then the primary problem is metabolic acidosis with little or no compensation. If both the pH and the Pco2 are low, there is metabolic acidosis with respiratory compensation. Then look at the bicarbonate concentration to confirm your diagnosis. It should be slightly increased in uncompensated respiratory acidosis, high in partially compensated respiratory acidosis, and low in metabolic acidosis. If the pH is high and the Pco2 is low, then the primary problem is respiratory alkalosis. If the pH is high and the Pco2 is near 40 mm Hg, then the problem is uncompensated metabolic alkalosis. If both the pH and the Pco2 are high, then there is partially compensated metabolic alkalosis. The bicarbonate should be slightly decreased in respiratory alkalosis, decreased in partially compensated respiratory alkalosis, and increased in metabolic alkalosis.

BASE EXCESS Calculation of the base excess or base deficit may be very useful in determining the therapeutic measures to be admin-

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istered to a patient. The base excess or base deficit is the number of milliequivalents of acid or base needed to titrate 1 L of blood to pH 7.4 at 37°C if the Paco2 were held constant at 40 mm Hg. It is not, therefore, just the difference between the plasma bicarbonate concentration of the sample in question and the normal plasma bicarbonate concentration because respiratory adjustments also cause a change in bicarbonate concentration: the arterial Pco2 must be considered, although in most cases the vertical deviation of the bicarbonate level above or below the blood–buffer line on the Davenport diagram at the pH of the sample is a reasonable estimate. Base excess can be determined by actually titrating a sample or by using a nomogram, diagram, or calculator program. Most blood gas analyzers calculate the base excess automatically. The base excess is expressed in milliequivalents per liter above or below the normal buffer-base range—it therefore has a normal value of 0 ± 2 mEq/L. A base deficit is also called a negative base excess. The base deficit can be used to estimate how much sodium bicarbonate (in mEq) should be given to a patient by multiplying the base deficit (in mEq/L) times the patient’s estimated extracellular fluid (ECF) space (in liters), which is the distribution space for the bicarbonate. The ECF is usually estimated to be 0.3 times the lean body mass in kilograms.

ANION GAP Calculation of the anion gap can be helpful in determining the cause of a patient’s metabolic acidosis. It is determined by subtracting the sum of a patient’s plasma chloride and bicarbonate concentrations (in mEq/L) from his or her plasma sodium concentration: Anion gap =[Na+]–([C1–]+[HCO3–])

(5)

The anion gap is normally 12 ± 4 mEq/L. The sum of all of the plasma cations must equal the sum of all of the plasma anions, so the anion gap exists only because all of the plasma cations and anions are not measured when standard blood chemistry is done. Sodium, chloride, and bicarbonate concentrations are almost always reported. The normal anion gap is a result of the presence of more unmeasured anions than unmeasured cations in normal blood: [Na+]+[Unmeasured cations]= [ C1 ]+[HCO3–]+[Unmeasured anions]

(6)

[Na+]–([ C1–]+[HCO3–])= [Unmeasured anions]–[Unmeasured cations]

(7)

–

The anion gap is therefore the difference between the unmeasured anions and the unmeasured cations. The negative charges on the plasma proteins probably make up most of the normal anion gap, because the total charges of the other plasma cations (K+, Ca2+, Mg2+) are approximately equal to the total charges of the other anions (PO43−, SO42−, organic anions).

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An increased anion gap usually indicates an increased number of unmeasured anions (those other than C1– and HCO3−) or a decreased number of unmeasured cations (K+, Ca2+, or Mg2+), or both. This is most likely to happen when the measured anions, [HCO3−] or [Cl–], are lost and replaced by unmeasured anions. For example, the buffering by HCO3− of H+ from ingested or metabolically produced acids produces an increased anion gap. Thus, metabolic acidosis with an abnormally great anion gap (i.e., greater than 16 mEq/L) would probably be caused by lactic acidosis or ketoacidosis; ingestion of organic anions such as salicylate, methanol, and ethylene glycol; or renal retention of anions such as sulfate, phosphate, and urate.

