The regulation of acid–base balance depends on renal mechanisms that determine net excretion of acid or base and breathing mechanisms that alter the partial pressure of carbon dioxide (PCO 2 ) in body tissues. The level of ventilation (breathing) is regulated, in part, by pH-sensitive receptors called chemoreceptors, which are present peripherally at the carotid body and centrally within the hindbrain. Their physiology is the subject of this chapter. Arterial, and tissue, PCO 2 is very sensitive to changes in ventilation, which, in turn, is very sensitive to changes in pH. Metabolic acidosis stimulates ventilation lowering PCO 2 , which minimizes the acidosis, a classic feed-back control system. Chemoreception is surprisingly complex with an emerging understanding of the interdependence of peripheral and central sites and of the functions of multiple central sites.
Key Words
carbon dioxide, brainstem, bicarbonate, cerebrospinal fluid, acid–base balance, control of breathing, chemoreception
Introduction
Our thinking on mammalian acid–base regulation focuses on pH. Intracellular pH, which is of great importance in the maintenance of normal protein function, is regulated by membrane ion transporters, intracellular buffers, and by changes in cell metabolism. The success of intracellular pH regulation is dependent on the extracellular pH being constrained in its variation. Renal processes can alter extracellular proton and bicarbonate balance by changes in ion excretion. In this chapter we focus on how breathing can affect the partial pressure of carbon dioxide in extracellular fluid, here the partial pressure of carbon dioxide in arterial blood, PaCO 2 . The traditional approach utilizes the straightforward relationships shown in Eqs 1 and 2 .
CO 2 + H 2 O = H 2 CO 3 − = H + + HCO 3 −
pH = pK − + log ( [ HCO 3 − ] / [ S × PCO 2 ] )
Note that pH can be affected by primary changes in either bicarbonate or PCO 2 . Arterial bicarbonate changes by a small amount as CO 2 is changed due to the presence of blood buffers. But by far the most important changes in arterial bicarbonate occur either as the result of a primary metabolic disturbance, which changes the ionic composition of blood thereby affecting bicarbonate, or as the result of the kidney, which can also change the ionic composition of blood thereby affecting bicarbonate.
CO 2
Ventilation and CO 2
Arterial blood pH is the clinically relevant extracellular variable because changes in breathing alter the PaCO 2 directly. The PaCO 2 is determined by the ratio of CO 2 production and alveolar ventilation. For a constant metabolic rate (and CO 2 production), an increase in alveolar ventilation will lower the PaCO 2 and, conversely, a decrease in alveolar ventilation will elevate the PaCO 2 . Both events have acid–base consequences. Hyperventilation eliminates CO 2 faster than it is being produced and, as a result, pH increases; hypoventilation eliminates CO 2 more slowly than it is being produced and, as a result, pH decreases. The changes are quantitatively speaking not small. If alveolar ventilation doubles, the normal PaCO 2 of 40 mm Hg will quickly attain a new value of 20 mm Hg. Arterial pH will quickly change from the normal value of 7.40 to 7.70. Conversely, if alveolar ventilation is reduced by half, arterial PCO 2 will quickly attain a new value of 80 mm Hg. Arterial pH will change from the normal value of 7.4 to 7.10. Changes in alveolar ventilation quickly and dramatically affect PaCO 2 and pH. A 10% increase in alveolar ventilation will decrease PaCO 2 by 4 mm Hg and increase arterial pH from 7.40 to 7.45 all within seconds. This change in arterial pH is determined by the decrease in PCO 2 and by the effectiveness of blood buffers, which include most importantly the red blood cell hemoglobin concentration. In the absence of any protein buffers, the pH change would be much greater. If the hyperventilation and hypocapnia are sustained, there are secondary renal adjustments that act to excrete more bicarbonate and to lessen the initial alkalosis. These events take minutes to hours and are governed by the lowered PCO 2 . Changes in PCO 2 , whether decrease or increase, are quickly reflected in all blood and tissue compartments due to the diffusability of CO 2 .
Tissue CO 2
Tissue PCO 2 levels are determined by the arterial value, the tissue rate of CO 2 production, and the amount of tissue blood flow. Changes in blood flow and cell metabolism can affect cell PCO 2 and pH for any given arterial PCO 2 . For example, the brain has blood vessels that determine blood flow resistance and are very sensitive to changes in CO 2 . An increase in PaCO 2 would tend to directly cause an increase in tissue and cell PCO 2 and a decrease in their pH. The strong vasodilatory action of high CO 2 on cerebral vessels would decrease resistance and allow blood flow to increase, which would clear more CO 2 and indirectly minimize the increase in tissue and cell PCO 2 . Tissue and cell PCO 2 and pH are determined by blood flow for any PaCO 2 value and by metabolic rate.
