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(BQ) Part 1 book Medical physiology principles for clinical medicine presents the following contents: Cellular physiology, neuromuscular physiology, blood and immunology, cardiovascular physiology. (BQ) Part 1 book Medical physiology principles for clinical medicine presents the following contents: Cellular physiology, neuromuscular physiology, blood and immunology, cardiovascular physiology.
Medical Physiology Principles for Clinical Medicine Fourth Edition Rhoades_FM.indd i 11/12/2011 3:53:53 PM Medical Physiology Principles for Clinical Medicine Fourth Edition EDI T ED B Y Rodney A Rhoades, Ph.D Professor Emeritus Department of Cellular and Integrative Physiology Indiana University School of Medicine Indianapolis, Indiana David R Bell, Ph.D Associate Professor Department of Cellular and Integrative Physiology Indiana University School of Medicine Fort Wayne, Indiana Rhoades_FM.indd iii 11/12/2011 3:53:53 PM Acquisitions Editor: Crystal Taylor Product Managers: Angela Collins & Catherine Noonan Development Editor: Kelly Horvath Marketing Manager: Joy Fisher-Williams Vendor Manager: Bridgett Dougherty Manufacturing Manager: Margie Orzech Design & Art Direction: Doug Smock & Jen Clements Compositor: SPi Global Fourth Edition Copyright © 2013, 2008, 2003, 1995 Lippincott Williams & Wilkins, a Wolters Kluwer business 351 West Camden Street Two Commerce Square Baltimore, MD 21201 2001 Market Street Philadelphia, PA 19103 Printed in China All rights reserved This book is protected by copyright No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews Materials appearing in this book prepared by individuals as part of their official duties as U.S government employees are not covered by the above-mentioned copyright To request permission, please contact Lippincott Williams & Wilkins at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at permissions@lww.com, or via website at lww.com (products and services) Library of Congress Cataloging-in-Publication Data Medical physiology : principles for clinical medicine / edited by Rodney A Rhoades, David R Bell — 4th ed p ; cm Includes index ISBN 978-1-60913-427-3 Human physiology I Rhoades, Rodney II Bell, David R., 1952[DNLM: Physiological Phenomena QT 104] QP34.5.M473 2013 612—dc23 2011023900 DISCLAIMER Care has been taken to confirm the accuracy of the information present and to describe generally accepted practices However, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of the publication Application of this information in a particular situation remains the professional responsibility of the practitioner; the clinical treatments described and recommended may not be considered absolute and universal recommendations The authors, editors, and publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accordance with the current 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http://www.lww.com Lippincott Williams & Wilkins customer service representatives are available from 8:30 am to 6:00 pm, EST Rhoades_FM.indd iv 11/12/2011 3:53:57 PM Preface The function of the human body involves intricate and complex processes at the cellular, organ, and systems level The fourth edition of Medical Physiology: Principles for Clinical Medicine explains what is currently known about these integrated processes Although the emphasis of the fourth edition is on normal physiology, discussion of pathophysiology is also undertaken to show how altered functions are involved in disease processes This not only reinforces fundamental physiologic principles, but also demonstrates how basic concepts in physiology serve as important principles in clinical medicine Our mission for the fourth edition of Medical Physiology: Principles for Clinical Medicine is to provide a clear, accurate, and up-to-date introduction to medical physiology for medical students and other students in the health sciences as well as to waste no space in so doing—each element of this textbook presents a learning opportunity; therefore we have attempted to maximize those opportunities to the fullest ● AUDIENCE AND FUNCTION This book, like the previous edition, is written for medical students as well as for dental, nursing graduate, and veterinary students who are in healthcare professions This is not an encyclopedic textbook Rather, the fourth edition focuses on the basic physiologic principles necessary to understand human function, presented from a fundamentally clinical perspective and without diluting important content and explanatory details Although the book is written primarily with the student in mind, the fourth edition will also be helpful to physicians and other healthcare professionals seeking a physiology refresher In the fourth edition, each chapter has been rewritten to minimize the compilation of isolated facts and make the text as lucid, accurate, and up-to-date as possible, with clearly understandable explanations of processes and mechanisms The chapters are written by medical school faculty members who have had many years of experience teaching physiology and who are experts in their field They have selected material that is important for medical students to know and have presented this material in a concise, uncomplicated, and understandable fashion We have purposefully avoided discussion of research laboratory methods, and/or historical material Although such issues are important in other contexts, most medical students prefer to focus on the essentials We have also avoided topics that are as yet unsettled, while recognizing that new research constantly provides fresh insights and sometimes challenges old ideas ● CONTENT AND ORGANIZATION This book begins with a discussion of basic physiologic concepts, such as homeostasis and cell signaling, in Chapter Chapter covers the cell membrane, membrane transport, and the cell membrane potential Most of the remaining chapters discuss the different organ systems: nervous (Chapters 3–7), muscle (Chapter 8), cardiovascular (Chapters 11–17), respiratory (Chapters 18–21), renal (Chapters 22–23), gastrointestinal (Chapters 25 and 26), endocrine (Chapters 30–35), and reproductive physiology (Chapters 36–38) Special chapters on the blood (Chapter 9), immunology (Chapter 10), and the liver (Chapter 27) are included The immunology chapter emphasizes physiologic applications of immunology Chapters on acid–base regulation (Chapter 24), temperature regulation (Chapter 28), and exercise (Chapter 29) discuss these complex, integrated functions The order of presentation of topics follows that of most United States medical school courses in physiology After the first two chapters, the other chapters can be read in any order, and some chapters may be skipped if the subjects are taught in other courses (e.g., neurobiology or biochemistry) An important objective for the fourth edition is to demonstrate to the student that physiology, the study of normal function, is key to understanding