THE CAUSES OF HYPOXIA Thus far, only two of the three variables referred to as the arterial blood gases, the arterial Pco2, and pH have been discussed. Many abnormal conditions or diseases can cause a low arterial Po2. They are discussed in the following section about the causes of tissue hypoxia in the discussion of hypoxic hypoxia. The causes of tissue hypoxia can be classified (in some cases rather arbitrarily) into four or five major groups (Table 37–7). The underlying physiology of most of these types of hypoxia has already been discussed in this or previous chapters.

HYPOXIC HYPOXIA Hypoxic hypoxia refers to conditions in which the arterial Po2 is abnormally low. Because the amount of oxygen that will combine with hemoglobin is mainly determined by the Po2, such conditions may lead to decreased oxygen delivery to the tissues if reflexes or other responses cannot adequately increase the cardiac output or hemoglobin concentration of the blood.

Low Alveolar PO2 Conditions causing low alveolar Po2 inevitably lead to low arterial Po2 and oxygen contents because the alveolar Po2 determines the upper limit of arterial Po2. Hypoventilation leads to both alveolar hypoxia and hypercapnia (high CO2), as discussed in Chapter 33. Hypoventilation can be caused by depression or injury of the respiratory centers in the brain (discussed in Chapter 38), interference with the nerves supplying the respiratory muscles, as in spinal cord injury, neuromuscular junction diseases such as myasthenia gravis, and altered mechanics of the lung or chest wall, as in noncompliant lungs due to sarcoidosis, reduced chest wall mobility because of kyphoscoliosis or obesity, and airway obstruction. Ascent to high altitude causes alveolar hypoxia because of the reduced total barometric pressure encountered above sea level. Reduced FIo2 (fractional concentration of inspired oxygen) has a similar effect. Alveolar carbon dioxide is decreased because of the reflex increase in ventilation caused by hypoxic stimulation, as will be discussed in Chapter 71. Hypoventilation and ascent to high altitude lead to decreased venous Po2 and oxygen content as oxygen is extracted from the already hypoxic arterial blood. Administration of increased oxygen concentrations in the inspired gas can alleviate the alveolar and arterial hypoxia in hypoventilation and in ascent to high altitude, but it cannot reverse the hypercapnia of hypoventilation. In fact, administration of increased FIo2 to spontaneously breathing patients hypoventilating because of a depressed central response to carbon dioxide (see Chapter 38) can further depress ventilation.

Diffusion Impairment Alveolar–capillary diffusion is discussed in greater detail in Chapter 35. Conditions such as interstitial fibrosis and interstitial or alveolar edema can lead to low arterial Po2 and contents with normal or elevated alveolar Po2. High FIo2 that increases the alveolar Po2 to very high levels may increase the

TABLE 37–7 A classification of the causes of hypoxia. PAO2

PaO2

CaO2

P –V O2

C–V O2

Increased FIO2 Helpful?

Low

Low

Low

Low

Low

Yes

Diffusion impairment

N

Low

Low

Low

Low

Yes

Right-to-left shunts

N

Low

Low

Low

Low

No

˙V/ Q ˙ mismatch

N

Low

Low

Low

Low

Yes

Anemic hypoxia

N

N

Low

Low

Low

No

CO poisoning

N

N

Low

Low

Low

Possibly

Hypoperfusion hypoxia

N

N

N

Low

Low

No

Histotoxic hypoxia

N

N

N

High

High

No

Classification Hypoxic hypoxia Low alveolar PO

2

N, normal. Reproduced with permission from Levitzky MG: Pulmonary Physiology, 7th ed. New York: McGraw-Hill Medical, 2007.

CHAPTER 37 Acid–Base Regulation and Causes of Hypoxia arterial Po2 by increasing the partial pressure gradient for oxygen diffusion.

