Guyton and Hall Physiology - Chapter 42 Regulation of Respiration PDF

CHAPTER 42 UNIT VII Regulation of Respiration The nervous system normally adjusts the rate of al...

CHAPTER 42 UNIT VII Regulation of Respiration The nervous system normally adjusts the rate of alveo- rons. Even when all the peripheral nerves entering the lar ventilation to meet the demands of the body almost medulla have been sectioned, and the brain stem has exactly so that the oxygen partial pressure (Po2) and car- been transected above and below the medulla, this group bon dioxide partial pressure (Pco2) in the arterial blood of neurons still emits repetitive bursts of inspiratory neu- are hardly altered, even during heavy exercise and most ronal action potentials. The basic cause of these repeti- other types of respiratory stress. This chapter describes tive discharges is unknown. In primitive animals, neural the function of this neurogenic system for regulation of networks have been found in which activity of one set of respiration. neurons excites a second set, which in turn inhibits the first. Then, after a period of time, the mechanism repeats itself, continuing throughout the life of the animal. Similar RESPIRATORY CENTER networks of neurons are present in the human being, lo- The respiratory center is composed of several groups of cated entirely within the medulla; it probably involves not neurons located bilaterally in the medulla oblongata only the dorsal respiratory group but adjacent areas of the and pons of the brain stem, as shown in Figure 42-1. It medulla as well and is responsible for the basic rhythm of is divided into three major collections of neurons: (1) a respiration. dorsal respiratory group, located in the dorsal portion of the medulla, which mainly causes inspiration; (2) a ven- Inspiratory “Ramp” Signal. The nervous signal that tral respiratory group, located in the ventrolateral part of is transmitted to the inspiratory muscles, mainly the the medulla, which mainly causes expiration; and (3) the diaphragm, is not an instantaneous burst of action po- pneumotaxic center, located dorsally in the superior por- tentials. Instead, it begins weakly and increases steadily tion of the pons, which mainly controls rate and depth of in a ramp manner for about 2 seconds in normal res- breathing. piration. It then ceases abruptly for approximately the next 3 seconds, which turns off the excitation of the dia- phragm and allows elastic recoil of the lungs and chest DORSAL RESPIRATORY GROUP OF wall to cause expiration. Next, the inspiratory signal NEURONS CONTROLS INSPIRATION AND begins again for another cycle; this cycle repeats again RESPIRATORY RHYTHM and again, with expiration occurring in between. Thus, The dorsal respiratory group of neurons plays a fundamen- the inspiratory signal is a ramp signal. The obvious ad- tal role in the control of respiration and extends most of the vantage of the ramp is that it causes a steady increase in length of the medulla. Most of its neurons are located in the the volume of the lungs during inspiration, rather than nucleus of the tractus solitarius (NTS), although additional inspiratory gasps. neurons in the adjacent reticular substance of the medulla Two qualities of the inspiratory ramp are controlled, also play important roles in respiratory control. The NTS is as follows: the sensory termination of both the vagal and the glosso- 1. Control of the rate of increase of the ramp signal so pharyngeal nerves, which transmit sensory signals into the that during heavy respiration, the ramp increases respiratory center from the following: (1) peripheral che- rapidly and therefore fills the lungs rapidly. moreceptors; (2) baroreceptors; (3) receptors in the liver, 2. Control of the limiting point at which the ramp pancreas, and multiple parts of the gastrointestinal tract; suddenly ceases, which is the usual method for and (4) several types of receptors in the lungs. controlling the rate of respiration. That is, the ear- lier the ramp ceases, the shorter the duration of in- Rhythmical Inspiratory Discharges From the Dorsal spiration. This method also shortens the duration Respiratory Group. The basic rhythm of respiration is of expiration. Thus, the frequency of respiration is generated mainly in the dorsal respiratory group of neu- increased. 531 UNIT VII Respiration 2. The ventral respiratory neurons do not appear to participate in the basic rhythmical oscillation that Pneumotaxic controls respiration. Fourth ventricle center 3. When the respiratory drive for increased pulmo- Inhibits nary ventilation becomes greater than normal, res- piratory signals spill over into the ventral respira- ? Apneustic center Dorsal respiratory tory neurons from the basic oscillating mechanism group (inspiration) Ventral respiratory of the dorsal respiratory area. As a consequence, the group (expiration ventral respiratory area also contributes extra res- and inspiration) piratory drive. 