pathophysiology and pharmacology, and that basic concepts in physiology serve as important principles in clinical medicine ● KEY CHANGES As in previous editions, we have continued to emphasize basic concepts and integrated organ function to deepen reader comprehension Many significant changes have been instituted in this fourth edition to improve the delivery and, thereby, the absorption of this essential content Art Most striking among these important changes is the use of full color to help make the fourth edition not only more visually appealing, but also more instructive, especially regarding the artwork Rather than applying color arbitrarily, color itself is used with purpose and delivers meaning Graphs, diagrams, and flow charts, for example, incorporate a coordinated scheme Red is used to indicate stimulatory, augmented, or increased effects, whereas blue connotes inhibitory, impaired, or decreased effects A coordinated color scheme is likewise used throughout to depict transport systems This key, in which pores and channels are blue, active transporters are red, facilitated transport is purple, cell chemical receptors are green, co- and counter-transporters are orange, and voltage-gated transporters are yellow, adds a level of instructiveness to the figures not seen in other physiology textbooks In thus differentiating these elements integral to the workings of physiology by their function, the fourth edition artwork provides visual consistency with meaning from one figure to the next v Rhoades_FM.indd v 11/12/2011 3:53:57 PM vi Preface Artwork was also substantially overhauled to provide a coherent style and point of view An effort has also been made to incorporate more conceptual illustrations alongside the popular and useful graphs and tables of data These beautiful new full-color conceptual diagrams guide students to an understanding of the general underpinnings of physiology Figures now work with text to provide meaningful, comprehensible content Students will be relieved to find concepts “clicking” like never before Text Another important improvement for the fourth edition is that most chapters were not only substantially revised and updated, but they were also edited to achieve unity of voice as well as to be as concise as possible, both of which approaches considerably enhance clarity All of the abundant chapter review questions (now numbering over 500) are again online and interactive They have been updated to United States Medical Licensing Examination (USMLE) format with explanations for right and wrong answers These questions are analytical in nature and test the student’s ability to apply physiologic principles to solving problems rather than test basic fact-based recall These questions were written by the author of the corresponding chapter and contain explanations of the correct and incorrect answers Also, the extensive test bank written by subject matter experts is once again available for instructors using this textbook in their courses ● PEDAGOGY Features This fourth edition incorporates many features designed to facilitate learning Guiding the student along his or her study of physiology are such in-print features as: Finally, we have also revised and improved the features in the book to be as helpful and useful as possible First, a set of active learning objectives at the beginning of each chapter indicate to the student what they should be able to with the material in the chapter once it has been mastered, rather than merely telling them what they should master, as in other textbooks These objectives direct the student to apply the concepts and processes contained in the chapter rather than memorize facts They urge the student to “explain,” “describe,” or “predict” rather than “define,” “identify,” or “list.” Next, chapter subheadings are presented as active concept statements designed to convey to the student the key point(s) of a given section Unlike typical textbook subheadings that simply title a section, these are given in full sentence form and appear in bold periodically throughout a chapter Taken together, these revolutionary concept statements add up to another way to neatly summarize the chapter for review The clinical focus boxes have once again been updated for the fourth edition These essays deal with clinical applications of physiology rather than physiology research In addition, we are reprising the “From Bench to Bedside” essays introduced in the third edition Because these focus on physiologic applications in medicine that are “just around the corner” for use in medical practice, readers will eagerly anticipate these fresh, new essays published with each successive edition Students will appreciate the book’s inclusion of such helpful, useful tools as the glossary of text terms, which has been expanded by nearly double for the fourth edition and corresponds to bolded terms within each chapter Updated lists of common abbreviations in physiology and of normal blood values are also provided in this edition As done previously, each chapter includes two online case studies, with questions and answers In addition, a third, new style of case study has been added in each chapter, designed to integrate concepts between organ function and the various systems These might require synthesizing material across multiple chapters to prepare students for their future careers and get them thinking like clinicians • Active Learning Objectives These active statements are supplied to the student to indicate what they should be able to with chapter material once it has been mastered • Readability The text is a pleasure to read, and topics are developed logically Difficult concepts are explained clearly, in a unified voice, and supported with plentiful illustrations Minutiae and esoteric topics are avoided • Vibrant Design The fourth edition interior has been completely revamped The new design not only makes navigating the text easier, but also draws the reader in with immense visual appeal and strategic use of color Likewise, the design highlights the pedagogical features, making them easier to find and use • Key Concept Subheadings Second-level topic subheadings are active full-sentence statements For example, instead of heading a section “Homeostasis,” the heading is “Homeostasis is the maintenance of steady states in the body by coordinated physiological mechanisms.” In this way, the key idea in a section is immediately obvious Add them up, and the student has another means of chapter review • Boldfacing Key terms are boldfaced upon their first appearance in a chapter These terms are explained in the text and defined in the glossary for quick reference • Illustrations and Tables Abundant full-color figures illustrate important concepts These illustrations often show interrelationships between different variables or components of a system Many of the figures are colorcoded flow diagrams, so that students can appreciate the sequence of events that follow