Chapter 36: Regulation of Respiration

After studying this chapter, you should be able to:

• Locate the pre-Bötzinger complex and describe its role in producing spontaneous respiration.

• Identify the location and probable functions of the dorsal and ventral groups of respiratory neurons, the pneumotaxic center, and the apneustic center in the brainstem.

• List the specific respiratory functions of the vagus nerves and the respiratory receptors in the carotid body, the aortic body, and the ventral surface of the medulla oblongata.

• Describe and explain the ventilatory responses to increased CO₂ concentrations in the inspired air.

• Describe and explain the ventilatory responses to decreased O₂ concentrations in the inspired air.

• Describe the effects of each of the main nonchemical factors that influence respiration.

• Describe the effects of exercise on ventilation and O₂ exchange in the tissues.

• Define periodic breathing and explain its occurrence in various disease states.

Spontaneous respiration is produced by rhythmic discharge of motor neurons that innervate the respiratory muscles. This discharge is totally dependent on nerve impulses from the brain; breathing stops if the spinal cord is transected above the origin of the phrenic nerves. The rhythmic discharges from the brain that produce spontaneous respiration are regulated by alterations in arterial Po₂, Pco₂, and H⁺ concentration, and this chemical control of breathing is supplemented by a number of nonchemical influences. The physiologic bases for these phenomena are discussed in this chapter.

CONTROL SYSTEMS

Two separate neural mechanisms regulate respiration. One is responsible for voluntary control and the other for automatic control. The voluntary system is located in the cerebral cortex and sends impulses to the respiratory motor neurons via the corticospinal tracts. The automatic system is driven by a group of pacemaker cells in the medulla. Impulses from these cells activate motor neurons in the cervical and thoracic spinal cord that innervate inspiratory muscles. Those in the cervical cord activate the diaphragm via the phrenic nerves, and those in the thoracic spinal cord activate the external intercostal muscles. However, the impulses also reach the innervation of the internal intercostal muscles and other expiratory muscles.

The motor neurons to the expiratory muscles are inhibited when those supplying the inspiratory muscles are active, and vice versa. Although spinal reflexes contribute to this reciprocal innervation, it is due primarily to activity in descending pathways. Impulses in these descending pathways excite agonists and inhibit antagonists. The one exception to the reciprocal inhibition is a small amount of activity in phrenic axons for a short period after inspiration. The function of this postinspiratory output appears to be to brake the lung’s elastic recoil and make respiration smooth.

MEDULLARY SYSTEMS

The main components of the respiratory control pattern generator responsible for automatic respiration are located in the medulla. Rhythmic respiration is initiated by a small group of synaptically coupled pacemaker cells in the pre-Bötzinger complex (pre-BÖTC) on either side of the medulla between the nucleus ambiguus and the lateral reticular nucleus (Figure 36–1). These neurons discharge rhythmically, and they produce rhythmic discharges in phrenic motor neurons that are abolished by sections between the pre-BÖTC complex and these motor neurons. They also contact the hypoglossal nuclei, and the tongue is involved in the regulation of airway resistance.

Neurons in the pre-BÖTC complex discharge rhythmically in brain slice preparations in vitro, and if the slices become hypoxic, discharge changes to one associated with gasping. Addition of cadmium to the slices causes occasional sigh-like discharge patterns. There are NK1 receptors and μ-opioid receptors on these neurons, and, in vivo, substance P stimulates and opioids inhibit respiration. Depression of respiration is a side effect that limits the use of opioids in the treatment of pain. However, it is now known that 5HT₄ receptors are present in the pre-BÖTC complex and treatment with 5HT₄ agonists blocks the inhibitory effect of opioids on respiration in experimental animals, without inhibiting their analgesic effect.

In addition, dorsal and ventral groups of respiratory neurons are present in the medulla (Figure 36–2). However, lesions of these neurons do not abolish respiratory activity, and they apparently project to the pre-BÖTC pacemaker neurons.

PONTINE & VAGAL INFLUENCES

Although the rhythmic discharge of medullary neurons concerned with respiration is spontaneous, it is modified by neurons in the pons and afferents in the vagus from receptors in the airways and lungs. An area known as the pneumotaxic center in the medial parabrachial and Kölliker-Fuse nuclei of the dorsolateral pons contains neurons active during inspiration and neurons active during expiration. When this area is damaged, respiration becomes slower and tidal volume greater, and when the vagi are also cut in anesthetized animals, there are prolonged inspiratory spasms that resemble breath holding (apneusis; section B in Figure 36–2). The normal function of the pneumotaxic center is unknown, but it may play a role in switching between inspiration and expiration.

