Medical Physiology, 3rd Edition

Chemical Control of Ventilation

In fulfilling its mission to exchange O2 and CO2 between the atmosphere and the capillaries of the systemic circulation, the respiratory system attempts to regulate the blood-gas parameters, that is, the arterial levels of O2, CO2, and pH. These are overwhelmingly the most important influences on breathing. The body senses these parameters via two sets of chemoreceptors—the peripheral chemoreceptors and the central chemoreceptors. Hypoxia, hypercapnia, and acidosis all cause an increase in ventilation, which tends to raise image, to lower image, and to raise pH, thereby correcting deviations in the three blood-gas parameters. Although small variations in arterial image and image occur with activities such as sleep, exercise, talking, and panting, the control of arterial blood gases is so tight in normal individuals that it is rare for arterial image to change from the normal 40 mm Hg by more than a few mm Hg. Thus, the peripheral and central chemoreceptors form the vital sensory arm of a negative-feedback mechanism that stabilizes arterial imageimage, and pH.

Peripheral Chemoreceptors

Peripheral chemoreceptors (carotid and aortic bodies) respond to hypoxia, hypercapnia, and acidosis

A decrease in arterial image is the primary stimulus for the peripheral chemoreceptors. Increases in image and decreases in pH also stimulate these receptors and make them more responsive to hypoxia.

Sensitivity to Decreased Arterial image

Perfusion of the carotid body with blood having a low image—but a normal image and pH—causes a prompt and reversible increase in the firing rate of axons in the carotid sinus nerve. Figure 32-9A shows an illustrative experiment on an isolated chemoreceptor cell of the carotid body. Under normal acid-base conditions, increasing image above the normal value of ~100 mm Hg has only trivial effects on the firing rate of the nerve. However, at normal values of image and pH (see Fig. 32-9B, blue curve), decreasing image to values <100 mm Hg causes a progressive increase in the firing rate.

image

FIGURE 32-9 Chemosensitivity of the carotid body. A, Effect of anoxia on a single, isolated glomus cell. Anoxia elicits a depolarization and small action potentials, as measured with a patch pipette. B, Effect of respiratory acid-base disturbances on O2 sensitivity. C, Effect of pH changes on CO2 sensitivity. In B and C, the y-axis represents the frequency of action potentials in single sensory fibers from the carotid body. Vm, membrane potential. (A, Data from Buckler KJ, Vaughan-Jones RD: Effects of hypoxia on membrane potential and intracellular calcium in rat neonatal carotid body type I cells. J Physiol 476:423–428, 1994; B, data from Cunningham DJC, Robbins PA, Wolff CB: Integration of respiratory responses to changes in alveolar partial pressures of CO2 and O2 and in arterial pH. In Cherniack NS, Widdicombe J [eds]: Handbook of Physiology, Section 3: The Respiratory System, vol 2. Bethesda, MD, American Physiological Society, 1986, pp 475–528; C, data from Biscoe TJ, Purves MJ, Sampson SR: The frequency of nerve impulse in single carotid body chemoreceptor afferent fibers recorded in vivo with intact circulation. J Physiol 208:121–131, 1970.)

Sensitivity to Increased Arterial image

The carotid body can sense hypercapnia in the absence of hypoxia or acidosis. During in vitro experiments, it is possible to maintain a constant extracellular pH (pHo) while increasing image by keeping the ratio image constant (see p. 641). The maroon curve in Figure 32-9C shows the results of experiments in which graded increases in image—at a fixed blood pH of 7.45 and a fixed image of 80 mm Hg—produced graded increases in the firing rate of the carotid sinus nerve.

Sensitivity to Decreased Arterial pH

The carotid body also can sense acidosis in the absence of hypoxia or hypercapnia. The green curve in Figure 32-9C shows the results of experiments that are the same as those represented by the maroon curve, except that blood pH was fixed at 7.25 rather than at 7.45. Over the entire range of image values, the firing rate of the carotid sinus nerve is greater at a pH of 7.25 than at 7.45. Thus, metabolic acidosis (see p. 635) stimulates the carotid body.

In summary, besides being sensitive to hypoxia, the carotid body is sensitive to both components of respiratory acidosis (see p. 633)—high image and low pH. In fact, respiratory acidosis makes the carotid body more sensitive to hypoxia (see Fig. 32-9B, orange curve), whereas respiratory alkalosis has the opposite effect (see Fig. 32-9B, red curve).