when a factor changes Red is used to indicate stimulatory effects, and blue indicates inhibitory effects All illustrations are now rendered in full color to reinforce concepts and enhance reader comprehension Review tables provide useful summaries of material explained in more detail in the text • Clinical Focus and Bench to Bedside Boxes Each chapter contains two Clinical Focus boxes and one all-new Bench to Bedside box, which illustrate the relevance of Rhoades_FM.indd vi 11/12/2011 3:53:57 PM Preface • • • • the physiology discussed in the chapter to clinical medicine and help the reader make those connections Bulleted Chapter Summaries These bulleted statements provide a concise summative description of the chapter, and provide a good review of the chapter Abbreviations and Normal Values This third edition includes an appendix of common abbreviations in physiology and a table of normal blood, plasma, or serum values on the inside book covers for convenient access All abbreviations are defined when first used in the text, but the table of abbreviations in the appendix serves as a useful reminder of abbreviations commonly used in physiology and medicine Normal values for blood are also embedded in the text, but the table on the inside front and back covers provides a more complete and easily accessible reference Index A comprehensive index allows the student to easily look up material in the text Glossary A glossary of all boldfaced terms in the text is included for quick access to definition of terms Ancillary Package Still more features round out the colossal ancillary package online at These bonus offerings provide ample opportunities for self-assessment, additional reading on tangential topics, and animated versions of the artwork to further elucidate the more complex concepts vii • Case Studies Each chapter is associated with two online case studies with questions and answers These case studies help to reinforce how an understanding of physiology is important in dealing with clinical conditions A new integrated case study has also been added to each chapter to help the student better understand integrated function • Review Questions and Answers Students can use the interactive online chapter review questions to test whether they have mastered the material These USMLE-style questions should help students prepare for the Step examination Answers to the questions are also provided online and include complete explanations as to why the choices are correct or incorrect • Suggested Reading A short list of recent review articles, monographs, book chapters, classic papers, or websites where students can obtain additional information associated with each chapter is provided online • Animations The fourth edition contains online animations illustrating difficult physiology concepts • Image Bank for Instructors An image bank containing all of the figures in the book, in both pdf and jpeg formats is available for download from our website at Rodney A Rhoades, Ph.D David R Bell, Ph.D Visit http://thePoint.lww.com for chapter review Q&A, case studies, animations, and more! Rhoades_FM.indd vii 11/12/2011 3:53:57 PM Contributors DAVID R BELL, PH.D Associate Professor of Cellular and Integrative Physiology Indiana University School of Medicine Fort Wayne, Indiana ROBERT V CONSIDINE, PH.D Associate Professor of Medicine and Physiology Indiana University School of Medicine Indianapolis, Indiana JEFFREY S ELMENDORF, PH.D Associate Professor of Cellular and Integrative Physiology Physiology Indiana University School of Medicine Indianapolis, Indiana RODNEY A RHOADES, PH.D Professor Emeritus Department of Cellular and Integrative Physiology Indiana University School of Medicine Indianapolis, Indiana GEORGE A TANNER, PH.D Emeritus Professor of Cellular and Integrative Physiology Indiana University School of Medicine Indianapolis, Indiana GABI NINDL WAITE, PH.D Associate Professor of Cellular and Integrative Physiology Indiana University School of Medicine Terre Haute Center for Medical Education Terre Haute, Indiana PATRICIA J GALLAGHER, PH.D Associate Professor of Cellular and Integrative Physiology Indiana University School of Medicine Indianapolis, Indiana FRANK A WITZMANN, PH.D Professor of Cellular and Integrative Physiology Indiana University School of Medicine Indianapolis, Indiana JOHN C KINCAID, M.D Professor of Neurology and Physiology Indiana University School of Medicine Indianapolis, Indiana JACKIE D WOOD, PH.D Professor of Physiology Ohio State University College of Medicine Columbus, Ohio viii Rhoades_FM.indd viii 11/12/2011 3:53:58 PM Acknowledgments We would like to express our deepest thanks and appreciation to all of the contributing authors Without their expertise and cooperation, this fourth edition would have not been possible We also wish to express our appreciation to all of our students and colleagues who have provided helpful comments and criticisms during the revision of this book, particularly, Shloka Anathanarayanan, Robert Banks, Wei Chen, Steve Echtenkamp, Alexandra Golant, Michael Hellman, Jennifer Huang, Kristina Medhus, Ankit Patel, and Yuri Zagvazdin We would also like to give thanks for a job well done to our editorial staff for their guidance and assistance in significantly improving each edition of this book A very special thanks goes to our Developmental Editor, Kelly Horvath, who was a delight to work with, and whose patience and editorial talents were essential to the completion of the fourth edition of this book We are indebted as well to our artist, Kim Battista Finally, we would like to thank Crystal Taylor, our Acquisitions Editor at Lippincott Williams and Wilkins, for her support, vision, and commitment to this book We are indebted to her administrative talents and her managing of the staff and material resources for this project Lastly, we would like to thank our wives, Pamela Bell and Judy Rhoades, for their love, patience, support, and understanding of our need to devote a great deal of personal time and energy to the development of this book ix Rhoades_FM.indd ix 11/12/2011 3:53:58 PM Contents Preface v Contributors viii Acknowledgments ix PA RT I • CEL L ULAR PHYSIOLOGY Homeostasis and Cellular Signaling Patricia J Gallagher, Ph.D CHAPTER • Basis of Physiologic Regulation Communication and Signaling Modes Molecular Basis of Cellular Signaling Second Messengers Roles 15 Mitogenic Signaling Pathways 21 Plasma Membrane, Membrane Transport, and Resting Membrane Potential Robert V Considine, Ph.D CHAPTER • Plasma Membrane Structure 24 Solute Transport Mechanisms 26 Water Movement Across the Plasma Membrane Resting Membrane Potential 39 PA RT I I • 24 37 NE UROM U SCU LAR PHYSIOLOGY 42 Action Potential, Synaptic Transmission, and Maintenance of Nerve Function John C Kincaid, M.D CHAPTER • 42 Neuronal Structure 42 Action Potentials 46 Synaptic Transmission 51 Neurotransmission 54 Sensory Physiology David R Bell, Ph.D., Rodney A Rhoades, Ph.D 61 CHAPTER • Sensory System 61 Somatosensory System 67 Visual System 69 Auditory System 76 Vestibular System 82 Gustatory and Olfactory Systems 85 Motor System John C Kincaid, M.D 91 CHAPTER • x Rhoades_FM.indd x Skeleton as Framework for Movement 91 Muscle Function and Body Movement 91 Nervous System Components for the Control of Movement Spinal Cord in the Control of Movement 96 Supraspinal Influences on Motor Control 98 92 11/12/2011 3:53:58 PM 17 A CT I V E Control Mechanisms in Circulatory Function LE ARNING OBJ E CTIVE S set into motion to restore normal blood pressure and cardiac output upon standing • Predict the effect of hypotensive events on the metabolism and viability based on the neurohumoral mechanisms activated by the hypotension • Explain the mechanisms responsible for progressive shock • Correctly identify the initiating causes and unique complications of shock caused by hemorrhage, severe vomiting, sweating, diarrhea, decreased fluid and electrolyte intake, kidney damage, adrenal cortical destruction, severe burns, intestinal obstructions, general or spinal anesthesia, fever, emotional stress, anaphylaxis, and sepsis T hormone or ADH), angiotensin II, aldosterone, and atrial natriuretic peptide (ANP), serve as effectors for the regulation of blood volume by regulating salt and water balance Neural control of cardiac output and SVR plays a larger role in the moment-to-moment regulation of arterial pressure, whereas hormones play a larger role in the long-term regulation of arterial pressure In some situations, factors other than blood volume and arterial pressure regulation strongly influence cardiovascular control mechanisms These situations include the fight-or-flight response, diving, thermoregulation, standing, and exercise he mechanisms controlling the circulation involve individual and cooperative effects among neural control mechanisms, hormonal control mechanisms, and local control mechanisms Local vascular control mechanisms were discussed in Chapter 15, “Microcirculation and Lymphatic System.” This chapter will focus on neural and hormonal mechanisms Neural and hormonal mechanisms are primarily involved with the control of central blood volume and arterial pressure Adequate central blood volume is necessary to ensure proper cardiac output In addition, autoregulation of blood flow would not function properly without some mechanism to maintain a relatively constant arterial blood pressure Neural control of the cardiovascular system involves sympathetic and parasympathetic branches of the autonomic nervous system (ANS) Blood volume and arterial pressure are monitored by stretch receptors in the heart and arteries Afferent nerve traffic from these receptors is integrated with other afferent information in the medulla oblongata, which leads to activity in sympathetic and parasympathetic nerves that adjust heart rate, myocardial contraction, arterial resistance, and venous tone In this way, cardiac output and systemic vascular resistance (SVR) are adjusted to maintain arterial pressure. Sympathetic nerve activity and, more important, hormones, such as arginine vasopressin (AVP) (i.e., antidiuretic ● Cardiovascular Physiology Upon mastering the material in this chapter, you should be able to: • Correctly identify changes in cardiovascular variables that can cause hypotension and explain their mechanism of action • Explain how hypotension leads to the activation of neurogenic reflexes that correct the hypotension, and explain the cardiovascular mechanism of the correction • Explain the hormonal mechanisms involved in the defense against hypotension and how these synergize with neurogenic reflexes to control blood pressure • Explain the mechanism of pressure diuresis and how this sets the long-term level of mean arterial pressure • Explain how standing results in a decrease in cardiac output and blood pressure and what mechanisms are AUTONOMIC NEURAL CONTROL OF THE CIRCULATORY SYSTEM Neural regulation of the cardiovascular system involves the firing of postganglionic parasympathetic and sympathetic neurons, triggered by preganglionic neurons in the brain (parasympathetic) and spinal cord (sympathetic and parasympathetic) Afferent inputs influencing these neurons come from specified locations in the cardiovascular system and operate as sensors for arterial pressure and blood volume as well as from other organs and the external environment 311 Rhoades_Chap17.indd 311 11/12/2011 3:27:41 PM ● 312 Part IV / Cardiovascular Physiology Sympathetic fibers to the heart are also tonically active and release NE, which binds to b1-adrenergic receptors in the SA node, the atrioventricular node and specialized conducting tissues, and cardiac muscle Stimulation of these fibers causes increased heart rate, conduction velocity, and contractility Activity along the two divisions of the ANS changes in a reciprocal manner to create changes in heart rate For example, an increase in heart rate is brought about by a simultaneous decrease in parasympathetic and an increase in sympathetic nerve activity to the heart However, control of heart rate is dominated by parasympathetic effects Activation of the parasympathetic system can slow the heart even when the sympathetic system is maximally activated At submaximal sympathetic rates, activation of the vagus nerve can totally suppress the SA node and temporarily cause the heart to stop In contrast to the relationships controlling heart rate, control of cardiac contractility is dominated by sympathetic over parasympathetic effects Inotropic state is only minimally affected by vagal influence, and myocardial contractility is, therefore, primarily modulated by the level of the activity in the sympathetic nerves to ventricular muscle Neurogenic control of the heart involves reciprocal activation of parasympathetic and sympathetic nerves Autonomic control of the heart and blood vessels was described in Chapter 6, “Autonomic Nervous System.” Briefly, the heart is innervated by parasympathetic (vagus) and sympathetic (cardioaccelerator) nerve fibers (Fig 17.1) Parasympathetic fibers to the heart are tonically active That is, they exhibit a steady stream of action potential firing at rest Acetylcholine (ACh) released from these fibers binds to muscarinic receptors of the sinoatrial (SA) and atrioventricular nodes as well as the specialized conducting tissues Stimulation of parasympathetic fibers causes a slowing of the heart rate and conduction velocity The ventricular muscle is only sparsely innervated by parasympathetic nerve fibers, and stimulation of these fibers has only a small negative inotropic effect on the heart Some cardiac parasympathetic fibers end on sympathetic nerves and inhibit the release of norepinephrine (NE) from sympathetic nerve fibers Therefore, in the presence of sympathetic nervous system activity, parasympathetic activation reduces cardiac contractility Sympathetic Parasympathetic Vagus nerves Ganglion – + ACh SA NE ACh + – ACh