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(BQ) Part 1 book Netter''s Essential physiology presents the following contents: Cell physiology, fluid homeostasis, and membrane transport; the nervous system and muscle; cardiovascular physiology; respiratory physiology.
This page intentionally left blank This page intentionally left blank NETTER’S ESSENTIAL PHYSIOLOGY Susan E Mulroney, PhD Professor of Physiology & Biophysics Director, Special Master’s Program Georgetown University Medical Center Adam K Myers, PhD Professor of Physiology & Biophysics Associate Dean for Graduate Education Georgetown University Medical Center Illustrations by Frank H Netter, MD Contributing Illustrators Carlos A.G Machado, MD John A Craig, MD James A Perkins, MS, MFA 1600 John F Kennedy Blvd Ste 1800 Philadelphia, PA 19103-2899 NETTER’S ESSENTIAL PHYSIOLOGY Copyright © 2009 by Saunders, an imprint of Elsevier Inc ISBN: 978-1-4160-4196-2 All rights reserved No part of this book may be produced 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 publishers Permissions for Netter Art figures may be sought directly from Elsevier’s Health Science Licensing Department in Philadelphia PA, USA: phone 1-800-523-1649, ext 3276 or (215) 239-3276; or email H.Licensing@elsevier.com Notice Neither the Publisher nor the Authors assume any responsibility for any loss or injury and/or damage to persons or property arising out of or related to any use of the material contained in this book It is the responsibility of the treating practitioner, relying on independent expertise and knowledge of the patient, to determine the best treatment and method of application for the patient The Publisher Library of Congress Cataloging-in-Publication Data Mulroney, Susan E Netter’s essential physiology / Susan E Mulroney, Adam K Myers ; illustrations by Frank H Netter ; contributing illustrators, Carlos A.G Machado, John A Craig, James A Perkins.—1st ed p ; cm ISBN 978-1-4160-4196-2 Human physiology I Myers, Adam K II Netter, Frank H (Frank Henry), 1906-1991 III Title IV Title: Essential physiology [DNLM: Cell Physiology—Atlases QU 17 M961n 2009] QP34.5.M85 2009 612—dc22 2008027016 Editor: Elyse O’Grady Developmental Editor: Marybeth Thiel Project Manager: David Saltzberg Design Direction: Lou Forgione Illustrations Manager: Karen Giacomucci Marketing Manager: Jason Oberacker Editorial Assistant: Julie Goolsby Working together to grow libraries in developing countries Printed in China Last digit is the print number: www.elsevier.com | www.bookaid.org | www.sabre.org We dedicate this book to our families, for their love and support and for their patience during the preparation of this book We dedicate it also to the students of Georgetown University, who are exceptional in their character and their love of learning This page intentionally left blank PREFACE Human physiology is the study of the functions of our bodies at all levels: whole organism, systems, organs, tissues, cells, and physical and chemical processes Physiology is a complex science, incorporating concepts and principles from biology, chemistry, biochemistry, and physics; and often, a true appreciation of physiological concepts requires multiple learning modalities, beyond standard texts or lectures This book, Netter’s Essential Physiology, has been prepared with this in mind Its generous illustrations and concise, bulleted, and highlighted text are designed to draw the student in, to focus the student’s efforts on understanding the essential aspects of difficult concepts It is intended not to be a detailed reference book, but rather a guide to learning the essentials of the field, in conjunction with classroom work and other texts when necessary This book is organized in the classical order in which subdisciplines of physiology are taught Beginning with fluid compartments, transport mechanisms, and cell physiology, it progresses through neurophysiology, cardiovascular physiology, the respiratory system, renal physiology, the gastrointestinal system, and endocrinology It is ideal for the visual learner Each section is thoroughly illustrated with the great drawings of the late Frank Netter as well as the more recent, beautiful work of Carlos Machado, John Craig, and James Perkins Recognizing that physiology, cell biology, and anatomy go hand in hand in the modern, integrated curriculum of many institutions, we have included more than the usual number of illustrations relevant to anatomy and histology By reading the text, studying the illustrations, and taking advantage of the review questions, the student will become familiar with the important concepts in each subdiscipline and gain the essential knowledge required in medical, dental, upper level undergraduate, or nursing courses in human physiology Too many textbooks, although very useful reference works, go for the most part unread by students It is our hope that students will find this book enriching and stimulating and that it will inspire them to thoroughly learn this fascinating field Susan E Mulroney, PhD Adam K Myers, PhD vii This page intentionally left blank Acknowledgments The preparation of this textbook has benefited from the efforts of numerous colleagues and students who reviewed various sections of the work and offered valuable criticisms and suggestions We especially wish to thank Charles Read, Henry Prange, Stefano Vicini, Jagmeet Kanwal, Peter Kot, Edward Inscho, Jennifer Rogers, Adam Mitchell, Milica Simpson, Lawrence Bellmore, and Joseph Garman for their critical reviews In addition, we express our appreciation to Adriane Fugh-Berman, whose insights and advice helped us avert many potential nightmares; Amy Richards, for her constant good humor and willingness to help; and all our colleagues and coworkers for their friendship, collegiality, and encouragement during this project Our special thanks go to the dedicated team at Elsevier, particularly Marybeth Thiel and Elyse O’Grady We also acknowledge Jim