The glomus cell is the chemosensor in the carotid and aortic bodies

The body has two sets of peripheral chemoreceptors: the carotid bodies, one located at the bifurcation of each of the common carotid arteries, and the aortic bodies, scattered along the underside of the arch of the aorta (Fig. 32-10A). The carotid bodies should not be confused with the carotid sinus (see pp. 534–535), which is the bulbous initial portion of the internal carotid artery that serves as a baroreceptor. Similarly, the aortic bodies should not be confused with baroreceptors of the aortic arch.

image

FIGURE 32-10 Anatomy of the peripheral chemoreceptors. (B, Data from Williams PL, Warwick R [eds]: Splanchnology. In Gray's Anatomy. Philadelphia, WB Saunders, 1980.)

The major function of the carotid and aortic bodies is to sense hypoxia in the arterial blood and signal cells in the medulla to increase ventilation. This signaling occurs via afferents of the glossopharyngeal nerve (CN IX) for the carotid bodies and of the vagus nerve (CN X) for the aortic bodies. The carotid bodies have been more extensively studied than the aortic bodies, which are smaller and less accessible. For the first description of their function as chemoreceptors, Corneille Heymans was awarded the 1938 Nobel Prize for Physiology or Medicine. imageN32-15

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Corneille Jean François Heymans

Contributed by Walter Boron

Corneille Jean François Heymans (1892–1968) was born in Ghent, Belgium. He obtained his doctorate in medicine at the University of Ghent in 1920. Afterward, he worked with E. Gley at the Collège de France in Paris, M. Arthus in Lausanne, H. Meyer in Vienna, E.H. Starling in University College London, and Carl Wiggers imageN22-1 at Western Reserve University in Cleveland. In 1922, Heymans returned to Ghent to become a lecturer in pharmacodynamics, and in 1930 succeeded his father as professor of pharmacology.

For his work on the carotid and aortic bodies and their role in the regulation of respiration, he received the 1938 Nobel Prize in Physiology or Medicine.

Reference

The Nobel Prize in Physiology or Medicine. Nobelprize.org website. Stockholm, Nobel Media AB, 2014.  http://nobelprize.org/nobel_prizes/medicine/laureates/1938/; 1938 [Accessed October 2015].

Aside from their chemosensitivity, three features characterize the carotid bodies. First, they are extremely small: each weighs only ~2 mg. Second, for their size, they receive an extraordinarily high blood flow—the greatest of any tissue in the body. Their blood flow, normalized for weight, is ~40-fold higher than that of the brain. Third, they have a very high metabolic rate, 2- to 3-fold greater than that of the brain. Thus, even though the metabolic rate is high, the blood flow is so much higher that the composition of blood (e.g., imageimage, and pH) in carotid body capillaries approaches that of systemic arteries.

The chemosensitive cells of the carotid body are the type I or glomus cells. They are ~10 µm in diameter, are roughly spherical, and occur in clusters (see Fig. 32-10B). Adjacent glomus cells may communicate with each other via gap junctions. Glomus cells are neuroectodermal in origin and share many characteristics with neurons of the peripheral nervous system as well as with adrenal chromaffin cells (see p. 1030). Indeed, glomus cells have four neuron-like characteristics:

1. Some are innervated by preganglionic sympathetic neurons.

2. They have a variety of voltage-gated ion channels.

3. Depolarization triggers action potentials.

4. They have numerous intracellular vesicles containing a variety of neurotransmitters—acetylcholine, dopamine, norepinephrine, substance P, and met-enkephalin—that are released upon depolarization. These neurotransmitters control firing of the sensory nerve endings.

Sensory endings of the carotid sinus nerve (a branch of CN IX) impinge on carotid body glomus cells. Neurotransmitter release from the glomus cells triggers action potentials in the carotid sinus nerve, which makes its first synapse on neurons of the NTS (part of the DRG) and thereby signals the medulla that the systemic arterial blood has a low image, a high image, or a low pH. imageN32-16

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The Glomus Cell

Contributed by George Richerson, Emile Boulpaep, Walter Boron

Curiously, the sensory endings of the carotid sinus nerve also contain vesicles, so the synapse formed with glomus cells may be bidirectional. The function of this synapse from the carotid sinus nerve onto the glomus cells is unknown.