Stretching of the lungs during inspiration initiates impulses in afferent pulmonary vagal fibers. These impulses inhibit inspiratory discharge. This is why the depth of inspiration is increased after vagotomy (Figure 36–2) and apneusis develops if the vagi are cut after damage to the pneumotaxic center. Vagal feedback activity does not alter the rate of rise of the neural activity in respiratory motor neurons (Figure 36–3).

When the activity of the inspiratory neurons is increased in intact animals, the rate and the depth of breathing are increased. The depth of respiration is increased because the lungs are stretched to a greater degree before the amount of vagal and pneumotaxic center inhibitory activity is sufficient to overcome the more intense inspiratory neuron discharge. The respiratory rate is increased because the after-discharge in the vagal and possibly the pneumotaxic afferents to the medulla is rapidly overcome.

A rise in the Pco₂ or H⁺ concentration of arterial blood or a drop in its Po₂ increases the level of respiratory neuron activity in the medulla, and changes in the opposite direction have a slight inhibitory effect. The effects of variations in blood chemistry on ventilation are mediated via respiratory chemoreceptors—the carotid and aortic bodies and collections of cells in the medulla and elsewhere that are sensitive to changes in the chemistry of the blood. They initiate impulses that stimulate the respiratory center. Superimposed on this basic chemical control of respiration, other afferents provide nonchemical controls that affect breathing in particular situations (Table 36–1).

The chemical regulatory mechanisms adjust ventilation in such a way that the alveolar Pco₂ is normally held constant, the effects of excess H⁺ in the blood are combated, and the Po₂ is raised when it falls to a potentially dangerous level. The respiratory minute volume is proportional to the metabolic rate, but the link between metabolism and ventilation is CO₂, not O₂. The receptors in the carotid and aortic bodies are stimulated by a rise in the Pco₂ or H⁺ concentration of arterial blood or a decline in its Po₂. After denervation of the carotid chemoreceptors, the response to a drop in Po₂ is abolished; the predominant effect of hypoxia after denervation of the carotid bodies is a direct depression of the respiratory center. The response to changes in arterial blood H⁺ concentration in the pH 7.3–7.5 range is also abolished, although larger changes exert some effect. The response to changes in arterial Pco₂, on the other hand, is affected only slightly; it is reduced no more than 30–35%.

CAROTID & AORTIC BODIES

There is a carotid body near the carotid bifurcation on each side, and there are usually two or more aortic bodies near the arch of the aorta (Figure 36–4). Each carotid and aortic body (glomus) contains islands of two types of cells, type I and type II cells, surrounded by fenestrated sinusoidal capillaries. The type I or glomus cells are closely associated with cuplike endings of the afferent nerves (Figure 36–5). The glomus cells resemble adrenal chromaffin cells and have dense-core granules containing catecholamines that are released upon exposure to hypoxia and cyanide. The cells are excited by hypoxia, and the principal transmitter appears to be dopamine, which excites the nerve endings by way of D₂ receptors. The type II cells are glia-like, and each surrounds four to six type I cells. The function of type II cells is not fully defined.

Outside the capsule of each body, the nerve fibers acquire a myelin sheath; however, they are only 2–5 μm in diameter and conduct at the relatively low rate of 7–12 m/s. Afferents from the carotid bodies ascend to the medulla via the carotid sinus and glossopharyngeal nerves, and fibers from the aortic bodies ascend in the vagi. Studies in which one carotid body has been isolated and perfused while recordings are being taken from its afferent nerve fibers show that there is a graded increase in impulse traffic in these afferent fibers as the Po₂ of the perfusing blood is lowered (Figure 36–6) or the Pco₂ is raised.

Type I glomus cells have O₂-sensitive K⁺ channels, whose conductance is reduced in proportion to the degree of hypoxia to which they are exposed. This reduces the K⁺ efflux, depolarizing the cell and causing Ca²⁺ influx, primarily via L-type Ca²⁺ channels. The Ca²⁺ influx triggers action potentials and transmitter release, with consequent excitation of the afferent nerve endings. The smooth muscle of pulmonary arteries contains similar O₂-sensitive K⁺ channels, which mediate the vasoconstriction caused by hypoxia. This is in contrast to systemic arteries, which contain adenosine triphosphate- (ATP-) dependent K⁺ channels that permit more K⁺ efflux with hypoxia and consequently cause vasodilation instead of vasoconstriction.