Perkins for his talented work on the new illustrations in this volume, which gracefully complement the original drawings of the master illustrator, Frank Netter Finally, we acknowledge the role of our students in this project, for their encouragement and for their enthusiasm in learning, which is the greatest inspiration for our work ix 180 Respiratory Physiology Oxygen Transport O2 in solution in plasma 0.003 mL O2/100 mL plasma/mm Hg PO2 O2 combined with Hb 1.34 mL O2/g Hb O2 HbO2 HbO2 Hb O2 Hb Bloodstream Alveoli of lung Red blood cell Plasma Body tissues Figure 15.1 Oxygen Transport Oxygen diffuses into the blood flowing through alveolar capillaries and is transported to tissues, where it diffuses out of the blood along its concentration gradient Transport of oxygen in the blood is mainly in the form of oxygen combined with hemoglobin, with only a minor portion carried in the form of dissolved oxygen oxygen content of blood and cardiac output, oxygen consumption can be estimated Thus, at rest, O2 consumption = [a − v]O2 × cardiac output = (5 mL O2/100 mL) × 5000 mL/min = 250 mL O2/min At the usual respiratory quotient (CO2 production/O2 consumption) of 0.8, CO2 production is 200 mL/min of oxygen from a molecule of hemoglobin makes dissociation of the other bound oxygen molecules from that molecule more likely To summarize: ■ ■ THE OXYHEMOGLOBIN DISSOCIATION CURVE As discussed, at PO2 of 100 mm Hg, hemoglobin is nearly 100% saturated with oxygen (actually, 97.5%), and at 40 mm Hg, hemoglobin is 75% saturated The oxyhemoglobin dissociation curve (Fig 15.2) describes the relationship between oxygen saturation of blood (SO2) and PO2 The sigmoidal shape of the curve is due to cooperative binding of hemoglobin Each molecule of hemoglobin is capable of binding four oxygen molecules; when one molecule binds to an oxygen binding site, the other three sites bind oxygen more readily, causing the middle portion of the curve to be steep Thus, exposure of blood to the high PO2 in the respiratory zone of the lung results in binding of a substantial amount of oxygen Note also that due to the sigmoidal shape, PAO2 can fall substantially without greatly affecting the degree of saturation of hemoglobin (at PO2 of 80 mm Hg, SO2 is still above 95%) On the other hand, as PO2 falls in blood coursing through systemic capillaries, typically to 40 mm Hg, blood PO2 is on the steep portion of the curve, which facilitates delivery of oxygen to the tissues Dissociation of one molecule ■ Cooperative binding of oxygen to four binding sites per hemoglobin molecule is responsible for the sigmoidal shape of the oxyhemoglobin dissociation curve In the lungs, blood will become fully saturated with oxygen over a wide range of PO2, due to the flat, upper portion of the oxyhemoglobin dissociation curve At the lower PO2 levels in tissue capillaries, small changes in PO2 result in dissociation of relatively large amounts of oxygen, due to the steep middle portion of the curve, facilitating oxygen delivery to the tissues Factors Affecting the Oxyhemoglobin Dissociation Curve In addition to these qualities, another important characteristic of the oxyhemoglobin dissociation curve is that it is shifted to the right under conditions of increased PCO2, low pH, and high temperature (see Fig 15.2) These conditions occur locally during tissue hypoxia and increased metabolism (for example, during exercise), and the rightward shift of the curve results in decreased hemoglobin affinity for oxygen, and thus enhances delivery of oxygen to tissues The metabolite of red blood cell glycolysis, 2,3-diphosphoglycerate (2,3-DPG; also known as 2,3-bisphophoglycerate), also shifts the curve to the right and is elevated during hypoxia Oxygen and Carbon Dioxide Transport and Control of Respiration CLINICAL CORRELATE Anemia Anemia is the state of low hemoglobin or red blood cell count in blood, resulting in reduced oxygen binding capacity It may be the result of blood loss, insufficient erythropoiesis (reduced red blood cell production), or hemolysis (red blood cell destruction) Iron deficiency may also cause anemia in menstruating women Hypoxia associated with anemia cannot be corrected by adminis- 181 tration of oxygen, because only the minor proportion of oxygen that is dissolved in arterial blood will be raised by elevating alveolar oxygen concentration, and oxyhemoglobin (oxygen bound to hemoglobin) will remain low due to the hemoglobin deficiency Although mild anemia can be treated by a variety of interventions that address the primary cause of the anemia, severe anemia requiring immediate medical attention must be treated by blood transfusion Signs and symptoms Abnormalities of production Stomatitis and glossitis Low dietary iron Thyroid disease Liver disease Malabsorption Chemotherapy/ Radiation Shortness of breath (late) Abnormalities of destruction Excessive blood loss (menorrhagia) Hemolysis Sickle cell disease Laboratory studies Mean corpuscular volume (MCV), reticulocyte count, blood smear, hemoglobin electrophoresis Other studies as indicated on a per case basis: serum iron, total iron binding capacity, serum ferritin, B12, folate Anemia Destruction of red blood cells, bleeding, or abnormalities of red blood cell production are causes of anemia Laboratory studies are useful in differential diagnosis of the cause Oxygen delivery to the fetus involves transfer of oxygen from maternal blood to fetal blood across the placenta Fetal blood contains a form of hemoglobin known as fetal hemoglobin (hemoglobin F) that has higher affinity for oxygen than adult hemoglobin (hemoglobin A), facilitating transfer of oxygen from maternal to fetal blood Thus, the oxyhemoglobin dissociation curve for hemoglobin F is shifted to the left, compared with the dissociation curve for hemoglobin A At a given PO2, oxygen saturation of hemoglobin F will be higher than that of hemoglobin A Hemoglobin F is replaced by hemoglobin A within the first months of life TRANSPORT OF