Surrounding individual clusters of glomus cells are the type II or sustentacular cells (see Fig. 32-10B), which are supporting cells similar to glia. Also close to the glomus cells is a dense network of fenestrated capillaries. This vascular anatomy as well as the exceptionally high blood flow puts the glomus cells in an ideal position to monitor the arterial blood gases with fidelity.

Both the sympathetic and parasympathetic divisions of the autonomic nervous system innervate the carotid body. As already noted, preganglionic sympathetic neurons synapse on glomus cells and presumably can alter their function. Autonomic fibers also contact blood vessels; increased sympathetic tone decreases local blood flow. Because the metabolic rate of the carotid body is high, a large decrease in blood flow produces a local fall in image near the glomus cells, even when systemic arterial image remains constant. Increased sympathetic tone thus “fools” the carotid body into behaving as if a hypoxic state existed. Hence, by modulating blood flow to the carotid body, the autonomic nervous system can fine-tune the response of the peripheral chemoreceptors.

The aortic bodies also include scattered glomus cells that presumably have functions similar to those of glomus cells in the carotid bodies. However, aortic and carotid bodies exhibit distinct differences in their responses to stimuli and the effects they have on ventilation. For the purposes of this section, we focus our discussion here on the carotid bodies, about which more is known.

Hypoxia, hypercapnia, and acidosis inhibit K+ channels, raise glomus cell [Ca2+]i, and release neurotransmitters

The sensitivity of the glomus cell to hypoxia, hypercapnia, and acidosis is a special case of chemoreception that we discussed in connection with sensory transduction (see p. 354). It is interesting that one cell type—the glomus cell—is able to sense all three blood-gas parameters. The final common pathway for the response to all three stimuli (Fig. 32-11) is an inhibition of BK K+ channels (see p. 196), depolarization of the glomus cell, possible firing of action potentials, opening of voltage-gated Ca2+ channels, an increase in [Ca2+]i, secretion of neurotransmitters, and stimulation of the afferent nerve fiber. What differs among the three pathways is how the stimulus inhibits K+ channels.

image

FIGURE 32-11 Response of glomus cell to hypoxia, hypercapnia, and acidosis. Vm, membrane potential.

Hypoxia imageN32-17

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Peripheral Chemoreceptors

Contributed by George Richerson, Emile Boulpaep, Walter Boron

Recent progress on the physiology of glomus cells has largely been a result of the ability to study glomus cells in culture and in the isolated carotid body in vitro.

Regarding the model in Figure 32-11, some controversy—which may reflect species differences—exists about which K+ channel is the target of hypoxia. Some evidence favors the charybdotoxin-sensitive Ca2+-activated K+ channel. Other data point to a Ca2+-insensitive voltage-gated K+ channel and a voltage-insensitive “resting” K+ channel.

Although one report (Williams et al, 2004) suggested that hemoxygenase-2 (HO-2) is a universal O2 sensor, the results of a later study (Ortega-Sáenz et al, 2006) showed that mice deficient in HO-2 have a normal ability to sense a decrease in [O2].

References

Hoshi T, Lahiri S. Oxygen sensing: It's a gas!. Science. 2004;306:2050–2051.

Ortega-Sáenz P, Pascual A, Gómez-Díaz R, López-Barneo J. Acute oxygen sensing in heme oxygenase-2 null mice. Proc J Gen Physiol. 2006;128:405–411.

Williams SEJ, Wootton P, Mason HS, et al. Hemoxygenase-2 is an oxygen sensor for a calcium-sensitive potassium channel. Science. 2004;306:2093–2097.

Investigators have proposed three mechanisms by which low image might inhibit K+ channels. First, some evidence suggests that a heme-containing protein responds to a decrease in image by lowering the open probability of closely associated K+ channels. Second, in rabbit glomus cells, hypoxia raises [cAMP]i, which inhibits a cAMP-sensitive K+ current. Third, small decreases in image inhibit reduced nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) in mitochondria, thus increasing the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG; see p. 955), which directly inhibits certain K+channels. The relative roles of the three pathways may depend on the species. Regardless of how hypoxia inhibits which K+ channels, the resulting depolarization activates voltage-gated Ca2+ channels.