The blood flow in each 2 mg carotid body is about 0.04 mL/min, or 2000 mL/100 g of tissue/min compared with a blood flow of 54 mL or 420 mL per 100 g/min in the brain and kidneys, respectively. Because the blood flow per unit of tissue is so enormous, the O₂ needs of the cells can be met largely by dissolved O₂ alone. Therefore, the receptors are not stimulated in conditions such as anemia or carbon monoxide poisoning, in which the amount of dissolved O₂ in the blood reaching the receptors is generally normal, even though the combined O₂ in the blood is markedly decreased. The receptors are stimulated when the arterial Po₂ is low or when, because of vascular stasis, the amount of O₂ delivered to the receptors per unit time is decreased. Powerful stimulation is also produced by cyanide, which prevents O₂ utilization at the tissue level. In sufficient doses, nicotine and lobeline activate the chemoreceptors. It has also been reported that infusion of K⁺ increases the discharge rate in chemoreceptor afferents, and because the plasma K⁺ level is increased during exercise, the increase may contribute to exercise-induced hyperpnea.

Because of their anatomic location, the aortic bodies have not been studied in as great detail as the carotid bodies. Their responses are probably similar but of lesser magnitude. In humans in whom both carotid bodies have been removed but the aortic bodies left intact, the responses are essentially the same as those following denervation of both carotid and aortic bodies in animals: little change in ventilation at rest, but the ventilatory response to hypoxia is lost and the ventilatory response to CO₂ is reduced by 30%.

Neuroepithelial bodies composed of innervated clusters of amine-containing cells are found in the airways. These cells have an outward K⁺ current that is reduced by hypoxia, and this would be expected to produce depolarization. However, the function of these hypoxia-sensitive cells is uncertain because, as noted above, removal of the carotid bodies alone abolishes the respiratory response to hypoxia.

CHEMORECEPTORS IN THE BRAINSTEM

The chemoreceptors that mediate the hyperventilation produced by increases in arterial Pco₂ after the carotid and aortic bodies are denervated are located in the medulla oblongata and consequently are called medullary chemoreceptors. They are separate from the dorsal and ventral respiratory neurons and are located on the ventral surface of the medulla (Figure 36–7). Recent evidence indicates that additional chemoreceptors are located in the vicinity of the solitary tract nuclei, the locus ceruleus, and the hypothalamus.

The chemoreceptors monitor the H⁺ concentration of cerebrospinal fluid (CSF), including the brain interstitial fluid. CO₂ readily penetrates membranes, including the blood–brain barrier, whereas H⁺ and HCO₃⁻ penetrate slowly. The CO₂ that enters the brain and CSF is promptly hydrated. The H₂CO₃ dissociates, so that the local H⁺ concentration rises. The H⁺ concentration in brain interstitial fluid parallels the arterial Pco₂. Experimentally produced changes in the Pco₂ of CSF have minor, variable effects on respiration as long as the H⁺ concentration is held constant, but any increase in spinal fluid H⁺ concentration stimulates respiration. The magnitude of the stimulation is proportional to the rise in H⁺ concentration. Thus, the effects of CO₂ on respiration are mainly due to its movement into the CSF and brain interstitial fluid, where it increases the H⁺ concentration and stimulates receptors sensitive to H⁺.

VENTILATORY RESPONSES TO CHANGES IN ACID–BASE BALANCE

In metabolic acidosis due, for example, to the accumulation of acid ketone bodies in the circulation in diabetes mellitus, there is pronounced respiratory stimulation (Kussmaul breathing). The hyperventilation decreases alveolar Pco₂ (“blows off CO₂”) and thus produces a compensatory fall in blood H⁺ concentration. Conversely, in metabolic alkalosis due, for example, to protracted vomiting with loss of HCl from the body, ventilation is depressed and the arterial Pco₂ rises, raising the H⁺ concentration toward normal. If there is an increase in ventilation that is not secondary to a rise in arterial H⁺ concentration, the drop in Pco₂ lowers the H⁺ concentration below normal (respiratory alkalosis); conversely, hypoventilation that is not secondary to a fall in plasma H⁺ concentration causes respiratory acidosis.