CARBON DIOXIDE The concentration of carbon dioxide is highest in the mitochondria, where it is produced during cellular respiration From there, it diffuses to the interstitium and eventually into the blood, which transports it to the alveoli Within the blood, CO2 is transported in three forms (Fig 15.3): ■ Approximately 7% of CO2 in blood is dissolved CO2 Because solubility of CO2 in plasma is relatively high (20 times the solubility of O2), the dissolved form of CO2 has a significant role in its transport 182 Respiratory Physiology Oxyhemoglobin Dissociation Curve (at pH 7.4, PCO2 40 mm Hg, 37° C) 100 80 12 O2 combined with Hb 60 SO2 (%) 10 40 20 O2 in solution in plasma 80 40 60 PO2 (mm Hg) 20 100 100 PCO2 20 PCO2 40 SO2 (%) Effects of PCO2, pH, and Temperature on O2 Dissociation Curve 100 100 pH 7.6 60 40 pH 7.4 60 40 PCO2 80 60 20 40 60 80 PO2 (mm Hg) 100 37° C 40 pH 7.2 43° C 20 20 20 20° C 80 80 80 O2 content (mL/100 mL blood) 20 20 40 60 80 PO2 (mm Hg) 100 20 40 60 80 PO2 (mm Hg) 100 Figure 15.2 Oxyhemoglobin Dissociation Curves The oxyhemoglobin binding curve describes the association between partial pressure of oxygen and the degree of oxygen saturation of hemoglobin Saturation of hemoglobin is nearly 100% (97.5%) when PO2 is 100 mm Hg The sigmoidal shape of this curve results in a high degree of oxygen saturation of blood after passing through alveolar capillaries and significant dissociation of oxygen from hemoglobin at the PO2 levels to which blood is exposed as it perfuses systemic capillaries The values given for oxygen content on the graph are those expected at the normal blood hemoglobin concentration of 15 g/100 mL blood Note that the amount of dissolved hemoglobin in blood is very low over a wide range of PO2 High PCO2, low pH, and high temperature shift the oxyhemoglobin dissociation curve to the right, which promotes oxygen dissociation from hemoglobin in capillaries supplying actively metabolizing tissues B Carbon dioxide transport A CO2 equilibrium curves (for normal arterial and venous blood) CO2 content (mL/dL blood) 55 Mixed venous 50 Red blood cell Hb•NH2 Hb•NH2 Hb•NHCOO– Hb•NHCOO– Carbonic anhydrase + H2O CO2 CO2 Arterial 45 Hb•NHCOO– (carbaminoHb) Alveoli of lung 40 Bicarbonate 30 40 PCO2 (mm Hg) 50 Cl– HCO3– + H+ CO2 in physical solution + H2O Body tissues Figure 15.3 Carbon Dioxide Transport Carbon dioxide is transported in blood as bicarbonate anion (approximately 70%), carbaminohemoglobin (approximately 23%), and dissolved CO2 (approximately 7%) The CO2 equilibrium (dissociation) curve (A) is steep and linear, unlike the oxyhemoglobin dissociation curve, accounting for the relatively small difference in PCO2 between arterial and venous blood (40 mm Hg vs 45 mm Hg) Note also that the dissociation curve is shifted to the left when hemoglobin is in the form of deoxyhemoglobin, as in venous blood (the Haldane effect) Oxygen and Carbon Dioxide Transport and Control of Respiration CLINICAL CORRELATE Sickle Cell Disease Patients suffering from sickle cell disease have a variant form of hemoglobin known as hemoglobin S The allele causing this disease is recessive and is most common in people of subSaharan African origin Hemoglobin S has the tendency to polymerize when it is deoxygenated, causing red blood cells to assume a sickle-like shape In a “sickle cell crisis,” red blood cells lodge in the microcirculation, causing painful ischemia and infarction of tissue Sickle cell disease confers resistance to malaria, a parasite attacking red blood cells, and is believed to have evolved and persisted in sub-Saharan Africa due to evolutionary advantage associated with malaria resistance 183 In normal venous blood, the partial pressures of carbon dioxide and oxygen are similar (approximately 45 mm Hg and 40 mm Hg, respectively) According to Henry’s law, the concentration of dissolved gas in a solution is directly proportional to its partial pressure Although this law applies to both oxygen and carbon dioxide, because the solubility of carbon dioxide is 20 times that of oxygen, at similar partial pressures, much more carbon dioxide is present in blood in the form of dissolved gas than is the case for oxygen Although the approximate values given earlier for CO2 transport as dissolved gas, carbaminohemoglobin, and bicarbonate anion are prevalent in the literature and textbooks, the value for carbaminohemoglobin may be significantly overstated, because the original studies of CO2 carriage in blood were performed in the absence of 2,3-DPG, which binds with higher affinity to hemoglobin than CO2 formed, it diffuses out of the red blood cell while Cl− diffuses into the cell to maintain electrochemical equilibrium This process is known as the chloride shift Most of the H+ formed is buffered within the red blood cell by binding to hemoglobin The reaction forming H2CO3 is driven forward in capillary blood, as CO2 diffuses from tissues into the blood At the lungs, the reverse reaction occurs, as CO2 is breathed off The Haldane Effect Sickled Red Blood Cells ■ ■ Up to 23% of CO2 may be combined with protein, including hemoglobin (as carbaminohemoglobin, which gives venous blood its bluish tinge) CO2 binds to terminal amino groups of blood proteins About 70% of CO2 in blood is carried in the form of bicarbonate anion (HCO3-) Carbon Dioxide Transport in the Form of Bicarbonate Ion The bulk of CO2 is transported in the form of HCO3− within red blood cells (see Fig 15.3) CO2 dissolved in blood reacts with H2O to form carbonic acid (H2CO3), which dissociates to form H+ and HCO3−: CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3− This reaction, which is normally slow, is catalyzed by the enzyme carbonic anhydrase in red blood cells As HCO3− is Unlike the sigmoidal oxyhemoglobin dissociation curve, the dissociation curve for CO2 in blood is linear (see Fig 15.3) However, it is shifted to the left when hemoglobin is in the form of deoxyhemoglobin, as in venous blood This is known as the