CO 2 and Ventilation
A change in pH is detected by a physiological process called chemoreception. The pH sensors are present in the peripheral blood at the bifurcation of the carotid artery, the carotid body, and within the brainstem at multiple locations. Both the carotid body and the brainstem respond to a fall in pH, for example, by increased stimulation of breathing, which lowers PaCO 2 and tends to minimize the initial acidosis. This feedback control of the alveolar ventilation level, and hence the PaCO 2 , by chemoreceptor-detected changes in pH is the essence of this chapter. The body can detect small pH changes at many sites and quickly bring about a change in breathing that acts to correct the initial perturbation. It is an appropriate response to correct pH. This system detects arterial pH at the carotid body and at the central chemoreceptors; it likely detects a pH value somewhere between the arterial and brain interstitial fluid pH.
Peripheral Chemoreceptors
Location of Carotid Body
The carotid body is well located to detect changes in arterial pH and PCO 2 . In fact, this location at the bifurcation of the carotid body rapidly detects small changes in PaCO 2 that reflect minor variations in the normal level of alveolar ventilation, and thus serves admirably as a feedback control detector site for the maintenance of a normal level of alveolar ventilation. This site is also a useful one for the detection of pH changes that reflect abnormal physiology, but for this purpose it is difficult to construct an argument that makes this anatomical location of special utility. In fact, a chemoreceptor site closer to the tissue location of altered metabolism in a metabolic acid–base disorder might theoretically be of greater use. For example, mixed venous CO 2 receptors have long been sought for in order to explain the tight link between increased metabolism in muscular exercise and alveolar ventilation. Here venous CO 2 levels rise; but arterial PCO 2 remains normal or decreases slightly as alveolar ventilation changes to match the increase in metabolic rate. Sporadically, the discovery of mixed venous chemoreceptors has been reported, but none of these have stood the test of time. Specific central chemoreceptor locations in the brain might well reflect tissue and cell PCO 2 and pH, that is, tissue chemoreceptors may be present.
Carotid Body Function
The carotid body is a fascinating tissue. It is quite small, and is difficult to find by gross anatomical dissection, but has a large metabolic rate and a high perfusion. This tissue is arguably the only and certainly the major detector of low O 2 levels. Hypoxia strongly excites the carotid body with powerful stimulatory effects on breathing and arousal. It is the detector for the hypoxia emergency warning system, and also detects changes in PCO 2 , including values that may drop below normal. In non-rapid eye movement sleep, apneas that occur within seconds of a transient hyperventilation have been attributed to hypocapnia sensed at the carotid body. Thus, in sleep there is a tonic nervous activity from the carotid body to the brain that maintains a normal level of ventilation. Transient diminution of this activity by brief hypocapnia can lead to apnea, the cessation of breathing. There is evidence as well for tonic carotid afferent activity that is important in the maintenance of appropriate levels of ventilation in wakefulness. Surgical removal of the carotid bodies in experimental animals and in humans results in a stable new steady state of hypoventilation. The animal then maintains a “normal” PaCO 2 that is a few mmHg higher than in animals with intact peripheral chemoreceptors. This state is maintained despite the presence of central chemoreceptors. It seems that normal ventilation requires the tonic afferent input from peripheral chemoreceptors. In 1938, Heymans received the Nobel Prize for the discovery of the carotid body. He proposed that the carotid body was the major detector of CO 2 , as well as for hypoxia.
Central Chemoreceptors
There is clear evidence for receptors within the brain that detect changes in PCO 2 or pH and bring about a change in ventilation. The ventilatory response to changes in pH as mediated by central chemoreceptors is very sensitive. Figure 56.1 shows data obtained from unanesthetized goats in a series of classic experiments. Alveolar ventilation, VA, is plotted against the pH in cerebrospinal fluid. The shaded area presents data obtained during chronic metabolic acidosis and alkalosis maintained for days in the goats as they breathed air or inhaled CO 2 from 0 to 10%. Note that in these steady-state conditions of chronic metabolic acid–base disorders, the response of alveolar ventilation to changes in cerebral pH is very sensitive—it doubles for a cerebrospinal fluid (CSF) pH change from 7.33 to 7.28. The X symbols in Fig. 56.1 will be discussed below.