Hypercapnia

An increase in image causes CO2 to move into the glomus cell, thereby generating H+ (see p. 646) and leading to a virtually instantaneous fall of intracellular pH (pHi). As pHi decreases, the protons appear to inhibit high-conductance BK K+ channels (see Table 6-2, family No. 2) by displacing Ca2+ from their binding sites. The result is a depolarization, a rise in [Ca2+]i, and the release of neurotransmitter.

Extracellular Acidosis

A decrease in pHo inhibits acid-base transporters (e.g., Na/HCO3 cotransporters) that elevate pHi and stimulates acid-base transporters (e.g., Cl-HCO3 exchangers) that lower pHi, thereby leading to a slow fall in pHi (see pp. 645–646). Thus, even at a constant image, extracellular acidosis (i.e., metabolic acidosis) triggers the same cascade of events as was outlined above for hypercapnia, albeit more slowly.

Central Chemoreceptors

When the blood-gas parameters are nearly normal, the central chemoreceptors are the primary source of feedback for assessing the effectiveness of ventilation and also the major source of tonic drive for breathing. Just as the peripheral chemoreceptors are primarily sensitive to arterial hypoxia, the neurons that act as central chemoreceptors are primarily sensitive to arterial hypercapnia, which generally presents itself as respiratory acidosis (i.e., a decrease in pHo brought about by a rise in image; see p. 633). However, the actual parameter sensed appears to be a low pH in or around the chemoreceptor neurons.

The blood-brain barrier separates the central chemoreceptors in the medulla from arterial blood

In the 1950s, Isidore Leusen—working on dogs with denervated peripheral chemoreceptors—found that ventilation increased when he perfused the cerebral ventricles with an acidic solution having a high image. Because the resultant hyperventilation caused a respiratory alkalosis in the blood, it must have been the local acidosis in the brain that raised ventilation. From this and later experiments, we now believe that the primary stimulus driving respiration during respiratory acidosis is not actually an increase in arterial image but probably the ensuing pH decrease within brain tissue. Most evidence indicates that the central chemoreceptors are at a site within the brain parenchyma that responds to changes both in arterial image and cerebrospinal fluid (CSF) pH.

Starting from normal blood-gas parameters, an increase in the arterial image from 40 to ~45 mm Hg (an increase of only ~12.5%) doubles ventilation. By contrast, hypoxia doubles ventilation only if image falls by ~50%. If image increases suddenly, the increase in ventilation begins rapidly, augmenting first the depth and later the frequency of inspirations. However, the response may take as long as 10 minutes to develop fully (Fig. 32-12A). If, instead, the acid-base disturbance in arterial blood is a metabolic acidosis of comparable magnitude (i.e., a decrease in pHo and image at a fixed image; see p. 635), ventilation increases much more slowly and the steady-state increase is substantially less.

image

FIGURE 32-12 Effect of arterial hypercapnia on brain pH and ventilation. (A, Data from Padget P: The respiratory response to carbon dioxide. Am J Physiol 83:384–389, 1928; B, data from Fencl V: Acid-base balance in cerebral fluids. In Cherniack NS, Widdicombe J [eds]: Handbook of Physiology, Section 3: The Respiratory System, vol 2, part 1. Bethesda, MD, American Physiological Society, 1986, pp 115–140; C, data from Fencl V, Miller TB, Pappenheimer JR: Studies on the respiratory response to disturbances of acid-base balance, with deductions concerning the ionic composition of cerebral interstitial fluid. Am J Physiol 210:459–472, 1966.)

The reason for these observations is that the central chemoreceptors are located within the brain parenchyma (see Fig. 32-12B) and are bathed in brain extracellular fluid (BECF), which is separated from arterial blood by the blood-brain barrier (BBB). The BBB has a high permeability to small neutral molecules such as O2 and CO2 but a low permeability to ions such as Na+, Cl, H+, and image (see p. 286). An increase in arterial image rapidly leads to a image increase of similar magnitude in the BECF, in the CSF, and inside brain cells. The result is an acidosis in each of these compartments. In fact, because the protein concentration of CSF or BECF is lower than that of blood plasma (see Table 11-1), the image buffering power (see p. 629) of CSF and BECF is also substantially less. Thus, at least initially, raising image produces a larger signal (i.e., pH decrease) in the CSF and BECF than in the blood. imageN32-18

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CO2-Induced pH Changes in CSF and Brain Extracellular Fluid

Contributed by George Richerson, Emile Boulpaep, Walter Boron

As noted in the text, because the CSF and BECF have a lower protein content than either blood plasma or whole blood, the buffering power of the CSF and BECF is much lower than that of blood. Thus, increases in image—initially at least—cause larger pH decreases in the CSF and BECF than in blood. Over time, as summarized on page 713, the choroid plexus and perhaps the BBB itself increase the active transport of image into the CSF and BECF. This transport represents a metabolic compensation to respiratory acidosis (see p. 641). During this compensation, the pH values of the CSF and BECF gradually rise, and thus the size of the net CO2-induced acidification gradually becomes smaller.