Haldane effect As a result of the Haldane effect, as hemoglobin is deoxygenated in systemic capillaries, its affinity for CO2 is increased, facilitating CO2 transport Binding affinity for H+ (generated in red blood cells along with HCO3−) is also increased In the pulmonary circulation, as hemoglobin is oxygenated, its affinity for CO2 is reduced, and as a result, transfer of CO2 from blood to alveolar air is facilitated CARBON DIOXIDE TRANSPORT AND ACID–BASE BALANCE Normal blood pH is approximately 7.4 and is regulated within a tight range (7.35 to 7.45) by renal and respiratory mechanisms and by various other buffering systems (Fig 15.4 and see Chapter 20) Significant deviation of pH from the normal range is incompatible with life, as protein structure is affected and enzymatic function is disturbed CO2 transport plays an important role in maintaining acid–base equilibrium The “acid load” of the body consists of volatile acid, which is CO2 in its various forms, and nonvolatile acids such as lactic acid and amino acids Nonvolatile acids are buffered by intracellular and extracellular mechanisms; the bicarbonate buffering system of extracellular fluids including blood are 184 Respiratory Physiology CLINICAL CORRELATE Carbon Monoxide Poisoning Carbon monoxide (CO) is a toxic compound produced during combustion of gasoline, propane, charcoal, natural gas, and other fuels Prolonged exposure to air containing CO concentrations as low as 0.04% can be lethal CO binds to hemoglobin, myoglobin, and cytochrome oxidase, producing its toxic effects Its affinity for hemoglobin is 240 times higher than that of oxygen, and as a result, CO displaces oxygen bound to hemoglobin, forming carboxyhemoglobin and reducing oxygen-carrying capacity of hemoglobin (note the effects of a small concentration of CO on the oxyhemoglobin dissociation curve, compared with the effects of severe anemia) In addition, because binding at oxygen-binding sites of hemoglobin is cooperative, the presence of bound CO on hemoglobin increases hemoglobin affinity for oxygen (the oxyhe- moglobin dissociation curve is shifted to the left), compromising dissociation of oxygen from hemoglobin and thus its delivery at normal tissue pH Carbon monoxide poisoning is treated by respiration with 100% oxygen Hyperbaric oxygen is also used as a treatment (patients are placed in high-pressure chambers and breathe pure oxygen), although the degree of benefit derived from this therapy is somewhat controversial The pulse oximeter typically used in clinical settings to monitor arterial SO2 relies on colorimetric measurements, but because carboxyhemoglobin, like oxyhemoglobin, is red in color, false, high SO2 readings are obtained when this instrument is used in patients suffering from CO poisoning Stated another way, the finger-probe and earlobeprobe pulse oximeters cannot differentiate between carboxyhemoglobin and oxyhemoglobin CO poisoning results in symptoms of hypoxia, but without the typical blue appearance 20 O2 content (mL O2/100 mL blood) Normal Hb (15 g/100 mL) 15 Normal Hb; 50% as carboxyhemoglobin 10 Anemia (7.5 g /100 mL) 0 20 40 60 80 100 PO2 (mm Hg) Oxygen Content of Blood: Effects of Carbon Monoxide and Anemia The arterial oxygen content of normal blood containing 15 g Hb/100 mL blood is approximately 20 mL/100 mL In severe anemia, if hemoglobin is reduced by half, oxygen content at 100% saturation is also reduced by half In carbon monoxide poisoning, CO binds tightly to hemoglobin, reducing the number of sites available for oxygen binding, and also shifting the oxyhemoglobin curve to the left In the example shown above, half of the oxygen binding sites have been occupied by CO, forming carboxyhemoglobin Thus, despite normal hemoglobin concentration, oxygen content is reduced by half in arterial blood at PaO2 of 100 mm Hg Due to the left-shift of the dissociation curve, delivery of O2 to tissues at normal tissue pH and PO2 is greatly compromised, and thus venous PO2 is profoundly reduced Oxygen and Carbon Dioxide Transport and Control of Respiration 185 CO2 Volatile Acid (CO2) “Acid Load” H+ + HCO3– H2O + CO2 CO2 H+ H+ H+ H+ H+ H+ H+ H+ Nonvolatile Acid (HA) H+ H+ H+ + A– HA CO2 + H2O + NaA NH4+ Body tissues NaHCO3 NaHCO3 Replenish NH4A Figure 15.4 Role of Lungs and Kidneys in Acid–Base Balance The lungs and kidneys have a critical role in maintaining proper acid–base balance in the face of the acid load created by cellular metabolism of nutrients Carbon dioxide (“volatile acid”) produced by oxidative metabolism of carbohydrates and fats is efficiently eliminated by respiration in the lungs to maintain pH balance, whereas nonvolatile acids are primarily buffered by bicarbonate anion in extracellular fluid and intracellular proteins, with the kidneys replenishing the bicarbonate anion and excreting acid H+ is also eliminated in the urine as bicarbonate is regenerated When a metabolic acid–base disturbance occurs, intracellular and extracellular buffering systems (involving primarily proteins and bicarbonate, respectively) are the first line of defense, along with rapid compensation by the lungs, which adjust the rate of CO2 (volatile acid) elimination Over a longer period (hours to days), renal mechanisms compensate by adjusting acid secretion and bicarbonate regeneration When a respiratory acid–base disturbance occurs, the compensation is primarily renal important in this regard Acid balance is also maintained by renal excretion of acid (renal mechanisms are covered in Chapter 20) Normally, CO2 formed during metabolism of lipids and carbohydrates is readily eliminated by the respiratory system, but disturbances in respiration can result in acid–base imbalance, because changes in CO2 elimination will directly affect carbonic acid levels In addition, by adjusting respiration, the respiratory system can compensate for pH imbalances produced by metabolic disturbances solved CO2, and thus, 0.03 × PCO2 (0.03 mmol/L/mm Hg is the solubility coefficient