AV NE + NE – ACh ACh + Thoracic Adrenal medulla ACh ACh Arteries and veins + 90% E 10% NE + NE Lumbar NE + Sacral Blood vessels of external genitalia ACh Na+ and H20 retention ACh ● Figure 17.1 Autonomic innervation of the cardiovascular system ACh, acetylcholine; NE, norepinephrine; E, epinephrine; SA, sinoatrial node; AV, atrioventricular node Rhoades_Chap17.indd 312 11/12/2011 3:27:41 PM ● 313 Chapter 17 / Control Mechanisms in Circulatory Function There is no known parasympathetic innervation of blood vessels in systemic organs with the exception of those of the external genitalia Sympathetic fibers innervate arteries and veins of all the major systemic organs except the brain (see Fig 17.1) These fibers tonically release NE, which binds to a1-adrenergic and b2-adrenergic receptors on blood vessels However, because the arteries of all vascular beds except the heart and brain contain more a1-adrenergic than b2-adrenergic receptors, activation of the sympathetic nerves to the systemic circulations causes vasoconstriction and an increase in SVR Circulating epinephrine, released from modified sympathetic nerve endings in the adrenal medulla, binds to a1-adrenergic and b2-adrenergic receptors of vascular and smooth muscle cells, as well However, the affinity of both b1 and b2 receptors for epinephrine is greater than that for NE Therefore, at low circulating concentrations, epinephrine essentially activates only b receptors, with the effect of increasing cardiac output (chronotropic and inotropic effects) but decreasing SVR Postganglionic parasympathetic fibers release ACh and nitric oxide (NO) to blood vessels in the external genitalia ACh causes the further release of NO from endothelial cells, which results in vascular smooth muscle relaxation and vasodilation These fibers mediate erection in males and engorgement of the female genitalia Arterial effects of spinal cord injury The steady train of sympathetic nerve activity, or tone, to blood vessels, the heart, and the adrenal medulla produces a background level of sympathetic vasoconstriction, cardiac stimulation, and adrenal catecholamine secretion in the body All of these factors contribute to the maintenance of normal blood pressure This tonic activity is generated by excitatory signals from the medulla oblongata When the spinal cord is acutely transected and these excitatory signals can no longer reach sympathetic preganglionic fibers, their tonic firing is reduced and blood pressure falls This effect is known as spinal shock Humans have spinal reflexes of cardiovascular significance For example, the stimulation of pain fibers entering the spinal cord below the level of a chronic spinal cord transection can cause reflex vasoconstriction and increased blood pressure Cardiovascular reflex integration by the medulla oblongata The medulla oblongata has three major cardiovascular functions: (1) generating tonic excitatory signals to spinal sympathetic preganglionic fibers, (2) integrating cardiovascular reflexes, and (3) integrating signals from supramedullary neural networks, circulating hormones and drugs Specific pools of neurons are responsible for elements of these functions Neurons in the rostral ventrolateral nucleus (RVL) are normally active and provide tonic excitatory activity to the spinal cord Specific pools of neurons within the RVL have actions on the heart and blood vessels RVL neurons are critical in mediating reflex inhibition or activating sympathetic firing to the heart and blood vessels The cell bodies of cardiac preganglionic parasympathetic neurons are Rhoades_Chap17.indd 313 located in the nucleus ambiguus; the activity of these neurons is influenced by reflex input as well as input from respiratory neurons Respiratory sinus arrhythmia is primarily the result of the influence of medullary respiratory neurons that inhibit firing of preganglionic parasympathetic neurons during inspiration and excite these neurons during expiration Other inputs to the RVL and nucleus ambiguus will be described below Baroreceptor reflexes maintain the moment-to-moment level of arterial pressure The most important reflex control of the cardiovascular system originates in mechanoreceptors located in the aorta, carotid sinuses, atria, ventricles, and pulmonary vessels These mechanoreceptors are sensitive to the stretch of the walls of these structures The firing rate of nerves from these mechanoreceptors increases when the wall is stretched by increased transmural pressure For this reason, mechanoreceptors in the aorta and carotid sinuses are called baroreceptors, arterial baroreceptors, or high-pressure receptors Mechanoreceptors in the atria, ventricles, and pulmonary vessels primarily sense pressure changes brought about by changes in blood volume Therefore, these receptors are referred to as volume-receptors, low-pressure baroreceptors, or cardiopulmonary baroreceptors Changes in the firing rate of the arterial baroreceptors and cardiopulmonary baroreceptors initiate reflex responses of the ANS that alter cardiac output and SVR The central terminals for these receptors are located in the nucleus tractus solitarii (NTS) in the medulla oblongata Neurons from the NTS project to the RVL and nucleus ambiguus, where they influence the firing of sympathetic and parasympathetic nerves Baroreceptor reflex modulates cardiac output and total peripheral resistance to control mean arterial pressure Increased pressure in the carotid sinus and aorta stretches carotid sinus baroreceptors and aortic baroreceptors and raises their firing rate Nerve fibers from carotid sinus baroreceptors join the glossopharyngeal (cranial nerve IX) nerves and travel to the NTS Nerve fibers from the aortic baroreceptors, located in the wall of the arch of the aorta, travel with the vagus (cranial nerve X) nerves to the NTS The increased action potential traffic reaching the NTS leads to excitation of nucleus ambiguus neurons and inhibition of firing of RVL neurons This results in increased parasympathetic neural activity to the heart and decreased sympathetic neural activity to the heart, resistance vessels (primarily arterioles), and veins (Fig 17.2) Collectively, these effects cause decreased cardiac output and SVR Because mean arterial pressure is the product of SVR and cardiac output, mean arterial pressure is returned toward the normal level This completes a negative-feedback loop by which increase in mean arterial pressure can be attenuated Conversely, decreases in arterial pressure (and decreased stretch of the baroreceptors) increase sympathetic neural activity and decrease parasympathetic neural activity, 11/12/2011 3:27:42 PM ● 314 Part IV / Cardiovascular Physiology Intervention + – + Arterial pressure Baroreceptor stretch + Baroreceptor firing rate – Sympathetic activity + Parasympathetic activity ● Figure 17.2 Baroreceptor neural reflex responses to increased arterial pressure An intervention elevates arterial pressure (either mean arterial