History: Ventrolateral Medulla
The presence of central chemoreceptors was first suggested by the continued presence of a ventilatory response to an increase in PaCO 2 after surgical removal of the peripheral chemoreceptors and solidified by the presence of a ventilatory response to an acid load applied directly into the cerebral ventricles. Direct application of small pieces of cotton, soaked in an acidic solution, to various brainstem surfaces further localized the site of central chemoreception to the surface of the ventral lateral medulla, a site that still captures the imagination of investigators. All of these studies were performed under surgical anesthesia, which has a powerful depressant effect on the sensitivity of the ventilatory response to CO 2 , and required very acidic stimuli. Further, the blood supply to the medulla arises from vessels on the ventral surface, which could have easily carried the stimulus to deeper structures. Cooling or coagulation of this area decreased ventilatory output dramatically in anesthetized animals.
The effects of anesthesia on chemosensitivity cannot be overemphasized. For example, Akilesh et al. found that in rats, the change in ventilation breathing 7% CO 2 compared to breathing air is decreased by about 70% with the introduction of anesthesia. There are many similar examples of how much anesthesia affects the chemoreceptor response sensitivity. Nevertheless, these early studies demonstrated that chemoreception is present in the medulla, and it is accessible from the ventral medullary surface.
Widespread Central Chemoreception
More recently, a series of studies have led to the proposal that central chemoreception is a phenomenon that is widely present in the hindbrain. Before proceeding, a few clarifying definitions are warranted. A functional definition for chemoreception refers to a ventilatory response to a change in CO 2 /pH. Chemosensitivity or chemodetection refers to the response of a described unit, say a particular type of neuron, to changes in CO 2 /pH. Chemosensitivity and chemodetection do not necessarily translate to chemoreception, that is, the presence of a type of neuron with a known sensitivity in vitro to changes in CO 2 /pH does not necessarily mean that the neuron is important in a chemoreceptor response, one that involves a change in ventilation in vivo .
A number of experimental approaches support the concept that central chemoreception is a widely distributed function within the hindbrain. Experiments using expression of the early gene, c-fos, following exposure to elevated CO 2 , described the presence of activated neurons at locations near the ventral lateral medullary surface, as proposed in early studies, but also deeper in the brainstem at other locations including the locus ceruleus, nucleus tractus solitarius, medullary raphe, rostral aspect of the ventral respiratory group, and fastigial nucleus of the cerebellum. Studies of neurons in slice preparations of the medulla that included the deeper nucleus tractus solitarious, locus ceruleus, and medullary raphe have all described neurons that were excited by CO 2 . These experimental approaches did not demonstrate chemoreception, however. The neurons expressing c-fos could have been “downstream” to the actual chemodetector cells, and the neurons in the slice preparations were not connected to a ventilatory output.
A series of experiments have utilized the approach of examining the ventilatory response to a small region of focal acidosis produced at various sites within the brainstem. While studying the role of carbonic anhydrase in cerebral pH regulation, Coates et al. noted that focal application of acetazolamide, an inhibitor of carbonic anhydrase, resulted in focal acidosis. They then used tiny 1-nl injections of acetazolamide to produce very focal acidosis in the brainstem of anesthetized cats and rats. The presence of a ventilatory response following such injections indicated the presence of chemoreception at that site. Central chemoreception was present at many locations, including the retrotrapezoid nucleus (RTN) just below the ventral medullary surface (a possible site for the older surface chemoreceptors), nucleus tractus solitarious, locus ceruleus, midline medullary raphe, rostral aspect of the ventral respiratory group, and fastigial nucleus in the core of the cerebellum (the same sites as described by the c-fos studies). Focal acidosis produced by the 1-nl injections of acetazolamide resulted in an increase in fictive ventilatory output in these anesthetized animals, which provided functional evidence for multiple central chemoreceptor locations. Brain pH measurements showed the tissue pH change to be similar to that observed with a 20-mm Hg increase in arterial PCO 2 in anesthetized animals. A second approach to induce a focal acidosis in various regions of the brainstem utilizes reverse microdialysis with a CO 2 laden artificial cerebrospinal fluid (aCSF) , which reduced brain tissue pH by an amount like that observed with an increase in arterial PCO 2 of 5-6 mm Hg, a small stimulus intensity . This approach demonstrated ventilatory responses in the sites shown in Fig. 56.2 .
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