for PCO2) can be substituted for [H2CO3] and the equation becomes: pH ϭ 6.1 ϩ log Substituting normal values for arterial [HCO3−] and PCO2 yields the normal pH of 7.4: pH ϭ 6.1 ϩ log The Henderson-Hasselbalch Equation The pH of buffer systems can be calculated by the HendersonHasselbalch equation: pH ϭ pK ϩ log [AϪ] [HA] where K is the acid dissociation constant For the bicarbonate buffer system, pH ϭ pK ϩ log [HCO3Ϫ] [H2CO3] The pK for this system is 6.1 H2CO3 exists in low concentrations in extracellular fluids but is in equilibrium with dis- [HCO3Ϫ] 0.03 ϫ PCO2 [24] ϭ 7.4 0.03 ϫ 40 Based on these equations, it should be apparent that changes in PCO2 will result in alteration of pH If hypoventilation results in a rise in alveolar PACO2, for example, the accompanying rise in PaCO2 will cause a fall in blood pH ACID–BASE DISTURBANCES Acid–base disturbances are covered briefly in the following discussion, and in detail in Chapter 20 Acidemia is defined as increased acidity of blood (pH below 7.35), whereas alkalemia is increased alkalinity of blood (pH above 7.45) Technically, acidosis and alkalosis are more general terms referring 186 Respiratory Physiology Table 15.1 Acid–Base Disorders Disorder pH 1o Alteration Defense Mechanisms Metabolic acidosis ↓ ↓ [HCO3−] Buffers, ↓PCO2, ↑NAE Metabolic alkalosis ↑ ↑ [HCO3−] Buffers, ↑PCO2, ↓NAE Respiratory acidosis ↓ ↑ PCO2 Buffers & ↑NAE Respiratory alkalosis ↑ ↓ PCO2 Buffers & ↓NAE NAE, net acid excretion (Reprinted with permission from Hansen J: Netter’s Atlas of Human Physiology, Philadelphia, Elsevier, 2002.) to low pH and high pH, respectively, in body fluids and tissues but are usually used synonymously with acidemia and alkalemia Alterations in pH caused by respiratory abnormality are referred to as respiratory acidosis or respiratory alkalosis Respiratory alkalosis is caused by hyperventilation, whereas respiratory acidosis is caused by hypoventilation (due to either an acute cause, such as airway obstruction or central nervous system [CNS] depression, or a chronic lung disease) In contrast, when the primary cause of the acid–base imbalance is metabolic, for example due to a metabolic disease or abnormal renal function, it is described as metabolic acidosis or metabolic alkalosis Compensation for respiratory acidosis or alkalosis occurs by renal mechanisms, whereas respiratory adjustments compensate for metabolic acidosis or alkalosis (Table 15.1) The general role of the kidney and lungs in acid–base balance is illustrated in Figure 15.4 Differentiating between metabolic and respiratory causes of acidosis and alkalosis is usually a relatively simple process To identify the condition: Ultimately, signals involved in control of breathing are integrated in the medullary respiratory center, resulting in regulation of the activity of respiratory muscles (see Fig 14.1) and affecting tidal volume and respiratory rate and pattern Within the medulla, respiratory control is accomplished by the: ■ ■ ■ First examine the pH Values below 7.35 are defined as acidosis; pH above 7.45 is by definition alkalosis Second, examine the PaCO2 If the pH disturbance is respiratory in origin, the PaCO2 level will be abnormal and predictive of the pH change In other words, in respiratory acidosis, PaCO2 will be elevated above 40 mm Hg, whereas in respiratory alkalosis (caused by hyperventilation), PaCO2 will be lower than 40 mm Hg If the condition is acute, HCO3− level will be normal; if the respiratory condition is chronic, HCO3− will be elevated in acidosis and depressed in alkalosis, reflecting renal compensation Because of the compensation, pH will be closer to normal in chronic acidosis or alkalosis than would be expected based on a change in PaCO2 alone If PaCO2 level is abnormal in the opposite direction predicted for it to be the primary alteration, the disturbance is metabolic Examination of HCO3− should reveal that its level is consistent with a primary metabolic disturbance: HCO3− will be high in metabolic alkalosis and low in metabolic acidosis PaCO2 levels will be depressed in metabolic acidosis and elevated in metabolic alkalosis, reflecting respiratory compensation Because of this compensation, the pH will be closer to normal than would be predicted based on a change in HCO3− alone CONTROL OF RESPIRATION Although breathing can be controlled voluntarily (for example, during breath holding or hyperventilation), it is ultimately an involuntary process that closely controls PaO2 and PaCO2 Changes in both depth and rate of respiration are involved in this process Three essential components of the involuntary control system are as follows: ■ ■ ■ ■ ■ brainstem respiratory centers peripheral and central chemoreceptors mechanoreceptors in lungs and joints Ventral respiratory group, which includes the nucleus retroambiguous, nucleus ambiguous, and nucleus retrofacialis and innervates both inspiratory and expiratory muscles It is involved in regulation of inspiratory force and in voluntary expiration Dorsal respiratory group within the nucleus tractus solitarius, which innervates inspiratory muscles The medullary respiratory center receives input from two important pontine areas: ■ ■ The pneumotactic center, which regulates rate and depth of respiration by cyclical inhibition of inspiration This center has input from the cerebral cortex The apneustic center, which stimulates inspiration It is antagonized by the pneumotactic center Damage to the pons or upper medulla may result in apneusis (breathing characterized by prolonged inspiratory efforts and Oxygen and Carbon Dioxide Transport and Control of Respiration brief, intermittent exhalations) Experimentally, apneusis can be produced by ablation of the pneumotactic center and transection of the vagus nerve Role of Central and Peripheral Chemoreceptors Sensory information from central and peripheral chemoreceptors is important in this regulation of respiration by the brainstem Central chemoreceptors located at the