4. Electrical stimulation of a few of the neurons in the Respiratory motor ventral group causes inspiration, whereas stimula- Vagus and glossopharyngeal pathways tion of others causes expiration. Therefore, these neurons contribute to both inspiration and expira- tion. They are especially important in providing the powerful expiratory signals to the abdominal mus- Figure 42-1. Organization of the respiratory center. cles during very heavy expiration. Thus, this area operates more or less as an overdrive mechanism PNEUMOTAXIC CENTER LIMITS DURATION when high levels of pulmonary ventilation are re- OF INSPIRATION AND INCREASES quired, especially during heavy exercise. RESPIRATORY RATE A pneumotaxic center, located dorsally in the nucleus LUNG INFLATION SIGNALS LIMIT parabrachialis of the upper pons, transmits signals to INSPIRATION—THE HERING-BREUER the inspiratory area. The primary effect of this center is INFLATION REFLEX to control the “switch-off ” point of the inspiratory ramp, In addition to the central nervous system respiratory thereby controlling the duration of the filling phase of the control mechanisms operating entirely within the brain lung cycle. When the pneumotaxic signal is strong, inspi- stem, sensory nerve signals from the lungs also help con- ration might last for as little as 0.5 second, thus filling the trol respiration. Most importantly, located in the muscu- lungs only slightly; when the pneumotaxic signal is weak, lar portions of the walls of the bronchi and bronchioles inspiration might continue for 5 or more seconds, thus throughout the lungs are stretch receptors that transmit filling the lungs with much greater amounts of air. signals through the vagi into the dorsal respiratory group The function of the pneumotaxic center is primarily to of neurons when the lungs become overstretched. These limit inspiration, which has a secondary effect of increasing signals affect inspiration in much the same way as signals the rate of breathing because limitation of inspiration also from the pneumotaxic center; that is, when the lungs shortens expiration and the entire period of each respira- become overinflated, the stretch receptors activate an tion. A strong pneumotaxic signal can increase the rate of appropriate feedback response that “switches off ” the breathing to 30 to 40 breaths/min, whereas a weak pneumo- inspiratory ramp and thus stops further inspiration. This taxic signal may reduce the rate to only 3 to 5 breaths/min. mechanism is called the Hering-Breuer inflation reflex. This reflex also increases the rate of respiration, as is true VENTRAL RESPIRATORY GROUP OF for signals from the pneumotaxic center. NEURONS—FUNCTIONS IN BOTH In humans, the Hering-Breuer reflex probably is not INSPIRATION AND EXPIRATION activated until the tidal volume increases to more than Located in each side of the medulla, about 5 millimeters three times normal (>≈1.5 L/breath). Therefore, this reflex anterior and lateral to the dorsal respiratory group of neu- appears to be mainly a protective mechanism for prevent- rons, is the ventral respiratory group of neurons, found in ing excess lung inflation rather than an important factor the nucleus ambiguus rostrally and the nucleus retroam- in normal control of ventilation. biguus caudally. The function of this neuronal group dif- fers from that of the dorsal respiratory group in several CONTROL OF OVERALL RESPIRATORY important ways: CENTER ACTIVITY 1. The neurons of the ventral respiratory group re- main almost totally inactive during normal quiet Up to this point, we have discussed the basic mechanisms respiration. Therefore, normal quiet breathing is for causing inspiration and expiration, but it is also impor- caused only by repetitive inspiratory signals from tant to know how the intensity of the respiratory control the dorsal respiratory group transmitted mainly to signals is increased or decreased to match the ventilatory the diaphragm, and expiration results from elastic needs of the body. For example, during heavy exercise, recoil of the lungs and thoracic cage. the rates of oxygen (O2) usage and carbon dioxide (CO2) 532  Chapter 42 Regulation of Respiration formation are often increased to as much as 20 times normal, requiring commensurate increases in pulmonary ventilation. The major purpose of the rest of this chapter Chemosensitive area is to discuss this control of ventilation in accord with the respiratory needs of the body. UNIT VII CHEMICAL CONTROL OF RESPIRATION Inspiratory area H+ + HCO3 – The ultimate goal of respiration is to maintain proper concentrations of O2, CO2, and H+ in the tissues. It is fortunate, therefore, that respiratory activity is highly H2CO3 responsive to changes in each of these substances. Excess CO2 or excess H+ in the blood mainly act directly CO2 + H2O on the respiratory center, causing greatly increased strength of both the inspiratory and the expiratory motor signals to the respiratory muscles. Oxygen, in contrast, does not have a major direct effect on the respiratory cen- Figure 42-2. Stimulation of the brain stem inspiratory area by signals from the chemosensitive area located bilaterally in the medulla, lying ter of the brain in controlling respiration. Instead, it acts only a fraction of a millimeter beneath the ventral medullary surface. almost entirely on peripheral chemoreceptors located in Note also that H+ stimulates the chemosensitive area, but carbon di- the carotid and aortic bodies, and these chemoreceptors oxide in the fluid gives rise to most of the H+. in turn transmit appropriate nervous signals to the respi- ratory center for control of respiration. direct stimulatory effect on respiration. These reactions are shown in Figure 42-2. Why does blood CO2 have a more potent effect in DIRECT CONTROL OF RESPIRATORY stimulating the chemosensitive neurons than blood H+? CENTER ACTIVITY BY CO2 AND H+ The answer is that the blood–brain barrier is not very Chemosensitive Area of the Respiratory Center Be- permeable to H+, but CO2 passes through this barrier neath the Medulla’s Ventral Surface. We have mainly almost as if the barrier did not exist. Consequently, when- discussed three areas of the respiratory center—the dor- ever the blood Pco2 increases, so does the Pco2 of both sal respiratory group of neurons, the ventral respiratory the interstitial fluid of the medulla and the cerebrospinal group, and the pneumotaxic center. It is believed that fluid. In both these fluids, the CO2 immediately reacts none of these is affected directly by changes in blood CO2 with the water to form new H+. Thus, paradoxically, more