Although raising arterial image causes the pH of the BECF and CSF to fall rapidly, the choroid plexus (see pp. 279–282) and perhaps the BBB partially restore the pH of these compartments by actively transporting image from the blood into the CSF. Thus, after many hours or days of respiratory acidosis in the arterial blood, the low-pH signal in the BECF and CSF gradually wanes. Even so, respiratory acid-base disturbances lead to substantial changes in the steady-state pH of the BECF and CSF (see Fig. 32-12C, purple curve).

In contrast to its high CO2 permeability, the BBB's permeability to ions such as H+ and image is low. For this reason, and because the BBB actively regulates the pH of the BECF and CSF, metabolic acid-base disturbances alter steady-state brain pH only 10% to 35% as much as identical blood pH changes during respiratory acid-base disturbances (see Fig. 32-12C, red curve). Therefore, ventilation is much less sensitive to changes in arterial pH and [image] at constant arterial image. Ventilation correlates uniquely with the pH of the BECF (see Fig. 32-12D), regardless of whether respiratory or metabolic acid-base disturbances produce the pH changes.

Central chemoreceptors are located in the ventrolateral medulla and other brainstem regions

Early work on central chemoreceptors by Hans Loeschcke, Marianne Schläfke, and Robert Mitchell identified candidate regions near the surface of the ventrolateral medulla (VLM; Fig. 32-13A). The application of acidic solutions to the rostral or caudal VLM leads to a prompt increase in ventilation. Moreover, focal cooling of these areas to 20°C to reversibly inhibit neurons—or placement of lesions to permanently destroy the neurons—blunts the ventilatory response to respiratory acidosis. This and other work led to the conclusion that the central chemoreceptors are located near the surface of the VLM.

image

FIGURE 32-13 Chemosensitive neurons in the VLM and raphé. A, Ventral view of a cat medulla showing chemosensitive areas named after the three physiologists who first described them. The slice to the right shows the location of serotonergic neurons in the VLM and medullary raphé nuclei. B, Patch pipette recordings of neurons cultured from the medullary raphé of rats. Those that are stimulated by acidosis are serotonergic. Vm, membrane potential. C, Connections of acidosis-inhibited and acidosis-stimulated neurons of the medullary raphé. D, Transverse section of the rostral medulla, near the ventral surface, with blood vessels colored red and serotonergic neurons colored green. Yellow shows the overlap of red and green. B, basilar artery; P, pyramidal tracts. (A, Data from Dermietzel R: Central chemosensitivity, morphological studies. In Loeschke HL [ed]: Acid-base Homeostasis of the Brain Extracellular Fluid and the Respiratory Control System. Stuttgart, Germany, Thieme Edition/Publishing Sciences Group, 1976, pp 52–66; B, data from Wang W, Pizzonia JH, Richerson GB: Chemosensitivity of rat medullary raphe neurones in primary tissue culture. J Physiol 511:433–450, 1998; D, data from Risso-Bradley A, Pieribone VA, Wang W, et al: Nat Neurosci 5:401–402, 2002.)

More recent work with brain slices and cultured cells show that acidosis stimulates neurons in many brainstem nuclei, including the medullary raphé (see Fig. 32-13A, inset) and the NTS—both in the medulla—as well as the locus coeruleus and hypothalamus. Experiments in the laboratory of Eugene Nattie show that focal acidosis within many of these areas stimulates breathing in intact animals. imageN32-19 It is not clear how important each of these chemosensitive areas is in the control of ventilation under normal conditions. One possibility is that multiple sensors are another example of redundancy in a critical system. Alternatively, some may come into play only under special circumstances, such as during severe acid-base disturbances or during sleep, when airway obstruction leads to arousal.