VENTILATORY RESPONSES TO CO₂

The arterial Pco₂ is normally maintained at 40 mm Hg. When arterial Pco₂ rises as a result of increased tissue metabolism, ventilation is stimulated and the rate of pulmonary excretion of CO₂ increases until the arterial Pco₂ falls to normal, shutting off the stimulus. The operation of this feedback mechanism keeps CO₂ excretion and production in balance.

When a gas mixture containing CO₂ is inhaled, the alveolar Pco₂ rises, elevating the arterial Pco₂ and stimulating ventilation as soon as the blood that contains more CO₂ reaches the medulla. CO₂ elimination is increased, and the alveolar Pco₂ drops toward normal. This is why relatively large increments in the Pco₂ of inspired air (eg, 15 mm Hg) produce relatively slight increments in alveolar Pco₂ (eg, 3 mm Hg). However, the Pco₂ does not drop to normal, and a new equilibrium is reached at which the alveolar Pco₂ is slightly elevated and the hyperventilation persists as long as CO₂ is inhaled. The essentially linear relationship between respiratory minute volume and the alveolar Pco₂ is shown in Figure 36–8.

Of course, this linearity has an upper limit. When the Pco₂ of the inspired gas is close to the alveolar Pco₂, elimination of CO₂ becomes difficult. When the CO₂ content of the inspired gas is more than 7%, the alveolar and arterial Pco₂ begin to rise abruptly in spite of hyperventilation. The resultant accumulation of CO₂ in the body (hypercapnia) depresses the central nervous system, including the respiratory center, and produces headache, confusion, and eventually coma (CO₂ narcosis).

VENTILATORY RESPONSE TO OXYGEN DEFICIENCY

When the O₂ content of the inspired air is decreased, respiratory minute volume is increased. The stimulation is slight when the Po₂ of the inspired air is more than 60 mm Hg, and marked stimulation of respiration occurs only at lower Po₂ values (Figure 36–9). However, any decline in arterial Po₂ below 100 mm Hg produces increased discharge in the nerves from the carotid and aortic chemoreceptors. There are two reasons why this increase in impulse traffic does not increase ventilation to any extent in normal individuals until the Po₂ is less than 60 mm Hg. First, because Hb is a weaker acid than HbO₂, there is a slight decrease in the H⁺ concentration of arterial blood when the arterial Po₂ falls and hemoglobin becomes less saturated with O₂. The fall in H⁺ concentration tends to inhibit respiration. In addition, any increase in ventilation that does occur lowers the alveolar Pco₂, and this also tends to inhibit respiration. Therefore, the stimulatory effects of hypoxia on ventilation are not clearly manifest until they become strong enough to override the counterbalancing inhibitory effects of a decline in arterial H⁺ concentration and Pco₂.

The effects on ventilation of decreasing the alveolar Po₂ while holding the alveolar Pco₂ constant are shown in Figure 36–10. When the alveolar Pco₂ is stabilized at a level 2–3 mm Hg above normal, there is an inverse relationship between ventilation and the alveolar Po₂ even in the 90–110 mm Hg range; but when the alveolar Pco₂ is fixed at lower than normal values, there is no stimulation of ventilation by hypoxia until the alveolar Po₂ falls below 60 mm Hg.

EFFECTS OF HYPOXIA ON THE CO₂ RESPONSE CURVE

When the converse experiment is performed—that is, when the alveolar Po₂ is held constant while the response to varying amounts of inspired CO₂ is tested—a linear response is obtained (Figure 36–11). When the CO₂ response is tested at different fixed Po₂ values, the slope of the response curve changes, with the slope increased when alveolar Po₂ is decreased. In other words, hypoxia makes the individual more sensitive to an increase in arterial Pco₂. However, the alveolar Pco₂ level at which the curves in Figure 36–11 intersect is unaffected. In the normal individual, this threshold value is just below the normal alveolar Pco₂, indicating that normally there is a very slight but definite “CO₂ drive” of the respiratory area.