or H+ concentration. Instead, an additional neuronal area, H+ is released into the respiratory chemosensitive sen- a chemosensitive area, shown in Figure 42-2, is located sory area of the medulla when the blood CO2 concen- bilaterally, lying only 0.2 millimeter beneath the ventral tration increases than when the blood H+ concentration surface of the medulla. This area is highly sensitive to increases. For this reason, respiratory center activity is changes in either blood Pco2 or H+ concentration, and it increased very strongly by changes in blood CO2, a fact in turn excites the other portions of the respiratory center. that we subsequently discuss quantitatively. Excitation of the Chemosensitive Neurons by H+ Is Attenuated Stimulatory Effect of CO2 After the First Likely the Primary Stimulus. The sensor neurons in the 1 to 2 Days. Excitation of the respiratory center by CO2 is chemosensitive area are especially excited by H+; in fact, great the first few hours after the blood CO2 first increas- it is believed that H+ may be the only important direct es, but then it gradually declines over the next 1 to 2 days, stimulus for these neurons. However, H+ ions do not eas- decreasing to about one-fifth the initial effect. Part of this ily cross the blood–brain barrier. For this reason, changes decline results from renal readjustment of the H+ concen- in H+ concentration in the blood have considerably less tration in the circulating blood back toward normal after effect in stimulating the chemosensitive neurons than the CO2 first increases the H+ concentration. The kidneys changes in blood CO2, even though CO2 is believed to achieve this readjustment by increasing the blood HCO3−, stimulate these neurons secondarily by changing the H+ which binds with H+ in the blood and cerebrospinal fluid concentration, as explained in the following section. to reduce their concentrations. But, even more important- ly, over a period of hours, the HCO3− also slowly diffuses CO2 Indirectly Stimulates the Chemosensitive through the blood–brain and blood–cerebrospinal fluid Neurons. Although CO2 has little direct effect in stimu- barriers and combine directly with H+ adjacent to the res- lating the neurons in the chemosensitive area, it does have piratory neurons as well, thus reducing the H+ back to near a potent indirect effect. It has this effect by reacting with normal. A change in blood CO2 concentration therefore the water of the tissues to form carbonic acid, which dis- has a potent acute effect on controlling respiratory drive sociates into H+ and HCO3−; the H+ then have a potent but only a weak chronic effect after a few days’ adaptation. 533 UNIT VII Respiration 11 Alveolar ventilation (Basal rate = 1) 10 9 8 7 Medulla Glossopharyngeal nerve Normal 6 PCO2 5 Vagus nerve 4 3 Carotid body 2 1 0 20 30 40 50 60 70 80 90 100 PCO2 (mm Hg) 7.6 7.5 7.4 7.3 7.2 7.1 7.0 6.9 Aortic body pH Figure 42-3. Effects of increased arterial blood PCO2 and decreased arterial pH (increased H+ concentration) on the rate of alveolar ven- Figure 42-4. Respiratory control by peripheral chemoreceptors in tilation. the carotid and aortic bodies. Yet, for those special conditions in which the tissues Quantitative Effects of Blood Pco2 and H+ Concen- get into trouble for lack of O2, the body has a special tration on Alveolar Ventilation. Figure 42-3 shows mechanism for respiratory control located in the periph- quantitatively the approximate effects of blood Pco2 eral chemoreceptors, outside the brain respiratory center. and blood pH (which is an inverse logarithmic measure This mechanism responds when the blood O2 falls too of H+ concentration) on alveolar ventilation. Note espe- low, mainly below a Po2 of 70 mm Hg, as explained in the cially the marked increase in ventilation caused by an in- next section. crease in Pco2 in the normal range between 35 and 75 mm Hg, which demonstrates the tremendous effect that PERIPHERAL CHEMORECEPTOR CO2 changes have in controlling respiration. By contrast, SYSTEM—ROLE OF OXYGEN IN the change in respiration in the normal blood pH range, RESPIRATORY CONTROL which is between 7.3 and 7.5, is less than 10% as great. In addition to control of respiratory activity by the respi- Changes in O2 Have Little Direct Effect on Control of ratory center itself, still another mechanism is available the Respiratory Center. Changes in O2 concentration for controlling respiration. This mechanism is the periph- have virtually no direct effect on the respiratory center eral chemoreceptor system, shown in Figure 42-4. Special itself to alter respiratory drive—although O2 changes nervous chemical receptors, called chemoreceptors, are do have an indirect effect, acting through the peripheral located in several areas outside the brain. They are espe- chemoreceptors, as explained in the next section. cially important for detecting changes in O2 in the blood, We learned in Chapter 41 that the hemoglobin-oxygen although they also respond to a lesser extent to changes in buffer system delivers almost exactly normal amounts of CO2 and H+ concentrations. The chemoreceptors trans- O2 to the tissues, even when the pulmonary Po2 changes mit nervous signals to the respiratory center in the brain from a value as low as 60 mm Hg up to a value as high as to help regulate respiratory activity. 