Physiology SIXTH EDITION Physiolog y LINDA S. COSTANZO, PhD Professor of Physiology and Biophysics Virginia Commonwealth University School of Medicine Richmond, Virginia 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 PHYSIOLOGY, SIXTH EDITION ISBN: 978-0-323-47881-6 Copyright © 2018 by Elsevier, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. 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Library of Congress Cataloging-in-Publication Data Names: Costanzo, Linda S., 1947- author. Title: Physiology / Linda S. Costanzo. Other titles: Physiology (Elsevier) Description: Sixth edition. | Philadelphia, PA : Elsevier, [2018] | Includes index. Identifiers: LCCN 2017002153 | ISBN 9780323478816 (pbk.) Subjects: | MESH: Physiological Phenomena | Physiology Classification: LCC QP31.2 | NLM QT 104 | DDC 612–dc23 LC record available at https://lccn.loc.gov/2017002153 Executive Content Strategist: Elyse O’Grady Senior Content Development Specialist: Jennifer Ehlers Publishing Services Manager: Catherine Jackson Senior Project Manager: Daniel Fitzgerald Designer: Renee Duenow Cover image: Laguna Design/Nerve Cell, abstract artwork/Getty Images Printed in China. Last digit is the print number: 9 8 7 6 5 4 3 2 1 To Heinz Valtin and Arthur C. Guyton, who have written so well for students of physiology Richard, Dan, Rebecca, Sheila, Elise, and Max, who make everything worthwhile Preface Physiology is the foundation of medical practice. A firm grasp of its principles is essential for the medical student and the practicing physician. This book is intended for students of medicine and related disciplines who are engaged in the study of physiology. It can be used either as a companion to lectures and syllabi in discipline-based curricula or as a primary source in integrated or problem-based curricula. For advanced students, the book can serve as a reference in pathophysiology courses and in clinical clerkships. In the sixth edition of this book, as in the previous editions, the important concepts in physiology are covered at the organ system and cellular levels. Chapters 1 and 2 present the underlying principles of cellular physiology and the autonomic nervous system. Chapters 3 through 10 present the major organ systems: neurophysiology and cardiovascular, respiratory, renal, acid-base, gastrointestinal, endocrine, and reproduc- tive physiology. The relationships between organ systems are emphasized to underscore the integrative mechanisms for homeostasis. This edition includes the following features designed to facilitate the study of physiology: ♦ Text that is easy to read and concise: Clear headings orient the student to the orga- nization and hierarchy of the material. Complex physiologic information is presented systematically, logically, and in a stepwise manner. When a process occurs in a specific sequence, the steps are numbered in the text and often correlate with numbers shown in a companion figure. Bullets are used to separate and highlight the features of a process. Rhetorical questions are posed throughout the text to anticipate the questions that students may be asking; by first contemplating and then answering these questions, students learn to explain difficult concepts and rationalize unexpected or paradoxical findings. Chapter summaries provide a brief overview. ♦ Tables and illustrations that can be used in concert with the text or, because they are designed to stand alone, as a review: The tables summarize, organize, and make comparisons. Examples are (1) a table that compares the gastrointestinal hormones with respect to hormone family, site of and stimuli for secretion, and hormone actions; (2) a table that compares the pathophysiologic features of disorders of Ca2+ homeostasis; and (3) a table that compares the features of the action potential in different cardiac tissues. The illustrations are clearly labeled, often with main headings, and include simple diagrams, complex diagrams with numbered steps, and flow charts. ♦ Equations and sample problems that are integrated into the text: All terms and units in equations are defined, and each equation is restated in words to place it in a physiologic context. Sample problems are followed by complete numerical solutions and explanations that guide students through the proper steps in reasoning; by fol- lowing the steps provided, students acquire the skills and confidence to solve similar or related problems. ♦ Clinical physiology presented in boxes: Each box features a fictitious patient with a classic disorder. The clinical findings and proposed treatment are explained in terms of underlying physiologic principles. An integrative approach to the patient is used to emphasize the relationships between organ systems. For example, the case of type I diabetes mellitus involves a disorder not only of the endocrine system but also of the renal, acid-base, respiratory, and