Shunts True right-to-left shunts, such as anatomic shunts and absolute intrapulmonary shunts, can cause decreased arterial Po2 with normal or even increased alveolar Po2. Patients with intrapulmonary shunts have low arterial Po2, but may not have significantly increased Pco2 if they are able to increase their alveolar ventilation or if they are mechanically ventilated. This is a result of the different shapes of the oxyhemoglobin dissociation curve (see Figure 36–1) and the carbon dioxide dissociation curve (see Figure 36–5). The carbon dioxide dissociation curve is almost linear in the normal range of arterial Pco2, and arterial Pco2 is very tightly regulated by the respiratory control system (see Chapter 38). Carbon dioxide retained in the shunted blood stimulates increased alveolar ventilation, and because the carbon dioxide dissociation curve is nearly linear, increased ventilation will allow more carbon dioxide to diffuse from the nonshunted blood into well-ventilated alveoli and be exhaled. On the other hand, increasing alveolar ventilation will not get any more oxygen into the shunted blood and, because of the shape of the oxyhemoglobin dissociation curve, very little more into the unshunted blood. This is because the hemoglobin of well-ventilated and perfused alveoli is nearly saturated with oxygen, and little more will dissolve in the plasma. Similarly, arterial hypoxemia caused by true shunts is not relieved by high FIo2 because the shunted blood does not come into contact with the high levels of oxygen. The hemoglobin of the unshunted blood is nearly completely saturated with oxygen at a normal FIo2 of 0.21, and the small additional volume of oxygen dissolved in the blood at high FIo2 cannot make up for the low hemoglobin saturation of the shunted blood.

VENTILATION–PERFUSION MISMATCH ˙ /Q ˙) Alveolar–capillary units with low ventilation–perfusion (V ratios contribute to arterial hypoxia, as already discussed. Units ˙ /Q ˙ do not by themselves lead to arterial hypoxia, of with high V course, but large lung areas that are underperfused are usually associated either with overperfusion of other units or with low cardiac outputs (see the section “Hypoperfusion Hypoxia”). Hypoxic pulmonary vasoconstriction (discussed in Chapter 34) and local airway responses (discussed in Chapter 32) nor˙/Q ˙ mismatch. mally help minimize V ˙/Q ˙ mismatch Note that diffusion impairment, shunts, and V increase the alveolar–arterial Po2 difference (see Table 35–1 and the first two columns in Table 37–7).

ANEMIC HYPOXIA Anemic hypoxia is caused by a decrease in the amount of functioning hemoglobin, which can be a result of decreased hemoglobin or erythrocyte production, the production of abnormal hemoglobin or red blood cells, pathologic destruction of eryth-

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rocytes, or interference with the chemical combination of oxygen and hemoglobin. Carbon monoxide poisoning, for example, results from the greater affinity of hemoglobin for carbon monoxide than for oxygen. Methemoglobinemia is a condition in which the iron in hemoglobin has been altered from the Fe2+ to the Fe3+ form, which does not combine with oxygen. Anemic hypoxia results in a decreased oxygen content when both alveolar and arterial Po2 are normal. Standard analysis of arterial blood gases could therefore give normal values unless blood oxygen content is measured independently. Venous Po2 and oxygen content are both decreased. Administration of high FIo2 is not effective in greatly increasing the arterial oxygen content (except possibly in carbon monoxide poisoning).

HYPOPERFUSION HYPOXIA Hypoperfusion hypoxia (sometimes called stagnant hypoxia) results from low blood flow. This can occur either locally, in a particular vascular bed, or systemically, in the case of a low cardiac output. The alveolar Po2 and the arterial Po2 and oxygen content may be normal, but the reduced oxygen delivery to the tissues may result in tissue hypoxia. Venous Po2 and oxygen content are low. Increasing the FIo2 is of little value in hypoperfusion hypoxia (unless it directly increases the perfusion) because the blood flowing to the tissues is already oxygenated normally.

HISTOTOXIC HYPOXIA Histotoxic hypoxia refers to a poisoning of the cellular machinery that uses oxygen to produce energy. Cyanide, for example, binds to cytochrome oxidase in the respiratory chain and effectively blocks oxidative phosphorylation. Alveolar Po2 and arterial Po2 and oxygen content may be normal (or even increased, because low doses of cyanide increase ventilation by stimulating the arterial chemoreceptors). Venous Po2 and oxygen content are increased because oxygen is not utilized in the tissues.