1000 mm Hg. Therefore, except under special conditions, Most of the chemoreceptors are in the carotid bodies. adequate delivery of O2 can occur despite changes in lung However, a few are also in the aortic bodies, shown in the ventilation ranging from slightly below half-normal to as lower part of Figure 42-4, and a very few are located else- high as 20 or more times normal. This is not true for CO2 where in association with other arteries of the thoracic because both the blood and tissue Pco2 change inversely and abdominal regions. with the rate of pulmonary ventilation; thus, the processes The carotid bodies are located bilaterally in the bifur- of animal evolution have made CO2 the major controller cations of the common carotid arteries. Their affer- of respiration, not O2. ent nerve fibers pass through Hering’s nerves to the 534  Chapter 42 Regulation of Respiration 800 Artery impulses per second Carotid body nerve 600 P O2 K+ channel UNIT VII 400 ΔVm Ca2+ Ca2+ channel 200 ? K+ 0 Glomus [Ca2+] 0 100 200 300 400 500 cell Arterial PO2 (mm Hg) Figure 42-5. Effect of arterial PO2 on impulse rate from the carotid body. glossopharyngeal nerves and then to the dorsal respiratory ATP Acetylcholine area of the medulla. The aortic bodies are located along the arch of the aorta; their afferent nerve fibers pass through the vagi, also to the dorsal medullary respiratory area. Each of the chemoreceptor bodies receives its own spe- To CNS Afferent fiber cial blood supply through a minute artery directly from the adjacent arterial trunk. Blood flow through these bodies is extreme, 20 times the weight of the bodies themselves each minute. Therefore, the percentage of O2 removed from the Figure 42-6. Carotid body glomus cell oxygen sensing. When the PO2 flowing blood is virtually zero, which means that the che- decreases below around 60 mm Hg, potassium channels close, caus- moreceptors are exposed at all times to arterial blood, not ing cell depolarization, opening of calcium channels, and increased venous blood, and their Po2 values are arterial Po2 values. cytosolic calcium ion concentration. This stimulates transmitter re- lease (adenosine triphosphate [ATP] is likely the most important), which activates afferent fibers that send signals to the central nervous Decreased Arterial Oxygen Stimulates the Chemore- system (CNS) and stimulate respiration. The mechanisms whereby ceptors. When the oxygen concentration in the arterial low PO2 influences potassium channel activity are still unclear. ΔVm, blood falls below normal, the chemoreceptors become Change in membrane voltage. strongly stimulated. This effect is demonstrated in Figure 42-5, which shows the effect of different levels of arterial Po2 on the rate of nerve impulse transmission from a ca- be the main neurotransmitters, more recent studies sug- rotid body. Note that the impulse rate is particularly sen- gest that during hypoxia, adenosine triphosphate (ATP) sitive to changes in arterial Po2 in the range of 60 mm Hg may be the key excitatory neurotransmitter released by down to 30 mm Hg, a range in which hemoglobin satura- carotid body glomus cells. tion with oxygen decreases rapidly. Increased CO2 and H+ Concentration Stimulates the Basic Mechanism of Stimulation of the Chemorecep- Chemoreceptors. An increase in CO2 or H+ concentra- tors by O2 Deficiency. The exact means whereby low Po2 tion also excites the chemoreceptors and, in this way, in- excites the nerve endings in the carotid and aortic bod- directly increases respiratory activity. However, the direct ies are still not completely understood. However, these effects of both these factors in the respiratory center are bodies have multiple, highly characteristic glandular-like much more powerful than their effects mediated through cells, called glomus cells, that synapse directly or indirect- the chemoreceptors (about seven times as powerful). Yet, ly with the nerve endings. Current evidence suggests that there is one difference between the peripheral and cen- these glomus cells function as the chemoreceptors and tral effects of CO2—the stimulation via the peripheral then stimulate the nerve endings (Figure 42-6). Glomus chemoreceptors occurs as much as five times as rapidly cells have O2-sensitive potassium channels that are inac- as central stimulation, so the peripheral chemoreceptors tivated when blood Po2 decreases markedly. This inacti- might be especially important in increasing the rapidity of vation causes the cell to depolarize, which in turn opens response to CO2 at the onset of exercise. voltage-gated calcium channels and increases intracellu- lar calcium ion concentration. The increased number of Effect of Low Arterial PO2 to Stimulate calcium ions stimulates release of a neurotransmitter that Alveolar Ventilation When Arterial CO2 activates afferent neurons that send signals to the central and H+ Concentrations Remain Normal nervous system and stimulate respiration. Although early Figure 42-7 shows the effect of low arterial Po2 on alveo- studies suggested that dopamine or acetylcholine might lar ventilation when the Pco2 and H+ concentrations are 535 UNIT VII Respiration 7 60 PO2 (mm Hg) pH = 7.4 40 50 6 40 pH = 7.3 40 50 60 100 PCO2 50 Alveolar ventilation (L/min) Alveolar ventilation (normal = 1) 5 40 Arterial PCO2 (mm Hg) 60 4 30 30 3 100 20 2 Ventilation 20 10 1 0 0 0 160 140 120 100 80 60 40 20 0 0 10 20 30 40 50 60 Arterial PO2 (mm Hg) Alveolar PCO2 (mm Hg) Figure 42-7. The lower red curve demonstrates the effect of dif- Figure 42-8. Composite diagram showing the interrelated effects of ferent levels of arterial PO2 on alveolar ventilation, showing a 6-fold PCO2, PO2, and pH on alveolar ventilation. (Data from Cunningham DJC, increase in ventilation as the PO2 decreases from the normal level of Lloyd BB: The Regulation of Human Respiration. Oxford: Blackwell 100 mm Hg to 20 mm Hg. The upper green line shows that the arte- Scientific, 1963.) rial PCO2 was kept at a constant level during the measurements of this study; pH also was kept constant. which helps immensely in supplying additional O2 to the kept constant at their normal levels. In other words, in mountain climber. this figure, only the ventilatory drive caused by low O2 on the