EFFECT OF H⁺ ON THE CO₂ RESPONSE

The stimulatory effects of H⁺ and CO₂ on respiration appear to be additive and not, like those of CO₂ and O₂, complexly interrelated. In metabolic acidosis, the CO₂ response curves are similar to those in Figure 36–11, except that they are shifted to the left. In other words, the same amount of respiratory stimulation is produced by lower arterial Pco₂ levels. It has been calculated that the CO₂ response curve shifts 0.8 mm Hg to the left for each nanomole rise in arterial H⁺. About 40% of the ventilatory response to CO₂ is removed if the increase in arterial H⁺ produced by CO₂ is prevented. As noted above, the remaining 60% is probably due to the effect of CO₂ on spinal fluid or brain interstitial fluid H⁺ concentration.

BREATH HOLDING

Respiration can be voluntarily inhibited for some time, but eventually the voluntary control is overridden. The point at which breathing can no longer be voluntarily inhibited is called the breaking point. Breaking is due to the rise in arterial Pco₂ and the fall in Po₂. Individuals can hold their breath longer after removal of the carotid bodies. Breathing 100% oxygen before breath holding raises alveolar Po₂ initially, so that the breaking point is delayed. The same is true of hyperventilating room air, because CO₂ is blown off and arterial Pco₂ is lower at the start. Reflex or mechanical factors appear to influence the breaking point, since persons who hold their breath as long as possible and then breathe a gas mixture low in O₂ and high in CO₂ can hold their breath for an additional 20 s or more. Psychological factors also play a role, and persons can hold their breath longer when they are told their performance is very good than when they are not.

RESPONSES MEDIATED BY RECEPTORS IN THE AIRWAYS & LUNGS

Receptors in the airways and lungs are innervated by myelinated and unmyelinated vagal fibers. The unmyelinated fibers are C fibers. The receptors innervated by myelinated fibers are commonly divided into slowly adapting receptors and rapidly adapting receptors on the basis of whether sustained stimulation leads to prolonged or transient discharge in their afferent nerve fibers (Table 36–2). The other group of receptors presumably consists of the endings of C fibers, and they are divided into pulmonary and bronchial subgroups on the basis of their location.

The shortening of inspiration produced by vagal afferent activity (Figure 36–3) is mediated by slowly adapting receptors, as are the Hering-Breuer reflexes. The Hering-Breuer inflation reflex is an increase in the duration of expiration produced by steady lung inflation, and the Hering-Breuer deflation reflex is a decrease in the duration of expiration produced by marked deflation of the lung. Because the rapidly adapting receptors are stimulated by chemicals such as histamine, they have been called irritant receptors. Activation of rapidly adapting receptors in the trachea causes coughing, bronchoconstriction, and mucus secretion, and activation of rapidly adapting receptors in the lung may produce hyperpnea.

Because the C fiber endings are close to pulmonary vessels, they have been called J (juxtacapillary) receptors. They are stimulated by hyperinflation of the lung, but they respond as well to intravenous or intracardiac administration of chemicals such as capsaicin. The reflex response that is produced is apnea followed by rapid breathing, bradycardia, and hypotension (pulmonary chemoreflex). A similar response is produced by receptors in the heart (Bezold-Jarisch reflex or the coronary chemoreflex). The physiologic role of this reflex is uncertain, but it probably occurs in pathologic states such as pulmonary congestion or embolization, in which it is produced by endogenously released substances.

COUGHING & SNEEZING

Coughing begins with a deep inspiration followed by forced expiration against a closed glottis. This increases the intrapleural pressure to 100 mm Hg or more. The glottis is then suddenly opened, producing an explosive outflow of air at velocities up to 965 km (600 mi) per hour. Sneezing is a similar expiratory effort with a continuously open glottis. These reflexes help expel irritants and keep airways clear. Other aspects of innervation are considered in a special case (Clinical Box 36–1).

AFFERENTS FROM PROPRIOCEPTORS

Carefully controlled experiments have shown that active and passive movements of joints stimulate respiration, presumably because impulses in afferent pathways from proprioceptors in muscles, tendons, and joints stimulate the inspiratory neurons. This effect probably helps increase ventilation during exercise. Other afferents are considered in Clinical Box 36–2.

RESPIRATORY COMPONENTS OF VISCERAL REFLEXES

Inhibition of respiration and closure of the glottis during vomiting, swallowing, and sneezing not only prevent the aspiration of food or vomitus into the trachea but, in the case of vomiting, fix the chest so that contraction of the abdominal muscles increases the intra-abdominal pressure. Similar glottic closure and inhibition of respiration occur during voluntary and involuntary straining.