cardiovascular systems. vii viii • Preface ♦ Practice questions in “Challenge Yourself” sections book, they will find that their use becomes second at the end of each chapter: Practice questions, which nature. are designed for short answers (a word, a phrase, or a numerical solution), challenge the student to apply This book embodies three beliefs that I hold about principles and concepts in problem solving rather teaching: (1) even complex information can be trans- than to recall isolated facts. The questions are posed mitted clearly if the presentation is systematic, logical, in varying formats and are given in random order. and stepwise; (2) the presentation can be just as effec- They will be most helpful when used as a tool after tive in print as in person; and (3) beginning medical studying each chapter and without referring to the students wish for nonreference teaching materials that text. In that way, the student can confirm his or her are accurate and didactically strong but without the understanding of the material and can determine details that primarily concern experts. In essence, a areas of weakness. Answers are provided at the end book can “teach” if the teacher’s voice is present, if the of the book. material is carefully selected to include essential infor- mation, and if great care is given to logic and sequence. ♦ Teaching videos on selected topics: Because stu- This text offers a down-to-earth and professional pre- dents may benefit from oral explanation of complex sentation written to students and for students. principles, brief teaching videos on selected topics I hope that the readers of this book enjoy their study are included to complement the written text. of physiology. Those who learn its principles well will ♦ Abbreviations and normal values presented in be rewarded throughout their professional careers! appendices: As students refer to and use these common abbreviations and values throughout the Linda S. Costanzo Acknowledgments I gratefully acknowledge the contributions of Elyse O’Grady, Jennifer Ehlers, and Dan Fitzgerald at Elsevier in preparing the sixth edition of Physiology. The artist, Matthew Chansky, revised existing figures and created new figures—all of which beautifully complement the text. Colleagues at Virginia Commonwealth University have faithfully answered my ques- tions, especially Drs. Clive Baumgarten, Diomedes Logothetis, Roland Pittman, and Raphael Witorsch. Sincere thanks also go to the medical students worldwide who have generously written to me about their experiences with earlier editions of the book. My husband, Richard; our children, Dan and Rebecca; our daughter-in-law, Sheila; and our grandchildren, Elise and Max, have provided enthusiastic support and unquali- fied love, which give the book its spirit. ix 1 CHAPTER Cellular Physiology Understanding the functions of the organ systems Volume and Composition of Body Fluids, 1 requires profound knowledge of basic cellular mecha- nisms. Although each organ system differs in its overall Characteristics of Cell Membranes, 4 function, all are undergirded by a common set of physi- Transport Across Cell Membranes, 5 ologic principles. The following basic principles of physiology are Diffusion Potentials and Equilibrium introduced in this chapter: body fluids, with particular Potentials, 14 emphasis on the differences in composition of intracel- Resting Membrane Potential, 18 lular fluid and extracellular fluid; creation of these concentration differences by transport processes in cell Action Potentials, 19 membranes; the origin of the electrical potential differ- Synaptic and Neuromuscular Transmission, 26 ence across cell membranes, particularly in excitable cells such as nerve and muscle; generation of action Skeletal Muscle, 34 potentials and their propagation in excitable cells; Smooth Muscle, 40 transmission of information between cells across syn- apses and the role of neurotransmitters; and the Summary, 43 mechanisms that couple the action potentials to con- Challenge Yourself, 44 traction in muscle cells. These principles of cellular physiology constitute a set of recurring and interlocking themes. Once these principles are understood, they can be applied and integrated into the function of each organ system. VOLUME AND COMPOSITION OF BODY FLUIDS Distribution of Water in the Body Fluid Compartments In the human body, water constitutes a high proportion of body weight. The total amount of fluid or water is called total body water, which accounts for 50% to 70% of body weight. For example, a 70-kilogram (kg) man whose total body water is 65% of his body weight has 45.5 kg or 45.5 liters (L) of water (1 kg water ≈ 1 L water). In general, total body water correlates inversely with body fat. Thus total body water is a higher percentage of body weight when body fat is low and a lower percentage when