chemoreceptors is active. Figure 42-7 shows almost Composite Effects of PCO2, pH, and PO2 on no effect on ventilation as long as the arterial Po2 remains Alveolar Ventilation greater than 100 mm Hg. However, at pressures lower Figure 42-8 gives a quick overview of the manner in than 100 mm Hg, ventilation approximately doubles which Po2, Pco2, and pH together affect alveolar ventila- when the arterial Po2 falls to 60 mm Hg and can increase tion. To understand this diagram, first observe the four as much as fivefold at very low Po2 values. Under these red curves. These curves were recorded at different levels conditions, low arterial Po2 obviously drives the ventila- of arterial Po2—40, 50, 60, and 100 mm Hg. For each of tory process quite strongly. these curves, the Pco2 was changed from lower to higher Because the effect of hypoxia on ventilation is modest levels. Thus, this family of red curves represents the com- for Po2 values greater than 60 to 80 mm Hg, the Pco2 and bined effects of alveolar Pco2 and Po2 on ventilation. H+ responses are mainly responsible for regulating venti- Now observe the green curves. Whereas the red curves lation in healthy humans at sea level. were measured at a blood pH of 7.4, the green curves were measured at a pH of 7.3. We now have two families of Chronic Breathing of Low O2 curves representing the combined effects of Pco2 and Po2 Stimulates Respiration Even More—The on ventilation at two different pH values. Still other fami- Phenomenon of “Acclimatization” lies of curves would be displaced to the right at higher pH Mountain climbers have found that when they ascend and displaced to the left at lower pH. Therefore, using this a mountain slowly, over a period of days rather than diagram, one can predict the level of alveolar ventilation a period of hours, they breathe much more deeply and for most combinations of alveolar Pco2, alveolar Po2, and therefore can withstand far lower atmospheric O2 con- arterial pH. centrations than when they ascend rapidly. This phenom- enon is called acclimatization. REGULATION OF RESPIRATION DURING The reason for acclimatization is that within 2 to 3 days, EXERCISE the respiratory center in the brain stem loses about 80% of its sensitivity to changes in Pco2 and H+. Therefore, the During strenuous exercise, O2 consumption and CO2 excess ventilatory blow-off of CO2 that normally would formation can increase as much as 20-fold. Yet, in the inhibit an increase in respiration fails to occur, and low O2 healthy athlete, as illustrated in Figure 42-9, alveolar ven- can drive the respiratory system to a much higher level of tilation ordinarily increases almost exactly in step with alveolar ventilation than under acute conditions. Instead the increased level of oxygen metabolism. The arterial of the 70% increase in ventilation that might occur after Po2, Pco2, and pH remain almost exactly normal. acute exposure to low O2, the alveolar ventilation often In trying to analyze what causes the increased ven- increases by 400% to 500% after 2 to 3 days of low O2, tilation during exercise, one is tempted to ascribe this 536  Chapter 42 Regulation of Respiration 120 44 Arterial PCO2 Total ventilation (L/min) 110 42 (mm Hg) 100 40 UNIT VII 80 38 60 36 Exercise 40 Alveolar ventilation 18 20 Moderate Severe 14 (L/min) exercise exercise 0 10 0 1.0 2.0 3.0 4.0 O2 consumption (L/min) 6 Figure 42-9. Effect of moderate and severe exercise on oxygen con- 2 sumption and ventilatory rate. (From Gray JS: Pulmonary Ventilation 0 1 2 and Its Physiological Regulation. Springfield, IL: Charles C Thomas, Minutes 1950.) Figure 42-10. Changes in alveolar ventilation (bottom curve) and ar- terial PCO2 (top curve) during a 1-minute period of exercise and also after termination of exercise. (Data from Bainton CR: Effect of speed increased ventilation to increases in blood CO2 and H+, vs. grade and shivering on ventilation in dogs during active exercise. plus a decrease in blood O2. However, measurements of J Appl Physiol 33:778, 1972.) arterial Pco2, pH, and Po2 show that none of these val- ues changes significantly during exercise, so none of them becomes abnormal enough to stimulate respiration as increase in ventilation is usually great enough so that at vigorously as observed during strenuous exercise. There- first it actually decreases arterial Pco2 below normal, as fore, what causes intense ventilation during exercise? At shown in the figure. The presumed reason why the venti- least one effect seems to be predominant. The brain, on lation forges ahead of the buildup of blood CO2 is that the transmitting motor impulses to the exercising muscles, brain provides an “anticipatory” stimulation of respiration is believed to transmit collateral impulses into the brain at the onset of exercise, causing extra alveolar ventilation stem at the same time to excite the respiratory center. even before it is necessary. However, after 30 to 40 sec- This action is analogous to the stimulation of the vasomo- onds, the amount of CO2 released into the blood from the tor center of the brain stem during exercise that causes a active muscles approximately matches the increased rate simultaneous increase in arterial pressure. of ventilation, and the arterial Pco2 returns essentially Actually, when a person begins to exercise, a large share to normal, even as the exercise continues. This is shown of the total increase in ventilation begins immediately on ini- toward the end of 1 minute of exercise in the figure. tiation of the exercise, before any blood chemicals have had Figure 42-11 summarizes the control of respiration time to change. It is likely that most of the increase in respi- during exercise in another way, this time more quanti- ration results from neurogenic signals transmitted