Hiccup is a spasmodic contraction of the diaphragm and other inspiratory muscles that produces an inspiration during which the glottis suddenly closes. The glottic closure is responsible for the characteristic sensation and sound. Hiccups occur in the fetus in utero as well as throughout extrauterine life. Their function is unknown. Most attacks of hiccups are usually of short duration, and they often respond to breathholding or other measures that increase arterial Pco₂. Intractable hiccups, which can be debilitating, sometimes respond to dopamine antagonists and perhaps to some centrally acting analgesic compounds.

Yawning is a peculiar “infectious” respiratory act whose physiologic basis and significance are uncertain. Like hiccuping, it occurs in utero, and it occurs in fish and tortoises as well as mammals. The view that it is needed to increase O₂ intake has been discredited. Underventilated alveoli have a tendency to collapse, and it has been suggested that the deep inspiration and stretching them open prevents the development of atelectasis. However, in actual experiments, no atelectasis-preventing effect of yawning could be demonstrated. Yawning increases venous return to the heart, which may benefit the circulation. It has been suggested that yawning is a nonverbal signal used for communication between monkeys in a group, and one could argue that on a different level, the same thing is true in humans.

RESPIRATORY EFFECTS OF BARORECEPTOR STIMULATION

Afferent fibers from the baroreceptors in the carotid sinuses, aortic arch, atria, and ventricles relay to the respiratory neurons, as well as the vasomotor and cardioinhibitory neurons in the medulla. Impulses in them inhibit respiration, but the inhibitory effect is slight and of little physiologic importance. The hyperventilation in shock is due to chemoreceptor stimulation caused by acidosis and hypoxia secondary to local stagnation of blood flow, and is not baroreceptor-mediated. The activity of inspiratory neurons affects blood pressure and heart rate, and activity in the vasomotor and cardiac areas in the medulla may have minor effects on respiration.

EFFECTS OF SLEEP

Respiration is less rigorously controlled during sleep than in the waking state, and brief periods of apnea occur in normal sleeping adults. Changes in the ventilatory response to hypoxia vary. If the Pco₂ falls during the waking state, various stimuli from proprioceptors and the environment maintain respiration, but during sleep, these stimuli are decreased and a decrease in Pco₂ can cause apnea. During rapid eye movement (REM) sleep, breathing is irregular and the CO₂ response is highly variable.

ASPHYXIA

In asphyxia produced by occlusion of the airway, acute hypercapnia and hypoxia develop together. Stimulation of respiration is pronounced, with violent respiratory efforts. Blood pressure and heart rate rise sharply, catecholamine secretion is increased, and blood pH drops. Eventually the respiratory efforts cease, the blood pressure falls, and the heart slows. Asphyxiated animals can still be revived at this point by artificial respiration, although they are prone to ventricular fibrillation, probably because of the combination of hypoxic myocardial damage and high circulating catecholamine levels. If artificial respiration is not started, cardiac arrest occurs in 4–5 min.

DROWNING

Drowning is asphyxia caused by immersion, usually in water. In about 10% of drownings, the first gasp of water after the losing struggle not to breathe triggers laryngospasm, and death results from asphyxia without any water in the lungs. In the remaining cases, the glottic muscles eventually relax and fluid enters the lungs. Fresh water is rapidly absorbed, diluting the plasma and causing intravascular hemolysis. Ocean water is markedly hypertonic and draws fluid from the vascular system into the lungs, decreasing plasma volume. The immediate goal in the treatment of drowning is, of course, resuscitation, but long-term treatment must also take into account the circulatory effects of the water in the lungs.

PERIODIC BREATHING

The acute effects of voluntary hyperventilation demonstrate the interaction of the chemical mechanisms regulating respiration. When a normal individual hyperventilates for 2–3 min, then stops and permits respiration to continue without exerting any voluntary control over it, a period of apnea occurs. This is followed by a few shallow breaths and then by another period of apnea, followed again by a few breaths (periodic breathing). The cycles may last for some time before normal breathing is resumed (Figure 36–12). The apnea apparently is due to a lack of CO₂ because it does not occur following hyperventilation with gas mixtures containing 5% CO₂. During the apnea, the alveolar Po₂ falls and the Pco₂ rises. Breathing resumes because of hypoxic stimulation of the carotid and aortic chemoreceptors before the CO₂ level has returned to normal. A few breaths eliminate the hypoxic stimulus, and breathing stops until the alveolar Po₂ falls again. Gradually, however, the Pco₂ returns to normal, and normal breathing resumes. Changes in breathing patterns can be symptomatic of disease (Clinical Box 36–3).