pressure or pulse pressure), stretches the baroreceptors, and initiates the reflex The resulting reduced systemic vascular resistance and cardiac output return arterial pressure toward the level existing before the intervention Hormonal responses (not shown in the figure) involving adrenal epinephrine and the renin–angiotensin system are also involved in the reflex but more so as a response to hypotension rather than to hypertension Red (+) arrows signify positive effects Blue (−) arrows signify negative effects resulting in increased heart rate, stroke volume, and SVR; this returns blood pressure toward the normal level If the fall in mean arterial pressure is large, increased sympathetic neural activity to veins is added to the above responses, causing contraction of the venous smooth muscle and reducing venous compliance Decreased venous compliance shifts blood toward the central blood volume, increasing right atrial pressure and, in turn, stroke volume The reflex activation of the cardiovascular system in response to changes in mean arterial pressure in order to maintain that pressure within narrow limits is called the baroreceptor reflex This reflex is extremely sensitive in that firing rate from nerves exiting the baroreceptors can sense changes in arterial pressure as little as 0.001 mm Hg These receptors also respond rapidly to the rate of rise in arterial pressure and changes in pulse pressure; firing rate is greater in systole compared to diastole and greater early in systole than later Increased pulse pressure will activate baroreceptor firing even in the absence of a change in mean arterial pressure Baroreceptor reflex activates hormonal systems affecting blood pressure The baroreceptor reflex influences hormone levels in addition to vascular and cardiac muscles The most important influence is on the renin–angiotensin–aldosterone system (RAAS) A decreased baroreceptor firing from decreased systemic arterial pressure results in increased sympathetic nerve activity to the kidneys, which, through activation of renal b2 receptors, causes the kidneys to release renin Renin converts a precursor peptide called angiotensinogen into the peptide angiotensin I, which, in turn, is enzymatically cleaved by pulmonary endothelium to produce an active peptide called angiotensin II A reduction in arterial pressure in the renal artery also stimulates renin release Angiotensin II is Rhoades_Chap17.indd 314 + – – α1-adrenergic β1-adrenergic receptor activation receptor activation – – Force of contraction Systemic vascular resistance – Venous Tone Muscarinic receptor activation – – Heart rate – Stroke volume – Cardiac ouput – a potent vasoconstrictor and stimulates the release of a steroid hormone called aldosterone from the adrenal gland, which causes the kidney to reabsorb salt and water The activation of this system increases vascular resistance and blood volume, ultimately causing blood pressure to rise The details of the RAAS are discussed later in this chapter and in Chapter 23, “Regulation of Fluid and Electrolyte Balance.” The information on the firing rate of the baroreceptors is also projected to the paraventricular nucleus of the hypothalamus, where the release of AVP by the posterior pituitary is controlled (see Chapter 31, “Hypothalamus and the Pituitary Gland”) AVP release is increased by a decrease in the firing rate of the baroreceptors AVP is a vasoconstrictor that also activates receptors in the kidney, causing the kidneys to save water, which results in an increase in blood volume An increase in arterial pressure causes decreased AVP release and increased excretion of water by the kidneys Hormonal effects on salt and water balance and, ultimately, on cardiac output and blood pressure are powerful, but they occur more slowly (a timescale of many hours to days) than ANS effects (seconds to minutes) Baroreceptor reflex preserves flow to the brain and heart The defense of arterial pressure by the baroreceptor reflex results in maintenance of blood flow to two vital organs: the heart and brain If resistance vessels of the heart and brain participated in the sympathetically mediated vasoconstriction found in skeletal muscle, skin, and the splanchnic region during the reflex, it would lower blood flow to these organs This does not happen The combination of a minimal or no vasoconstrictor effect of sympathetic nerves on cerebral blood vessels and a robust autoregulatory response keep brain blood flow nearly normal despite modest decreases in arterial pressure 11/12/2011 3:27:42 PM ● 315 Chapter 17 / Control Mechanisms in Circulatory Function (see Chapter 15, “Microcirculation and Lymphatic System”) Activation of sympathetic nerves to the heart causes b2-adrenergic receptor-mediated dilation of coronary arterioles and b1-adrenergic receptor–mediated increases in cardiac muscle metabolism (see Chapter 16, “Special Circulations”) The net effect is a marked increase in coronary blood flow In summary, when arterial pressure drops, the generalized vasoconstriction caused by the baroreceptor reflex restores blood pressure without vasoconstricting the brain and heart This prevents blood flow from decreasing to the heart and brain whenever blood pressure falls Baroreceptor activation is site-, pressure-, and time-dependent The effective range of the carotid sinus baroreceptor mechanism is approximately 40 mm Hg (when the receptor stops firing) to 180 mm Hg (when the firing rate reaches a maximum) (Fig 17.3) Aortic baroreceptors initiate activation at about 70 mm Hg and reach maximum firing at a higher pressure An important property of the baroreceptor reflex is that it adapts during a period of to days to the prevailing mean arterial pressure When the mean arterial pressure is suddenly raised, baroreceptor firing increases If arterial pressure is held at the higher level, baroreceptor firing declines during the next few seconds Firing rate then continues to decline more slowly until it returns to the original firing rate over the next to days Consequently, if the mean arterial pressure is maintained at an elevated level, the tendency Baroreceptor firing rate Sustained hypertension Operating ranges 93 100 Hypertension Normotension 180 Arterial blood pressure (mm Hg) ● Figure 17.3 Carotid sinus baroreceptor nerve firing rate and mean arterial pressure With normal conditions, a mean arterial pressure of 93 mm Hg is near the midrange of the firing rates for the nerves Sustained hypertension causes the operating range to shift to the right, putting 93 mm Hg at the lower end of the firing range for the nerves Aortic baroreceptors show similar relationships, except the point at which pressure activates the receptor and reaches maximum response is higher than that seen in carotid receptors Rhoades_Chap17.indd 315 Cardiopulmonary baroreceptors sense central blood volume Cardiopulmonary baroreceptors are located in the cardiac atria, at the junction of the great veins and atria, in the ventricular