THE EFFECTS OF HYPOXIA Hypoxia can result in reversible tissue injury or even tissue death. The outcome of an hypoxic episode depends on whether the tissue hypoxia is generalized or localized, how severe the hypoxia is, the rate of development of the hypoxia (see Chapter 71), and the duration of the hypoxia. Different cell types have different susceptibilities to hypoxia; unfortunately, brain cells and heart cells are the most susceptible.

CLINICAL CORRELATION A 15-year-old adolescent entered the emergency department with dyspnea (shortness of breath), a feeling of chest tightness, coughing, wheezing, and anxiety. His nail beds and lips were blue (cyanosis).

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He has had frequent episodes of dyspnea and wheezing for several years, especially in the spring, and has been diagnosed with asthma. Pulmonary function tests done at the time of his diagnosis showed lower-than-predicted forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), FEV1/FVC, and peak expiratory flow (PEF). Inhaling a bronchodilator improved all of these. An arterial blood gas was obtained to help determine the severity of the episode. The arterial Po2 was 55 mm Hg, the arterial Pco2 was 32 mm Hg, the arterial pH was 7.52, and the bicarbonate was 25 mEq/L, indicating hypoxemia and uncompensated respiratory alkalosis. Asthma is an episodic obstructive disease and it is reasonable to assume that it would cause CO2 retention and therefore respiratory acidosis during attacks. This is true in very severe asthma attacks, but most asthma attacks result in hypocapnia and respiratory alkalosis. As the asthma attack occurs, bronchial smooth muscle spasm and mucus secretion obstruct the ventilation to some alveoli. Although some hypoxic pulmonary vasoconstriction may occur, it is not sufficient to divert all of the mixed venous blood flow away from these poorly ventilated alveoli. This results in a right-to-left shunt or shuntlike state (Chapter 35), which would therefore be expected to cause the arterial Po2 to decrease and the arterial Pco2 to increase. However, the Pco2 decreases because the patient increases alveolar ventilation if he or she is able to. Irritant receptors in the airways are stimulated by the mucus and by chemical mediators released during the attack. Hypoxia caused by the shunt stimulates the arterial chemoreceptors; the patient also has the feeling of dyspnea (many asthma attacks have an emotional component). All of these factors cause increased breathing and therefore increased alveolar ventilation. Increasing ventilation will get more CO2 out of the blood perfusing ventilated alveoli (and therefore out of the body) but it will not get much oxygen into alveoli supplied by obstructed airways, nor will it get much more oxygen into the blood of the unobstructed alveoli because of the shape of the oxyhemoglobin dissociation curve. Remember that the hemoglobin is already 97.4% saturated with oxygen and not much more will dissolve in the plasma. Therefore, during the attack the patient has hypoxemia, hypocapnia, and respiratory alkalosis. It is only when the attack is so severe that the patient cannot do the additional work of breathing that hypercapnia and respiratory acidosis occur. Acute treatment of asthma is aimed at dilating the airways with a bronchodilator, such as a β2-adrenergic agonist, and relieving the hypoxemia with oxygen. Mechanical ventilation may be used in more severe cases. Chronic treatment includes bronchodilators such as β2-adrenergic agonists; anticholinergics, to block parasympathetically mediated constriction and mucus production; antileukotriene drugs and inhaled corticosteroids, to prevent inflammation; and inhibition of mast cells to prevent them from releasing cytokines.

CHAPTER SUMMARY ■

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Hypoventilation causes respiratory acidosis; the compensation for respiratory acidosis is renal retention of base and excretion of hydrogen ions. Hyperventilation causes respiratory alkalosis; the compensation for respiratory alkalosis is renal excretion of base and retention of hydrogen ions. Ingestion, infusion, overproduction, or decreased renal excretion of hydrogen ions, or loss of bicarbonate ions, can cause metabolic acidosis; the compensation for metabolic acidosis is increased alveolar ventilation. Ingestion, infusion, or excessive renal reabsorption of bases, or loss of hydrogen ions, can cause metabolic alkalosis; the compensation for metabolic alkalosis is decreased alveolar ventilation. Metabolic acidosis with an abnormally elevated anion gap indicates an increased plasma concentration of anions other than chloride and bicarbonate or a decreased plasma concentration of potassium, calcium, or magnesium ions. Tissue hypoxia can be a result of low alveolar Po2,