Exercise provides a physiologic example to explore many of the control systems discussed above. Of course, many cardiovascular and respiratory mechanisms must operate in an integrated fashion if the O₂ needs of the active tissue are to be met and the extra CO₂ and heat removed from the body during exercise. Circulatory changes increase muscle blood flow while maintaining adequate circulation in the rest of the body. In addition, there is an increase in the extraction of O₂ from the blood in exercising muscles and an increase in ventilation. This provides extra O₂, eliminates some of the heat, and excretes extra CO₂. A focus on regulation of ventilation and tissue O₂ is presented below, as many other aspects of regulation have been presented in previous chapters.

CHANGES IN VENTILATION

During exercise, the amount of O₂ entering the blood in the lungs is increased because the amount of O₂ added to each unit of blood and the pulmonary blood flow per minute are increased. The Po₂ of blood flowing into the pulmonary capillaries falls from 40 to 25 mm Hg or less, so that the alveolar-capillary Po₂ gradient is increased and more O₂ enters the blood. Blood flow per minute is increased from 5.5 L/min to as much as 20–35 L/min. The total amount of O₂ entering the blood therefore increases from 250 mL/min at rest to values as high as 4000 mL/min. The amount of CO₂ removed from each unit of blood is increased, and CO₂ excretion increases from 200 mL/min to as much as 8000 mL/min. The increase in O₂ uptake is proportional to work load, up to a maximum. Above this maximum, O₂ consumption levels off and the blood lactate level continues to rise (Figure 36–13). The lactate comes from muscles in which aerobic resynthesis of energy stores cannot keep pace with their utilization, and an oxygen debt is being incurred.

Ventilation increases abruptly with the onset of exercise, which is followed after a brief pause by a further, more gradual increase (Figure 36–14). With moderate exercise, the increase is due mostly to an increase in the depth of respiration; this is accompanied by an increase in the respiratory rate when the exercise is more strenuous. Ventilation abruptly decreases when exercise ceases, which is followed after a brief pause by a more gradual decline to preexercise values. The abrupt increase at the start of exercise is presumably due to psychic stimuli and afferent impulses from proprioceptors in muscles, tendons, and joints. The more gradual increase is presumably humoral, even though arterial pH, Pco₂, and Po₂ remain constant during moderate exercise. The increase in ventilation is proportional to the increase in O₂ consumption, but the mechanisms responsible for the stimulation of respiration are still the subject of much debate. The increase in body temperature may play a role. Exercise increases the plasma K⁺ level, and this increase may stimulate the peripheral chemoreceptors. In addition, it may be that the sensitivity of the neurons controlling the response to CO₂ is increased or that the respiratory fluctuations in arterial Pco₂ increase so that, even though the mean arterial Pco₂ does not rise, it is CO₂ that is responsible for the increase in ventilation. O₂ also seems to play some role, despite the lack of a decrease in arterial Po₂, since during the performance of a given amount of work, the increase in ventilation while breathing 100% O₂ is 10–20% less than the increase while breathing air. Thus, it currently appears that a number of different factors combine to produce the increase in ventilation seen during moderate exercise.

When exercise becomes more vigorous, buffering of the increased amounts of lactic acid that are produced liberates more CO₂, and this further increases ventilation. The response to graded exercise is shown in Figure 36–15. With increased production of acid, the increases in ventilation and CO₂ production remain proportional, so alveolar and arterial CO₂ change relatively little (isocapnic buffering). Because of the hyperventilation, alveolar Po₂ increases. With further accumulation of lactic acid, the increase in ventilation outstrips CO₂ production and alveolar Pco₂ falls, as does arterial Pco₂. The decline in arterial Pco₂ provides respiratory compensation for the metabolic acidosis produced by the additional lactic acid. The additional increase in ventilation produced by the acidosis depends on the carotid bodies and does not occur if they are removed.