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Central Chemoreceptor

Contributed by George Richerson, Emile Boulpaep, Walter Boron

If the BBB is so permeable to CO2—and if the pH change in the BECF is so large and so fast—why does it take 5 to 10 minutes to produce a maximal ventilatory response to hypercapnia? The delay may be due to (1) a slower change in pH at the actual (i.e., unknown) location of chemosensation, (2) a delay in the chemotransduction events, or (3) a delay in the response of the CPG or respiratory motor neurons to input from the central chemoreceptor neurons.

More recent studies on brain slices and cultured cells show that acidosis stimulates neurons in many brainstem nuclei. These include the VLM discussed in the text, the medullary raphé (see Fig. 32-13B), the nucleus ambiguus, and the NTS—all in the medulla—as well as the locus coeruleus and the hypothalamus. Experiments in the laboratory of Eugene Nattie have provided evidence that at least some of these acidosis-stimulated neurons are in fact respiratory chemoreceptors. In intact animals, microinjecting acetazolamide into these regions increases ventilation. Acetazolamide blocks carbonic anhydrase, the enzyme that catalyzes the hydration of CO2 to H+ and image. imageN18-3 Presumably, this blockade produces a localized region of acidosis that activates nearby chemosensitive neurons. Indeed, the effects of acetazolamide microinjections suggest that chemosensitive areas include the VLM, medullary raphé, the nucleus ambiguus, the NTS, and the locus coeruleus.

It remains unclear how important the aforementioned regions are to normal respiratory chemoreception. If they all are central chemoreceptors, then these multiple sensors may be another example of redundancy in a critical system. Alternatively, instead of all being involved in the response to CO2 under normal conditions in adults, some of these neurons may come into play only under special circumstances, such as during severe acid-base disturbances, when one is asleep, or during a particular time in the development of an infant.

Some neurons of the medullary raphé and VLM are unusually pH sensitive

Certain medullary raphé neurons are unusually pH sensitive. In brain slices and in tissue culture, small decreases in extracellular pH raise the firing rate of one subset of medullary raphé neurons (see Fig. 32-13B) and lower the firing rate of another. imageN32-20 In both types of chemosensitive neurons, metabolic and respiratory disturbances have similar effects on firing, which indicates that the primary stimulus is a decrease in either extracellular or intracellular pH, rather than an increase in image.

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Medullary Raphé Neurons

Contributed by George Richerson

image

EFIGURE 32-3 A, An increase in image (respiratory acidosis) raises the firing rate of a serotonergic neuron. B, The same increase in image lowers the firing rate of a GABAergic neuron. The figure shows the results of patch-pipette recordings from neurons cultured from the medullary raphé of rats. Those that are stimulated by acidosis are serotonergic, and those that are inhibited are GABAergic. Vm, membrane potential. (Data from Wang W, Pizzonia JH, Richerson GB: Chemosensitivity of rat medullary raphe neurones in primary tissue culture. J Physiol 511:433–450, 1998.)

The two types of chemosensitive neurons have other distinguishing properties, including different shapes, basal firing patterns, and neurotransmitter content. For example, the neurons stimulated by acidosis contain the neurotransmitter serotonin, which induces pacemaker activity in preBötC neurons (see p. 707). These serotonergic neurons are also known to stimulate breathing in vivo. Serotonergic neurons are also present in the VLM. Those that are inhibited by acidosis may contain the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). When arterial image rises, acidosis-stimulated neurons may stimulate breathing as an accelerator does on a car, whereas acidosis-inhibited neurons may decrease the inhibition of breathing, as when one is letting off on the brake (see Fig. 32-13C).

The serotonergic neurons in the medullary raphé are located in close apposition to large branches of the basilar artery (see Fig. 32-13D), so that—like the glomus cells of the peripheral chemoreceptors—they can sense arterial image with fidelity. Thus, serotonergic neurons of the raphé and VLM have many properties that would be expected of central respiratory chemoreceptors. Many infants who have died of sudden infant death syndrome (SIDS) have a deficit of serotonergic neurons, which is consistent with a prevailing theory that a subset of SIDS infants have a defect in central respiratory chemoreception. imageN32-21

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Sudden Infant Death Syndrome