myocardium, and in pulmonary vessels Their nerve fibers run in the vagus nerve to the NTS, with projections to supramedullary areas as well Unloading (i.e., decreasing the stretch) of the cardiopulmonary receptors by reducing central blood volume results in increased sympathetic nerve activity to the heart and blood vessels and decreased parasympathetic nerve activity to the heart In addition, the cardiopulmonary reflex interacts with the baroreceptor reflex Unloading of the cardiopulmonary receptors enhances the baroreceptor reflex, and loading the cardiopulmonary receptors, by increasing central blood volume, inhibits the baroreceptor reflex Like the arterial baroreceptors, decreased stretch of the cardiopulmonary baroreceptors activates the RAAS and increases the release of AVP Chemoreceptors for PCO2, pH, and PO2 affect mean arterial pressure Normal 40 for the baroreceptors to initiate a decrease in cardiac output and SVR quickly disappears This occurs, in part, because of a reduction in the rate of baroreceptor firing for a given mean arterial pressure (see Fig 17.3) This is an example of receptor adaptation A “resetting” of the reflex in the central nervous system (CNS) occurs as well The baroreceptor mechanism can be viewed as the “first line of defense” in the maintenance of normal blood pressure; it makes possible the rapid control of blood pressure needed with changes in posture or blood loss However, this control mechanism does not provide for the long-term control of blood pressure The carotid and aortic bodies are specialized structures located in the areas of the carotid sinus and aortic arch that sense changes in blood O2, CO2, and pH These structures are sometimes referred to as chemoreceptors The carotid and aortic chemoreceptors are primarily involved with control of ventilation (see Chapter 21, “Control of Ventilation”), but they also affect the cardiovascular system through neurogenic reflexes Peripheral chemoreceptors send impulses to the NTS and exhibit increased firing rate when, either the Po2 or pH of the arterial blood is low, the Pco2 of arterial blood is increased, the flow through the bodies is low or stopped, or a chemical is given that blocks oxidative metabolism in the chemoreceptor cells There are also central medullary chemoreceptors that increase their firing rate primarily in response to elevated arterial Pco2, which causes a decrease in brain pH The increased firing of both peripheral and central chemoreceptors (via the NTS and RVL) leads to profound peripheral vasoconstriction that significantly elevates arterial pressure If respiratory movements are voluntarily stopped, the vasoconstriction is more intense and a striking bradycardia and decreased cardiac output occur This response pattern is typical of the diving response (discussed later) As in the case of the baroreceptor reflex, the coronary 11/12/2011 3:27:42 PM ● 316 Part IV / Cardiovascular Physiology and cerebral circulations are not subject to the sympathetic vasoconstrictor effects and instead exhibit vasodilation as a result of the combination of the direct effect of the abnormal blood gases and local metabolic effects In addition to its importance when arterial blood gases are abnormal, the chemoreceptor reflex is important in the cardiovascular response to severe hypotension As blood pressure falls, blood flow through the carotid and aortic bodies decreases and chemoreceptor firing increases, probably because of changes in local Pco2, pH, and Po2 The chemoreceptor reflex, however, does not respond to a change in blood pressure itself until mean arterial pressure drops to about 80 mm Hg Therefore, this reflex is not involved in maintenance of normal blood pressure on a moment-to-moment basis, but rather serves as a secondary emergency reflex if blood pressure continues to fall in spite of activation of the baroreceptor reflex Pain and myocardial ischemia initiate cardiovascular reflexes Two reflex cardiovascular responses to pain occur In the most common reflex, pain causes increased sympathetic activity to the heart and blood vessels, coupled with decreased parasympathetic activity to the heart These events lead to increases in cardiac output, SVR, and mean arterial pressure An example of this reaction is the cold pressor response, which is the elevated blood pressure that normally occurs from pain associated with placing an extremity in ice water The increase in blood pressure produced by this challenge is exaggerated in several forms of hypertension A second type of response is produced by deep pain The stimulation of deep pain fibers associated with crushing injuries, disruption of joints, testicular trauma, or distention of the abdominal organs results in diminished sympathetic activity and enhanced parasympathetic activity with decreased cardiac output, SVR, and blood pressure This hypotensive response contributes to cardiovascular shock from severe trauma (see below) Myocardial ischemia in the posterior and inferior myocardium causes reflex bradycardia and hypotension The bradycardia results from increased parasympathetic tone Dilation of systemic arterioles and veins in this situation is caused by withdrawal of sympathetic tone This response mimics that following an injection of bradykinin, 5-hydroxytryptamine (serotonin), certain prostaglandins, or various other compounds into the coronary arteries supplying the posterior and inferior regions of the ventricles This reflex is responsible for the bradycardia and hypotension that can occur in response to acute infarction of the posterior or inferior myocardium Higher-order ANS responses alter blood pressure and cardiac output The highest levels of organization in the ANS are the supramedullary networks of neurons with weigh stations in the limbic cortex, amygdala, and hypothalamus These supramedullary networks orchestrate cardiovascular responses to specific patterns of emotion and behavior by their projections to the ANS Unlike the medulla, supramedullary networks not contribute to the tonic maintenance of blood pressure, nor Rhoades_Chap17.indd 316 are they necessary for most cardiovascular reflexes However, they modulate reflex reactivity and can affect the behavior of the heart and systemic circulation Fear On stimulation of certain areas in the hypothalamus, cats demonstrate a stereotypical rage response, with spitting, clawing, tail lashing, and back arching This is accompanied by the autonomic fight-or-flight response described in Chapter 6, “Autonomic Nervous System.” This reaction occurs naturally whenever the cat feels threatened and/or experiences fear Cardiovascular responses include elevated heart rate and blood pressure The initial behavioral pattern during the fight-or-flight response includes increased skeletal muscle tone and general alertness There is increased sympathetic neural activity to blood vessels and the heart There is some evidence that sympathetic cholinergic fibers to the muscle arteries elicit