The respiratory rate after exercise does not reach basal levels until the O₂ debt is repaid. This may take as long as 90 min. The stimulus to ventilation after exercise is not the arterial Pco₂, which is normal or low, or the arterial Po₂, which is normal or high, but the elevated arterial H⁺ concentration due to the lactic acidemia. The magnitude of the O₂ debt is the amount by which O₂ consumption exceeds basal consumption from the end of exertion until the O₂ consumption has returned to preexercise basal levels. During repayment of the O₂ debt, the O₂ concentration in muscle myoglobin rises slightly. ATP and phosphorylcreatine are resynthesized, and lactic acid is removed. Eighty percent of the lactic acid is converted to glycogen and 20% is metabolized to CO₂ and H₂O.

CHANGES IN THE TISSUES

Maximum O₂ uptake during exercise is limited by the maximum rate at which O₂ is transported to the mitochondria in the exercising muscle. However, this limitation is not normally due to deficient O₂ uptake in the lungs, and hemoglobin in arterial blood is saturated even during the most severe exercise.

During exercise, the contracting muscles use more O₂, and the tissue Po₂ and the Po₂ in venous blood from exercising muscle fall nearly to zero. More O₂ diffuses from the blood, the blood Po₂ of the blood in the muscles drops, and more O₂ is removed from hemoglobin. Because the capillary bed of contracting muscle is dilated and many previously closed capillaries are open, the mean distance from the blood to the tissue cells is greatly decreased; this facilitates the movement of O₂ from blood to cells. The oxygen-hemoglobin dissociation curve is steep in the Po₂ range below 60 mm Hg, and a relatively large amount of O₂ is supplied for each drop of 1 mm Hg in Po₂ (see Figure 35–2). Additional O₂ is supplied because, as a result of the accumulation of CO₂ and the rise in temperature in active tissues—and perhaps because of a rise in red blood cell 2,3-diphosphoglycerate (2,3-DPG)—the dissociation curve shifts to the right. The net effect is a 3-fold increase in O₂ extraction from each unit of blood (see Figure 35–3). Because this increase is accompanied by a 30-fold or greater increase in blood flow, it permits the metabolic rate of muscle to rise as much as 100-fold during exercise.

EXERCISE TOLERANCE & FATIGUE

What determines the maximum amount of exercise that can be performed by an individual? Obviously, exercise tolerance has a time as well as an intensity dimension. For example, a fit young man can produce a power output on a bicycle of about 700 W for 1 min, 300 W for 5 min, and 200 W for 40 min. It used to be argued that the limiting factors in exercise performance were the rate at which O₂ could be delivered to the tissues or the rate at which O₂ could enter the body in the lungs. These factors play a role, but it is clear that other factors also contribute and that exercise stops when the sensation of fatigue progresses to the sensation of exhaustion. Fatigue is produced in part by bombardment of the brain by neural impulses from muscles, and the decline in blood pH produced by lactic acidosis also makes one feel tired, as does the rise in body temperature, dyspnea, and, perhaps, the uncomfortable sensations produced by activation of the J receptors in the lungs.

• Breathing is under both voluntary control (located in the cerebral cortex) and automatic control (driven by pacemaker cells in the medulla). There is a reciprocal innervation to expiratory and inspiratory muscles in that motor neurons supplying expiratory muscles are inactive when motor neurons supplying inspiratory muscles are active, and vice versa.

• The pre-Bötzinger complex on either side of the medulla contains synaptically coupled pacemaker cells that allow for rhythmic generation of breathing. The spontaneous activity of these neurons can be altered by neurons in the pneumotaxic center, although the full regulatory function of these neurons on normal breathing is not understood.

• Breathing patterns are sensitive to chemicals in the blood through activation of respiratory chemoreceptors. There are chemoreceptors in the carotid and aortic bodies and in collections of cells in the medulla. These chemoreceptors respond to changes in Po₂ and Pco₂ as well as H⁺ to regulate breathing.

• Receptors in the airway are additionally innervated by slowly adapting and rapidly adapting myelinated vagal fibers. Slowly adapting receptors can be activated by lung inflation. Rapidly adapting receptors, or irritant receptors, can be activated by chemicals such as histamine and result in cough or even hyperpnea.

• Receptors in the airway are also innervated by unmyelinated vagal fibers (C fibers) that are typically found next to pulmonary vessels. They are stimulated by hyperinflation (or exogenous substances including capsaicin) and lead to the pulmonary chemoreflex. The physiologic role for this response is not fully understood.