Contributed by George Richerson

SIDS is defined as the sudden death of an infant younger than 1 year of age that remains unexplained after a complete clinical review, autopsy, and death-scene investigation. SIDS is the leading cause of postneonatal infant death in developed countries, causing six deaths each day in the United States alone. SIDS usually occurs during sleep in infants that were previously thought to be healthy. The consensus is that the majority of SIDS cases are due to abnormalities of breathing and arousal in response to high CO2 or low O2. When a vulnerable infant is exposed to an exogenous stressor—such as covering of the mouth by a blanket—it is unable to respond appropriately. Consistent with this explanation, the incidence of SIDS has decreased by 50% since the recommendation was made for mothers to put babies to sleep on their backs (the “Back to Sleep” campaign). Although the pathophysiology of SIDS remains unknown, recent work has revealed a number of abnormalities of serotonin neurons in the medulla (Paterson et al, 2006) that may cause an infant to be vulnerable. These abnormalities seem to involve a delay in maturation of these neurons due to environmental or genetic factors. Because serotonin neurons are central respiratory chemoreceptors (Richerson, 2004) and are also involved in cardiovascular and thermoregulatory control, as well as regulation of sleep and arousal, a delay in their normal maturation could explain SIDS. Ongoing work is now aimed at identifying those infants with serotonin-neuron defects before they die and finding a treatment to prevent SIDS in those infants.

References

Paterson DS, Trachtenberg FL, Thompson EG, et al. Multiple serotonergic brainstem abnormalities in sudden infant death syndrome. JAMA. 2006;296:2124–2132.

Richerson GB. Serotonin neurons as CO2 sensors that maintain pH homeostasis. Nat Rev Neurosci. 2004;5:449–461.

A second proposed set of central chemoreceptor neurons is located in a part of the rostral VLM called the retrotrapezoid nucleus (RTN).imageN32-22 These neurons express the transcription factor Phox2b (see p. 340), mutations in which occur in the majority of cases of Ondine's curse (see Box 32-5).

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Neurons in the Retrotrapezoid Nucleus

Contributed by George Richerson

As discussed in the main text, central respiratory chemoreceptor neurons are present in several locations in the brain. One of these areas appears to be the RTN, located in the rostral VLM.

Properties of these neurons include the following:

• The RTN contains serotonergic neurons as well as glutamatergic neurons. Both are candidates for central chemoreceptors.

• These neurons might be intrinsically pH sensitive, or may be stimulated by serotonergic neurons or by astrocytes that release ATP in response to respiratory acidosis.

• The glutamatergic neurons in this region project to the preBötC and other respiratory nuclei.

• These neurons stimulate the respiratory network.

• These neurons respond to respiratory acidosis with an increase in firing rate in brain slices and in vivo.

• These neurons express the transcription factor Phox2b (see Box 14-1). Mutations in Phox2b occur in the majority of cases of Ondine's curse (see Box 32-5).

Integrated Responses to Hypoxia, Hypercapnia, and Acidosis

In real life, it is rare for arterial image to fall without accompanying changes in image and pH. In addition, changes in individual blood-gas parameters may independently affect both the peripheral and the central chemoreceptors. How does the respiratory system as a whole respond to changes in multiple blood-gas parameters?

Hypoxia accentuates the acute response to respiratory acidosis

Respiratory Acidosis

When the blood-gas parameters are nearly normal, respiratory acidosis (increased image/decreased pH) stimulates ventilation more than does hypoxia. If an animal breathes an air mixture containing CO2, the resultant respiratory acidosis causes ventilation to increase rapidly. Because both peripheral and central chemoreceptors respond to respiratory acidosis, both could contribute to the response. It is possible to isolate the function of the two sets of chemoreceptors by (1) denervating the peripheral chemoreceptors to study the response of the central chemoreceptors alone, or (2) perfusing the carotid bodies to study the response of the peripheral chemoreceptors alone. On the basis of approaches such as these, it appears that the central chemoreceptors account for 65% to 80% of the integrated response to respiratory acidosis under normoxic conditions. However, the response of the peripheral chemoreceptors is considerably more rapid than that of the central chemoreceptors, which require several minutes to develop a maximal response.