directly tatively. The lower curve of this figure shows the effect into the brain stem respiratory center at the same time that of different levels of arterial Pco2 on alveolar ventilation signals go to the body muscles to cause muscle contraction. when the body is at rest—that is, not exercising. The upper curve shows the approximate shift of this ventilatory curve Interrelationship Between Chemical and Nervous caused by neurogenic drive from the respiratory center Factors in Controlling Respiration During Exercise. that occurs during heavy exercise. The points indicated on When a person exercises, direct nervous signals presum- the two curves show the arterial Pco2 first in the resting ably stimulate the respiratory center by almost the proper state and then in the exercising state. Note in both cases amount to supply the extra O2 required for exercise and that the Pco2 is at the normal level of 40 mm Hg. In other to blow off extra CO2. Occasionally, however, the nerv- words, the neurogenic factor shifts the curve about 20-fold ous respiratory control signals are too strong or too weak. in the upward direction, so ventilation almost matches Chemical factors then play a significant role in bringing the rate of CO2 release, thus keeping arterial Pco2 near its about the final adjustment of respiration required to keep normal value. The upper curve of Figure 42-11 also shows the O2, CO2, and H+ concentrations of the body fluids as that if during exercise the arterial Pco2 does change from nearly normal as possible. its normal value of 40 mm Hg, it has an extra stimulatory This process is demonstrated in Figure 42-10. The effect on ventilation at a Pco2 value greater than 40 mm Hg lower curve shows changes in alveolar ventilation during and a depressant effect at a Pco2 value less than 40 mm Hg. 1 minute of exercise, and the upper curve shows changes in arterial Pco2. Note that at the onset of exercise, the Neurogenic Control of Ventilation During Exercise alveolar ventilation increases almost instantaneously, May Be Partly a Learned Response. Many experiments without an initial increase in arterial Pco2. In fact, this suggest that the brain’s ability to shift the ventilatory 537 UNIT VII Respiration Function of Lung J Receptors. A few sensory nerve 140 endings have been described in the alveolar walls in jux- taposition to the pulmonary capillaries—hence, the name Exercise J receptors. They are stimulated especially when the pul- 120 monary capillaries become engorged with blood or when Alveolar ventilation (L/min) pulmonary edema occurs in conditions such as congestive 100 heart failure. Although the functional role of the J receptors is not clear, their excitation may give the person a feeling of 80 dyspnea. Brain Edema Depresses the Respiratory Center. The 60 activity of the respiratory center may be depressed or even inactivated by acute brain edema resulting from a brain Resting concussion. For example, the head might be struck against 40 some solid object, after which the damaged brain tissues swell, compressing the cerebral arteries against the cranial 20 Normal vault and thus partially blocking the cerebral blood supply. Occasionally, respiratory depression resulting from 0 brain edema can be relieved temporarily by intravenous 20 30 40 50 60 80 100 injection of a hypertonic solution, such as a highly concen- Arterial PCO2 (mm Hg) trated mannitol solution. These solutions osmotically re- move some of the fluids of the brain, thus relieving intrac- Figure 42-11. Approximate effect of maximum exercise in an athlete ranial pressure and sometimes re-establishing respiration to shift the alveolar PCO2–ventilation response curve to a level much within a few minutes. higher than normal. The shift, believed to be caused by neurogenic factors, is almost exactly the right amount to maintain arterial PCO2 at Overdosage of Anesthetics and Narcotics. Perhaps the the normal level of 40 mm Hg in the resting state and during heavy most prevalent cause of respiratory depression and respira- exercise. tory arrest is overdosage with anesthetics or narcotics. For example, sodium pentobarbital depresses the respiratory center considerably more than many other anesthetics, such Depth of as halothane. At one time, morphine was used as an anes- respiration thetic, but this drug is now used only as an adjunct to an- esthetics because it greatly depresses the respiratory center while having less ability to anesthetize the cerebral cortex. PCO2 of Respiratory Because of their capacity to cause respiratory depres- respiratory center excited neurons sion, opioids are responsible for a high proportion of fa- tal drug overdoses around the world. In the United States, approximately 70,000 people died from drug overdose in PCO2 of 2017, largely due to respiratory arrest. lung blood Periodic Breathing. An abnormality of respiration Figure 42-12. Cheyne-Stokes breathing, showing changing PCO2 in called periodic breathing occurs in several disease condi- the pulmonary blood (red line) and delayed changes in the PCO2 of the tions. The person breathes deeply for a short interval and fluids of the respiratory center (blue line). then breathes slightly or not at all for an additional interval, response curve during exercise, as shown in Figure with the cycle repeating itself over and over. One type of periodic breathing, Cheyne-Stokes breathing, is character- 42-11, is at least partly a learned response. That is, ized by slowly waxing and waning respiration occurring with repeated periods of exercise, the brain becomes about every 40 to 60 seconds, as illustrated in Figure 42-12. progressively more able to provide the proper signals Basic Mechanism of Cheyne- Stokes Breathing. The required to keep the blood Pco2 at its normal level. basic