a neurogenic vasodilation in skeletal muscles The result of this cardiovascular response is an increase in cardiac output (by increasing both heart rate and stroke volume), SVR, and arterial pressure When the fightor-flight response is consummated by fight or flight, arterioles in skeletal muscle dilate because of accumulation of local metabolites from the exercising muscles This vasodilation may outweigh the sympathetic vasoconstriction in other organs, and SVR may actually fall With a fall in SVR, mean arterial pressure returns toward normal despite the increase in cardiac output Emotional stress Emotional situations often provoke the fight-or-flight response in humans, but it is usually not accompanied by muscle exercise (e.g., medical students taking an examination) The massive vasodilation in skeletal muscle associated with exercise, which helps prevent an elevation of blood pressure upon activation of the sympathetic nervous system, is lost when the system is activated by emotional stress alone For this reason, it has been postulated that repeated elevations in arterial pressure caused by dissociation of the cardiovascular component of the fight-or-flight response from the muscular exercise component are harmful Certain emotional experiences induce vasovagal syncope (fainting) Stimulation of specific areas of the cerebral cortex can lead to a sudden relaxation of skeletal muscles, depression of respiration, and loss of consciousness The cardiovascular events accompanying these somatic changes include profound parasympathetic-induced bradycardia and withdrawal of resting sympathetic vasoconstrictor tone There is a dramatic drop in heart rate, cardiac output, and SVR The resultant decrease in mean arterial pressure results in unconsciousness (fainting) because of lowered cerebral blood flow Vasovagal syncope appears in lower animals as the “playing dead” response typical of the opossum Exercise Exercise causes activation of supramedullary neural networks that inhibit the activity of the baroreceptor reflex The inhibition of medullary regions involved in the baroreceptor 11/12/2011 3:27:43 PM ● 317 Chapter 17 / Control Mechanisms in Circulatory Function reflex is called central command Central command results in withdrawal of parasympathetic tone to the heart, with a resulting increase in heart rate and cardiac output The increased cardiac output supplies the added requirement for blood flow to exercising muscle As exercise intensity increases, central command adds sympathetic tone that further increases heart rate and contractility It also recruits sympathetic vasoconstriction that redistributes blood flow away from splanchnic organs and resting skeletal muscle to exercising muscle The local metabolic vasodilator influences in exercising muscle overwhelm any enhanced sympathetic activity to arteries in the muscle, thereby overriding the constrictor influences of the sympathetic nerves in that muscle Finally, afferent impulses from exercising skeletal muscle terminate in the RVL, where they further augment sympathetic tone During exercise, blood flow of the skin is largely influenced by temperature regulation, as described in Chapter 16, “Special Circulations.” Diving response The diving response is best observed in seals and ducks, but it also occurs in humans An experienced diver can exhibit intense slowing of the heart rate (parasympathetic) and peripheral vasoconstriction (sympathetic) of the extremities and splanchnic regions when his or her face is submerged in cold water With breath holding during the dive, arterial Po2 and pH fall and Pco2 rises, and the chemoreceptor reflex reinforces the diving response The arterioles of the brain and heart not constrict and, therefore, cardiac output is distributed to these organs This heart–brain circuit makes use of the oxygen stored in the blood that would normally be used by the other tissues, especially skeletal muscle Once the diver surfaces, the heart rate and cardiac output increase substantially; vasodilation replaces peripheral vasoconstriction, restoring nutrient flow and washing out accumulated waste products Behavioral conditioning Cardiovascular responses can be conditioned Both classical and operant conditioning techniques have been used to raise and lower the blood pressure and heart rate of animals Humans can also be taught to alter their heart rate and blood pressure using a variety of behavioral techniques, such as biofeedback Behavioral conditioning of cardiovascular responses has significant clinical implications Animal and human studies indicate that psychological stress can raise blood pressure, increase atherogenesis, and predispose the person to fatal cardiac arrhythmias These effects are thought to result from activation of the fightor-flight response Other studies have shown beneficial effects of behavior patterns designed to introduce a sense of relaxation and well-being Some clinical regimens for the treatment of cardiovascular disease take these factors into account Baroreceptor override Supramedullary responses can override the baroreceptor reflex For example, the fight-or-flight response causes the Rhoades_Chap17.indd 317 heart rate to rise above normal levels despite a simultaneous rise in arterial pressure In such circumstances, the neurons connecting the hypothalamus to medullary areas inhibit the baroreceptor reflex and allow the corticohypothalamic response to predominate Also, during exercise, input from supramedullary regions inhibits the baroreceptor reflex, promoting increased sympathetic tone and decreased parasympathetic tone despite an increase in arterial pressure Moreover, the various cardiovascular response patterns not necessarily occur in isolation, as previously described Many response patterns interact, reflecting the extensive neural interconnections between all levels of the CNS and interaction with various elements of the local control systems For example, the baroreceptor reflex interacts with thermoregulatory responses Cutaneous sympathetic nerves participate in body temperature regulation but also serve the baroreceptor reflex At moderate levels of heat stress, the baroreceptor reflex can cause cutaneous arteriolar constriction despite elevated core temperature However, with severe heat stress, the baroreceptor reflex cannot overcome the cutaneous vasodilation; as a result, arterial pressure regulation may fail ● HORMONAL CONTROL OF THE CARDIOVASCULAR SYSTEM Various hormones play a role in the control of the cardiovascular system Important hormonal control mechanisms involved in cardiovascular homeostasis include epinephrine from the adrenal medulla, AVP (antidiuretic hormone) from the posterior pituitary gland, renin from the kidney, and ANP from the cardiac atrium Circulating epinephrine exerts different cardiovascular effects from those caused by sympathetic nerves When the sympathetic nervous system is activated, the adrenal medulla releases epinephrine (>90%) and NE (