At an alveolar image that is somewhat higher than normal, raising the alveolar image causes a linear increase in steady-state ventilation (Fig. 32-14A, red curve). Lowering the alveolar image has two effects (see Fig. 32-14A, other two curves). First, at a given image, hypoxia increases ventilation, which reflects the response of the peripheral chemoreceptors to hypoxia. Second, hypoxia increases the sensitivity of the integrated response to respiratory acidosis. That is, the slopes of the curves increase. At least part of the explanation for this increase in slopes is that the peripheral chemoreceptor itself—as judged by the activity of the carotid sinus nerve—becomes more sensitive to respiratory acidosis with coexisting hypoxia.

image

FIGURE 32-14 Integrated ventilatory response to changes in image (A) and image (B). The shaded triangles indicate the slopes. (A, Data from Nielsen M, Smith H: Studies on the regulation of respiration in acute hypoxia. Acta Physiol Scand 24:293–313, 1952; B, data from Loeschcke HH, Gertz KH: Einfluss des O2-Druckes in der Einatmungsluft auf die Atemtätigkeit der Menschen, geprüft unter Konstanthaltung des alveolaren CO2-Druckes. Pflugers Arch Ges Physiol 267:460–477, 1958.)

Metabolic Acidosis

Severe metabolic acidosis (e.g., diabetic ketoacidosis) leads to profound hyperventilation, known as Kussmaul breathing (see Box 32-2). This hyperventilation can drive arterial image down to low levels in an attempt to compensate for the metabolic acidosis. Acutely, the main stimulus for hyperventilation comes from peripheral chemoreceptors. Because a severe decrease in arterial pH does produce a small fall in CSF pH, central chemoreceptors also participate in this response. If the insult persists for many hours, CSF pH falls even farther, and central chemoreceptor drive becomes more prominent (Box 32-3).

Box 32-3

Chronic Hypercapnia in Pulmonary Disease

Chronic hypercapnia occurs in many people with diseases that affect the lungs (e.g., emphysema—destruction of alveoli and loss of proper gas exchange) or respiratory muscles (e.g., amyotrophic lateral sclerosis, neuropathies, and myopathies). An increase in image leads to an immediate respiratory acidosis in the arterial blood and brain. If CO2 remains elevated, the pH of the CSF/BECF slowly recovers (i.e., increases) over the following 8 to 24 hours. The mechanism of this pHCSF increase is probably an increase in image flux into the CSF/BECF across the choroid plexus (see Fig. 11-4) and BBB, representing a metabolic compensation to the respiratory acidosis (see p. 633). The increased CSF pH shifts the CO2 response curves in Figure 32-14A to the right because, compared with reference conditions, a higher image is needed to produce a given degree of CSF acidity (i.e., ventilatory drive). Such a resetting of the central chemoreceptors may be important clinically for patients who chronically retain CO2. Even though image may be quite high, adaptation of the CSF/BECF restores pHCSF toward normal. With central chemoreceptor drive for ventilation now decreased, the main drive for ventilation may become hypoxia via peripheral chemoreceptors. Administration of supplemental O2 to such a patient may remove the hypoxic drive as well, causing ventilation to decrease and image to rise to very high levels (e.g., image > 100 mm Hg). At such high levels, CO2 acts like a narcotic. This “CO2 narcosis” then directly inhibits ventilation and can cause death from hypoventilation—a classic example of “too much of a good thing.”

Respiratory acidosis accentuates the acute response to hypoxia

If an animal breathes an O2-deficient gas mixture, the resulting hypoxia causes ventilation to increase rapidly. As already discussed, the peripheral chemoreceptors respond primarily to hypoxia. To what extent do central mechanisms contribute to the integrated response to acute hypoxia? In an animal with denervated peripheral chemoreceptors, hypoxia actually depresses respiratory output. Thus, the integrated response actually underestimates the stimulatory contribution of the peripheral chemoreceptors.

At an arterial image that is slightly lower than normal, lowering alveolar image has very little effect on ventilation until image falls below 50 mm Hg (see Fig. 32-14B, red curve). The eventual response at very low image values indicates that the peripheral chemoreceptors play a vital, fail-safe role in responding to extreme hypoxia, as at high altitudes (see p. 1231). Raising the arterial image (i.e., respiratory acidosis) has two effects (see Fig. 32-14B, other two curves). First, at a given image, respiratory acidosis increases ventilation, which reflects the dual contributions of the peripheral and central chemoreceptors to hypercapnia and acidosis. Second, respiratory acidosis increases the sensitivity of the integrated response to hypoxia. That is, the curves become steeper. These effects on the integrated response (see Fig. 32-14B) are similar to—although more exaggerated than—the effects of respiratory acidosis on the response of the peripheral chemoreceptor to hypoxia (see Fig. 32-9B).