cause of Cheyne-Stokes breathing is the following. Also, there is reason to believe that even the cerebral When a person overbreathes, thus blowing off too much cortex is involved in this learning because experiments CO2 from the pulmonary blood while at the same time that block only the cortex also block the learned re- increasing blood O2, it takes several seconds before the sponse. changed pulmonary blood can be transported to the brain and inhibit the excess ventilation. By this time, the per- Other Factors That Affect Respiration son has already overventilated for an extra few seconds. Therefore, when the overventilated blood finally reaches Effect of Irritant Receptors in the Airways. The the brain respiratory center, the center becomes depressed epithelium of the trachea, bronchi, and bronchioles is to an excessive amount, at which point the opposite cycle supplied with sensory nerve endings called pulmonary begins—that is, CO2 increases, and O2 decreases in the al- irritant receptors that are stimulated by many factors. veoli. Again, it takes a few seconds before the brain can These receptors initiate coughing and sneezing, as dis- respond to these new changes. When the brain does re- cussed in Chapter 40. They may also cause bronchial spond, the person breathes hard once again and the cycle constriction in persons with diseases such as asthma repeats. and emphysema. 538  Chapter 42 Regulation of Respiration The basic cause of Cheyne-Stokes breathing occurs in eve- In persons with sleep apnea, loud snoring and labored ryone. However, under normal conditions, this mechanism is breathing occur soon after falling asleep. The snoring pro- highly damped. That is, the fluids of the blood and respiratory ceeds, often becoming louder, and is then interrupted by a center control areas have large amounts of dissolved and chem- long silent period during which no breathing (apnea) occurs. ically bound CO2 and O2. Therefore, normally, the lungs can- These periods of apnea result in significant decreases in Po2 UNIT VII not build up enough extra CO2 or depress the O2 sufficiently in and increases in Pco2, which greatly stimulate respiration. a few seconds to cause the next cycle of the periodic breathing. This stimulation, in turn, causes sudden attempts to breathe, However, under two separate conditions, the damping factors which result in loud snorts and gasps followed by snoring and can be overridden, and Cheyne-Stokes breathing does occur: repeated episodes of apnea. The periods of apnea and labored 1. When a long delay occurs for transport of blood from the breathing are repeated several hundred times during the night, lungs to the brain, changes in CO2 and O2 in the alveoli resulting in fragmented restless sleep. Therefore, patients with can continue for many more seconds than usual. Under sleep apnea usually have excessive daytime drowsiness, as well these conditions, the storage capacities of the alveoli and as other disorders, including increased sympathetic activity, pulmonary blood for these gases are exceeded; then, after a high heart rate, pulmonary and systemic hypertension, and a few more seconds, the periodic respiratory drive becomes greatly elevated risk for cardiovascular disease. extreme and Cheyne-Stokes breathing begins. This type Obstructive sleep apnea usually occurs in older obese of Cheyne-Stokes breathing often occurs in patients with persons in whom there is increased fat deposition in the soft severe cardiac failure because blood flow is slow, thus de- tissues of the pharynx or compression of the pharynx due to laying the transport of blood gases from the lungs to the excessive fat masses in the neck. In a few individuals, sleep brain. In patients with chronic heart failure, Cheyne-Stokes apnea may be associated with nasal obstruction, a very large breathing can sometimes occur on and off for months. tongue, enlarged tonsils, or certain shapes of the palate that 2. A second cause of Cheyne-Stokes breathing is increased greatly increase resistance to the flow of air to the lungs dur- negative feedback gain in the respiratory control areas, ing inspiration. The most common treatments of obstruc- which means that a change in blood CO2 or O2 causes a tive sleep apnea include the following: (1) surgery to remove far greater change in ventilation than normally. For ex- excess fat tissue at the back of the throat (a procedure called ample, instead of the normal two- to threefold increase uvulopalatopharyngoplasty), remove enlarged tonsils or ad- in ventilation that occurs when the Pco2 rises 3 mm Hg, enoids, or create an opening in the trachea (tracheostomy) the same 3-mm Hg rise might increase ventilation by to bypass the obstructed airway during sleep; and (2) nasal 10- to 20-fold. The brain feedback tendency for periodic ventilation with continuous positive airway pressure (CPAP). breathing is now strong enough to cause Cheyne-Stokes “Central” Sleep Apnea Occurs When the Neural Drive breathing without extra blood flow delay between the to Respiratory Muscles Is Transiently Abolished. In a few lungs and brain. This type of Cheyne-Stokes breathing persons with sleep apnea, the central nervous system drive occurs mainly in patients with damage to the respiratory to the ventilatory muscles transiently ceases. Disorders centers of the brain. The brain damage often turns off that can cause cessation of the ventilatory drive during the respiratory drive entirely for a few seconds, and then sleep include damage to the central respiratory centers or an extra-intense increase in blood CO2 turns it back on abnormalities of the respiratory neuromuscular apparatus. with great force. Cheyne-Stokes breathing of this type is Patients affected by central sleep apnea may have decreased frequently a