body fat is high. Because females have a higher percentage of adipose tissue than males, they tend to have less body water. The distribution of water among body fluid compart- ments is described briefly in this chapter and in greater detail in Chapter 6. Total body water is distributed between two major body fluid compartments: intracel- lular fluid (ICF) and extracellular fluid (ECF) (Fig. 1.1). The ICF is contained within the cells and is two-thirds of total body water; the ECF is outside the cells and is one-third of total body water. ICF and ECF are separated by the cell membranes. ECF is further divided into two compartments: plasma and interstitial fluid. Plasma is the fluid circulating in the blood vessels and is the smaller of the two ECF 1 2 • Physiology equivalent of chloride (Cl−). Likewise, one mole of TOTAL BODY WATER calcium chloride (CaCl ) in solution dissociates into 2 two equivalents of calcium (Ca2+) and two equivalents Intracellular fluid Extracellular fluid of chloride (Cl−); accordingly, a Ca2+ concentration of 1 mmol/L corresponds to 2 mEq/L. One osmole is the number of particles into which a solute dissociates in solution. Osmolarity is the con- Interstitial fluid Plasma centration of particles in solution expressed as osmoles per liter. If a solute does not dissociate in solution (e.g., glucose), then its osmolarity is equal to its molarity. If a solute dissociates into more than one particle in solution (e.g., NaCl), then its osmolarity equals the molarity multiplied by the number of particles in solu- Cell membrane Capillary wall tion. For example, a solution containing 1 mmol/L NaCl is 2 mOsm/L because NaCl dissociates into two Fig. 1.1 Body fluid compartments. particles. pH is a logarithmic term that is used to express subcompartments. Interstitial fluid is the fluid that hydrogen (H+) concentration. Because the H+ concen- actually bathes the cells and is the larger of the two tration of body fluids is very low (e.g., 40 × 10−9 Eq/L subcompartments. Plasma and interstitial fluid are in arterial blood), it is more conveniently expressed as separated by the capillary wall. Interstitial fluid is an a logarithmic term, pH. The negative sign means that ultrafiltrate of plasma, formed by filtration processes pH decreases as the concentration of H+ increases, and across the capillary wall. Because the capillary wall is pH increases as the concentration of H+ decreases. Thus virtually impermeable to large molecules such as plasma proteins, interstitial fluid contains little, if any, pH=−log [H+] 10 protein. The method for estimating the volume of the body fluid compartments is presented in Chapter 6. SAMPLE PROBLEM. Two men, Subject A and Subject B, have disorders that cause excessive acid production in the body. The laboratory reports the Composition of Body Fluid Compartments acidity of Subject A’s blood in terms of [H+] and the acidity of Subject B’s blood in terms of pH. Subject The composition of the body fluids is not uniform. ICF A has an arterial [H+] of 65 × 10−9 Eq/L, and Subject and ECF have vastly different concentrations of various B has an arterial pH of 7.3. Which subject has the solutes. There are also certain predictable differences higher concentration of H+ in his blood? in solute concentrations between plasma and interstitial SOLUTION. To compare the acidity of the blood of fluid that occur as a result of the exclusion of protein each subject, convert the [H+] for Subject A to pH from interstitial fluid. as follows: Units for Measuring Solute Concentrations pH= −log [H+] 10 Typically, amounts of solute are expressed in moles, = −log (65×10−9 Eq/L) 10 equivalents, or osmoles. Likewise, concentrations of = −log (6.5×10−8 Eq/L) solutes are expressed in moles per liter (mol/L), 10 equivalents per liter (Eq/L), or osmoles per liter log1006.5=0.81 (Osm/L). In biologic solutions, concentrations of log 10−8 = −8.0 10 solutes are usually quite low and are expressed in log 6.5×10−8 =0.81+(−8.0)= −7.19 10 millimoles per liter (mmol/L), milliequivalents per liter pH= −−(−7.19)=7.19 (mEq/L), or milliosmoles per liter (mOsm/L). One mole is 6 × 1023 molecules of a substance. One Thus Subject A has a blood pH of 7.19 computed millimole is 1/1000 or 10−3 moles. A glucose concentra- from the [H+], and Subject B has a reported blood tion of 1 mmol/L has 1 × 10−3 moles of glucose in 1 L pH of 7.3. Subject A has a lower blood pH, reflecting a higher [H+] and a more acidic condition. of solution. An equivalent is used to describe the amount of charged (ionized) solute and is the number of moles Electroneutrality of Body Fluid Compartments of the solute multiplied by its valence. For example, one mole of potassium chloride (KCl) in solution dis- Each body fluid compartment must obey the principle sociates into one equivalent of potassium (K+) and one of macroscopic electroneutrality; that is, each