ventrolateral surface of the medulla respond indirectly to changes in arterial Pco2 and play a critical role in acute regulation of PaCO2 The blood-brain barrier is largely impermeable to HCO3− and H+, but CO2 readily diffuses across the barrier and into the cerebrospinal fluid (CSF), where it affects CSF pH (by mechanisms discussed earlier) Thus, when PaCO2 is altered, respiration is affected: ■ ■ A rise in PaCO2 will cause a fall in CSF pH, which is detected by central chemoreceptors, resulting in an increase in respiratory rate A fall in PaCO2 will cause a rise in CSF pH, which is detected by central chemoreceptors, resulting in decreased ventilation Peripheral chemoreceptors, located in the carotid bodies and aortic bodies (see Section 3), also convey information concerning the quality of arterial blood to the respiratory center in the brainstem, thereby affecting ventilation Unlike the central chemoreceptors, these receptors respond directly to changes in PaO2 and PaCO2, as well as pH Through the peripheral chemoreceptor mechanism, ventilation is stimulated by the following: CLINICAL CORRELATE Sleep Apnea Sleep apnea is a disorder whereby normal breathing is periodically interrupted during sleep; the pauses in breathing can be the length of two to three breaths, and thus there can be a significant reduction in gas transport during these episodes Sleep apnea can be central, obstructive, or complex (both central and obstructive) In Normal breathing in sleep Recordings from patient with obstructive sleep apnea EEG Nasal Respiration Oral Chest O2 saturation ECG ■ ■ ■ 187 A fall in PaO2: The ventilatory effects of changes in PaO2 are relatively small when PaO2 is above 60 mm Hg, but peripheral chemoreceptors are very responsive when PaO2 falls below this level A rise in PaCO2: Changes in PaCO2 affect respiration through both central and peripheral chemoreceptors, although the central chemoreceptor mechanism is more responsive to the changes A fall in pH: Changes in H+ concentration in arterial blood affect peripheral chemoreceptors directly, independently of the effects of PaCO2 Chemical control of respiration by PaO2 and PaCO2 is illustrated in Figure 15.5 Additional Mechanisms Controlling Respiration Respiration is also controlled by a number of additional peripheral mechanisms: ■ ■ Pulmonary mechanoreceptors respond to inflation of the lung and result in termination of inspiration The afferent signals from these receptors in the smooth muscle of airway walls are transmitted through the vagus nerve to the medulla, where they inhibit the apneustic center, thereby terminating inspiration This response to lung inflation is known as the Hering-Breuer reflex (specifically, the Hering-Breuer inspiratory-inhibitory reflex) Irritant receptors in the large airways respond to noxious gases and particulate matter, for example, in cigarette smoke Activation of these receptors results in afferent central sleep apnea, brain centers are dysregulated, resulting in a lack of effort to breathe; in obstructive sleep apnea, although respiratory effort is normal, obstruction prevents airflow Disrupted sleep and fatigue are common symptoms Chronic sleep apnea is associated with increased incidence of heart disease and stroke Obstructive apnea Normal breathing in sleep 188 Respiratory Physiology CLINICAL CORRELATE Respiratory Control in Chronic Obstructive Pulmonary Disease Chronic obstructive pulmonary disease (COPD) is most often associated with tobacco smoking and may be exacerbated by occupational exposure to certain pollutants It is characterized by chronic bronchitis (coughing with sputum production) and emphysema (destruction of alveolar walls resulting in fewer, enlarged “alveoli” with reduction in total surface area for gas diffusion) As a result, patients with this disease become hypoxic and hypercapnic (PaO2 is below normal and PaCO2 is elevated); pH is somewhat lower than normal, although significant compensation occurs by elevation of HCO3− through renal mechanisms In other words, the patients suffer from chronic respiratory acidosis, with metabolic compensation In this state of chronic hypercapnea, normal CSF pH is maintained by elevation of HCO3− in the CSF The CNS is chronically exposed to high PCO2, and the central chemoreceptors become unresponsive to CO2 Thus, patients with COPD develop “hypoxic respiratory drive,” in which respiratory drive is mainly mediated by peripheral chemoreceptor responses to low PaO2 When an acute exacerbation arises in such a patient, if supplemental O2 is administered carelessly, results can be catastrophic and even fatal: PaO2 will rise, but respiratory drive may fail as a result, causing a fall in minute ventilation and a further rise in PaCO2 Ventilatory support with some supplemental oxygen may be beneficial, but suppression of ventilatory drive must be avoided Interrelationship of Chronic Bronchitis and Emphysema Normal Blue bloater Chronic bronchitis Emphysema Pink puffer Mixed (in variable degree) COPD is characterized by chronic bronchitis and emphysema COPD patients usually suffer to some extent from both and are classified based on the dominant symptomatology “Pink puffers” suffer mainly from emphysema and have ruddy complexions and elevated respiratory rate; “blue bloaters” suffer mainly from chronic bronchitis, resulting in hypoxema, cyanosis (bluish lips and skin), and often, symptoms of right heart failure, including swelling of feet and ankles (“bloating”) Oxygen and Carbon Dioxide Transport and Control of Respiration Chemical Control of Respiration (Feedback Mechanism) Glossopharyngeal (IX) nerve Vagus (X) nerve Elevated PCO2 of blood and of cerebrospinal fluid affects central chemoreceptors Lowered PO2 of blood affects chemoreceptors of carotid and aortic bodies (which are also responsive to lowered pH) Inadequate ventilation for bodily needs may depress PO2 and/or elevate PCO2 of blood (elevated PCO2 tends to lower pH) Impulses from carotid and aortic