prelude to death from brain malfunction. ventilation, even when they are awake, although they are Typical records of changes in pulmonary and respirato- fully capable of normal voluntary breathing. During sleep, ry center Pco2 during Cheyne-Stokes breathing are shown their breathing disorders usually worsen, resulting in more in Figure 42-12. Note that the Pco2 of the pulmonary frequent episodes of apnea that decrease Po2 and increase blood changes in advance of the Pco2 of the respiratory Pco2 until a critical level is reached that eventually stimu- neurons. However, the depth of respiration corresponds lates respiration. These transient instabilities of respiration with the Pco2 in the brain, not with the Pco2 in the pulmo- cause restless sleep and clinical features similar to those ob- nary blood where the ventilation is occurring. served in people with obstructive sleep apnea. In most patients, the cause of central sleep apnea is Sleep Apnea unknown, although instability of the respiratory drive can The term apnea means absence of spontaneous breathing. Oc- result from strokes or other disorders that make the respira- casional apneas occur during normal sleep, but in persons with tory centers of the brain less responsive to the stimulatory ef- sleep apnea, the frequency and duration are greatly increased, fects of CO2 and H+. Patients with this disease are extremely with episodes of apnea lasting for 10 seconds or longer and oc- sensitive to even small doses of sedatives or narcotics, which curring 300 to 500 times each night. Sleep apneas can be caused further reduce the responsiveness of the respiratory centers by obstruction of the upper airways, especially the pharynx, or to the stimulatory effects of CO2. Medications that stimu- by an impaired central nervous system respiratory drive. late the respiratory centers can sometimes be helpful, but Obstructive Sleep Apnea Is Caused by Blockage of the ventilation with CPAP at night is usually necessary. Upper Airway. The muscles of the pharynx normally keep In some cases, sleep apnea may be caused by a combina- this passage open to allow air to flow into the lungs during tion of obstructive and central mechanisms. This “mixed” inspiration. During sleep, these muscles usually relax, but type of sleep apnea is estimated to account for approxi- the airway passage remains open enough to permit adequate mately 15% of all sleep apnea cases, whereas pure “central” airflow. Some people have an especially narrow passage, and sleep apnea accounts for less than 1% of cases. The most relaxation of these muscles during sleep causes the pharynx common cause of sleep apnea is obstruction of the upper to close completely so that air cannot flow into the lungs. airway. 539 UNIT VII Respiration Voluntary Control of Respiration Guyenet PG, Bayliss DA, Stornetta RL, et al: Proton detection and breathing regulation by the retrotrapezoid nucleus. J Physiol Thus far, we have discussed mainly the involuntary system 594:1529, 2016. for control of respiration. However, we all know that respi- Guyenet PG, Bayliss DA: Neural control of breathing and CO2 homeo- ration can be controlled voluntarily for short periods, and stasis. Neuron 87:946, 2015. that a person can hyperventilate or hypoventilate to such Hilaire G, Pasaro R: Genesis and control of the respiratory rhythm in an extent that serious derangements in Pco2, pH, and Po2 adult mammals. News Physiol Sci 18:23, 2003. can occur in the blood. In fact, the world record for dura- Hoiland RL, Fisher JA, Ainslie PN: Regulation of the cerebral circula- tion of voluntary breath-holding (apnea) under static rest- tion by arterial carbon dioxide. Compr Physiol 9:1101, 2019. ing conditions (and not hyperventilating with pure oxygen Hoiland RL, Howe CA, Coombs GB, Ainslie PN: Ventilatory and cere- before the attempt) is reported to be 11 minutes and 54 brovascular regulation and integration at high-altitude. Clin Auton Res 28:423, 2018. seconds. Hyperventilation with pure oxygen and expelling Javaheri S, Barbe F, Campos-Rodriguez F, Dempsey JA, et al. Sleep ap- large amounts of CO2 before the apnea attempt has permit- nea: types, mechanisms, and clinical cardiovascular consequences. ted individuals to hold their breath underwater for over 24 J Am Coll Cardiol 69:841, 2017. minutes. Ultra-elite apnea competitors are able to suppress Nurse CA, Piskuric NA: Signal processing at mammalian carotid body respiratory urges to the point where oxygen saturations fall chemoreceptors. Semin Cell Dev Biol 24:22, 2013. to as low as about 50%, and unconsciousness limits the du- Plataki M, Sands SA, Malhotra A: Clinical consequences of altered ration of breath-holding. chemoreflex control. Respir Physiol Neurobiol 189:354, 2013. Prabhakar NR, Semenza GL: Oxygen sensing and homeostasis. Physi- ology (Bethesda) 30:340, 2015. Ramirez JM, Doi A, Garcia AJ 3rd, et al: The cellular building blocks of Bibliography breathing. Compr Physiol 2:2683, 2012. Bain AR, Drvis I, Dujic Z, MacLeod DB, Ainslie PN: Physiology of static Stuth EA, Stucke AG, Zuperku EJ: Effects of anesthetics, sedatives, breath holding in elite apneists. Exp Physiol 103:635, 2018. and opioids on ventilatory control. Compr Physiol 2:2281, 2012. Chang AJ: Acute oxygen sensing by the carotid body: from mitochon- Veasey SC, Rosen IM: Obstructive sleep apnea in adults. N Engl J Med dria to plasma membrane. J Appl Physiol 123:1335, 2017. 380:1442, 2019. Chowdhuri S, Badr MS: control of ventilation in health and disease. Wilson RJ, Teppema LJ: Integration of central and peripheral respira- Chest. 151:917, 2017. tory chemoreflexes. Compr Physiol 6:1005, 2016. Guyenet PG, Abbott SB, Stornetta RL: The respiratory chemore- ception conundrum: light at the end of the tunnel? Brain Res 1511:126, 2013. 540