bodies reach respiratory center via glossopharyngeal and vagus nerves Medulla Blood PCO2 (pH) Cerebrospinal fluid PCO2 (pH) Impulses from central chemoreceptors reach respiratory center Phrenic nerve O2 CO2 Impulses from respiratory centers descend in spinal cord to reach diaphragm via phrenic nerves and intercostal muscles via intercostal nerves to increase rate and amplitude of respiration Intercostal nerves Intercostal muscles Alveolar capillary Diaphragm Alveolus Accelerated respiration improves ventilation and thus tends to normalize PO2, PCO2, and pH of blood Ventilation (L/min) 40 30 O2 CO2 20 10 20 30 40 50 60 70 Partial Pressure (mm Hg) 80 90 100 Figure 15.5 Control of Respiration Central and peripheral chemoreceptors regulate respiration by responding to arterial blood gas levels Central chemoreceptors respond primarily to changes in arterial PCO2, which diffuses into the CSF and alters pH of the CSF (the blood-brain barrier is largely impermeable to HCO3− and H+), while peripheral chemoreceptors in the carotid bodies and aortic bodies respond to changes in PaO2, and also PaCO2 and pH Brainstem respiratory centers adjust the rate and depth of respiration, producing changes in PaO2 and PaCO2 (and thus pH) In the bottom graph, the effects of PaCO2 and PaO2 on minute ventilation are illustrated 189 190 Respiratory Physiology A Ven Exercise Recovery on a ti til Heart rate PO2 PCO2 Arterial pH rature Body tempe Factors that may account for initial abrupt rise and sharp terminal drop in ventilation Time (minutes) Factors that may play a part in continued elevation of ventilation during continuing exercise Rise in body temperature accounts for a small part of elevation Collaterals to respiratory center from motor pathways for muscle activation Proprioceptive afferents from joint receptors to respiratory centers H؉ Lactate Other unknown factors Respiratory neurons seem to be more responsive to change in chemoreceptor activity Centers may be more sensitive to fluctuation than to absolute values of PO2, PCO2, or pH Lactic acid production due to anaerobic metabolism in muscle may increase H+ concentratin of blood, thus affecting chemoreceptors Possible metabolic receptors in exercising muscle B Other unknown factors Figure 15.6 Respiratory Response to Exercise Increased oxygen consumption and carbon dioxide production during exercise requires adjustments of cardiac output and respiration (A) Factors accounting for the rapid adjustments in respiration at the onset and termination of exercise, as well as feedback mechanisms during continued exercise, are illustrated (B) ■ ■ signals to the CNS mainly through the vagus nerve and causes reflexive bronchoconstriction and coughing Juxtacapillary receptors (J receptors) in the alveoli are stimulated by hyperinflation of the lungs and various chemical stimuli; reflexive rapid, shallow breathing occurs as a result Joint and muscle mechanoreceptors are stimulated during movement of joints and muscles, producing an increase in respiratory rate Respiratory Control in Exercise Control of respiration is a critical component of the integrated response to exercise (Fig 15.6) During dynamic (aerobic) exercise, oxygen consumption rises from the average resting rate of 250 mL O2/min to as high as L O2/min, without substantial change in either PaO2 or PaCO2 At the onset of dynamic exercise, there is a rapid increase in respiration through neural and reflexive mechanisms, although the control Oxygen and Carbon Dioxide Transport and Control of Respiration mechanisms are not fully understood Activation of motor pathways results in collateral activation of the respiratory center, and respiration is further stimulated by afferent signals from muscle and joint mechanoreceptors and other, unknown factors With continuing exercise, feedback mechanisms become important The rise in core body temperature and elevation of lactic acid production (and plasma H+ concentration) contribute to the further, more gradual rise in ventilation Although PaO2 and PaCO2 change only modestly (except at high levels of exercise), respiratory control systems may be more sensitive to such changes during exercise When exercise is terminated, ventilation diminishes rapidly at first but requires some time to fall to the resting level, due to the continued activation of feedback mechanisms until the metabolic alterations associated with exercise (including the elevation of lactic acid) are reversed Adaptation to High Altitude The control of respiration is also important in adaptation to high altitude At the lower atmospheric pressures associated with high altitudes, the PO2 of inspired air is reduced, resulting in hypoxemia The fall in PaO2 stimulates ventilation through peripheral chemoreceptors, but this effect is tempered by the resulting fall in PaCO2 and the accompanying alkalosis, which inhibit ventilation through central and peripheral chemoreceptor mechanisms Over a period of time, renal compensatory mechanisms result in elevation of plasma HCO3−, and as pH returns to normal, ventilation again increases In addition to increased ventilation, other factors that contribute to the adaptation to high altitude include the following: ■ ■ Hypoxemia stimulates red blood cell production; the resulting polycythemia (and higher plasma hemoglobin) increases the oxygen-carrying capacity of blood Elevation of 2,3-DPG causes a rightward shift of the oxyhemoglobin dissociation curve, and thus, oxygen more readily dissociates from hemoglobin at the tissue level 191 CLINICAL CORRELATE Acute Altitude Sickness Acute altitude sickness is a relatively common response to high altitude (greater than 8000 feet above sea level) in people who are accustomed to living at low altitudes, especially when the ascent is rapid Symptoms include headache, tachycardia, shortness of breath, nausea and vomiting, loss of appetite, lightheadedness, and fatigue In most cases, symptoms are mild and resolve in a matter of days as acclimation takes place In rare, extreme cases, life-threatening pulmonary edema or cerebral edema may develop Pulmonary edema occurs as a result of pulmonary vasoconstriction and an increase in pulmonary vascular permeability As discussed earlier, pulmonary vasoconstriction is a normal response to alveolar hypoxia, but it is exaggerated in high-altitude pulmonary edema The cause of high-altitude cerebral edema has not been established but likely involves cerebral vasodilation in response to hypoxemia, resulting in high capillary hydrostatic pressure Descent to lower altitude is a critical component of treatment in these severe cases Effects of High Altitude on Respiratory Mechanism Response to hypercapnia persists, thus maintaining normal blood gas tensions; but CO2 response may be lost under anesthesia, resulting in dangerous hypoxemia CO2 O2 Respiratory response to hypoxemia is blunted or lost 192 Respiratory Physiology Review Questions CHAPTER 13: PULMONARY VENTILATION AND PERFUSION AND DIFFUSION OF GASES D the ventilation-to-perfusion ratio approaches zero E the ventilation-to-perfusion ratio approaches infinity The reduction in pulmonary vascular resistance that occurs when pulmonary artery pressure is increased is mainly a result of: CHAPTER 14: THE MECHANICS OF BREATHING A B C D E recruitment and distension of pulmonary capillaries autoregulation by myogenic mechanisms redistribution of pulmonary blood flow metabolic vasodilation active vasodilation of pulmonary arterioles Which of the following lung volumes or capacities can NOT be measured by spirometry alone? A B C D E Tidal volume Expiratory reserve volume Inspiratory reserve volume Total lung capacity Vital capacity With regard to the ventilation, the perfusion, or the ventilation-to-perfusion ratio in regions of the lung in a person in the standing position, A perfusion is highest at the top of the lung B ventilation is lowest at the bottom of the lung C the ventilation-to-perfusion ratio is greatest at the top of the lung D the ventilation-to-perfusion ratio approaches infinity in areas of shunt E the ventilation-to-perfusion ratio is zero in areas of dead space Diffusion of gas through a membrane: A is inversely related to the surface area for diffusion B is directly related to the difference in partial pressure of the gas on each side of the membrane C requires active transport D is inversely related to the diffusion constant of the gas E is directly related to the thickness of the membrane In zone of the lung (in a standing person), A both pulmonary arterial and venous pressures exceed alveolar pressure B both pulmonary arterial and venous pressures are below alveolar pressure C alveolar pressure is higher than pulmonary venous pressure but less than arterial pressure The mechanical system that produces breathing is at rest (outward elastic recoil pressure of the chest wall is equal to and opposing inward elastic recoil pressure of the lungs) at: A B C D E residual volume functional residual capacity 60% of total lung capacity 70% of total lung capacity total lung capacity In the respiratory system as a whole, the greatest resistance to flow occurs in the: A B C D E respiratory bronchioles terminal bronchioles medium-sized airways bronchi trachea Dynamic compression of airways is responsible for: effort independence of expiratory flow the vital capacity of the lung normal resting tidal volume the total lung capacity that can be achieved during inspiration E peak flow during expiration A B C D In severe (COPD), A B C D E chronic obstructive pulmonary disease lung compliance is reduced elastic recoil of the lung is decreased total lung capacity is reduced functional residual capacity is reduced residual volume is reduced 10 Which of the following is NOT a characteristic or function of surfactant? A B C D E Decreases pulmonary compliance Reduces the work of breathing Reduces surface tension of alveoli and small airways Deficient in respiratory distress syndrome Contains dipalmitoyl phosphatidyl choline Review Questions 193 CHAPTER 15: OXYGEN AND CARBON DIOXIDE TRANSPORT AND CONTROL OF RESPIRATION 14 In the control of respiration, central chemoreceptors respond mainly to changes in: 11 Which of the following changes will result in the greatest increase in oxygen content of arterial blood, assuming normal alveolar oxygen concentration? A B C D E A An increase in hematocrit from 40 to 45 B An increase in alveolar oxygen concentration from 100 to 150 mm Hg C A 10% increase in blood level of 2,3-DPG D A fall in blood pH from 7.4 to 7.35 E A 10% increase in alveolar ventilation 12 Lab tests reveal that a patient has blood pH of 7.3, elevated arterial PCO2, and slightly elevated arterial plasma bicarbonate level The acid–base status is: A B C D E metabolic acidosis metabolic alkalosis respiratory acidosis respiratory alkalosis impossible to determine from these values 13 The major mechanism of long-term adaptation to high altitude is: A B C D E increased heart rate increased respiratory rate reduced 2,3-DPG in blood polycythemia reduced plasma bicarbonate arterial pH arterial PCO2 2,3-DPG in blood arterial HCO3− arterial O2 15 The rapid adjustment of respiratory rate at the onset of exercise is mediated in part by: A B C D E a fall in arterial pH a rise in arterial PCO2 2,3-DPG in blood mechanoreceptors in joints a rise in body temperature This page intentionally left blank ... ISBN 978 -1- 416 0- 419 6-2 Human physiology I Myers, Adam K II Netter, Frank H (Frank Henry), 19 06 -19 91 III Title IV Title: Essential physiology [DNLM: Cell Physiology—Atlases QU 17 M961n 2009] QP34.5.M85... 97 10 1 10 7 11 3 12 5 14 2 Section 4: Respiratory Physiology 13 Pulmonary Ventilation and Perfusion and Diffusion of Gases 14 The Mechanics of Breathing... Perkins, MS, MFA 16 00 John F Kennedy Blvd Ste 18 00 Philadelphia, PA 19 103-2899 NETTER’S ESSENTIAL PHYSIOLOGY Copyright © 2009 by Saunders, an imprint of Elsevier Inc ISBN: 978 -1- 416 0- 419 6-2 All rights