With decreases in PaO2, afferent fibers from the carotid body increase their discharge hyperbolically. Reduction in PO2 rather than in O2 content in the arterial blood is mainly responsible for the increasing activity. The biochemical and physiologic mechanism that allows the carotid body to respond to even relatively mild hypoxia has not been completely elucidated, but some details are known. Although blood flow in the carotid body is unusually high, so is the metabolic rate. Vascular shunts through the carotid body as well as its high metabolic rate may produce areas of hypoxia within the carotid body, even when the arterial blood is fully saturated with O2. Measurements of carotid body PO2 have shown some extremely low tensions, but the range of tensions is wide. Cytochrome enzymes within the carotid body may have an especially low affinity for O2, thus accounting for the sensitivity of the carotid body to changes in PO2. Although the primary function of the peripheral arterial chemoreceptors is to transduce changes in arterial PO2, PCO2, and/or hydrogen ion levels into nerve signals, there is no general agreement as to how this is accomplished, nor is it known whether all stimuli act through a common mechanism.
Ultrastructural studies of the carotid and aortic bodies demonstrate the presence of two distinct types of cells. Afferent nerve terminals from the carotid sinus nerve appose type I glomus cells, which contain abundant, dense, clear-cored synaptic vesicles, mitochondria, and conspicuous rough endoplasmic reticulum. The cytology of type II (sustentacular) cells resembles that of Schwann cells. They envelop the afferent terminal-glomus cell complex.
Whereas it was originally proposed that the afferent terminals are chemosensitive and that the type I cells function as modulatory interneurons, subsequent studies have suggested that the integrity of the glomus cells (type I and perhaps type II cells) is essential for the process of chemoreception. After the glomus cells are destroyed, nerve endings alone seem unable to respond to physiologic stimuli.
Glomus cells (type I cells) contain a variety of agents, including acetylcholine, norepinephrine, dopamine, and 5-hydroxytryptamine. Recent immunocytochemical studies also have shown the presence of at least three polypeptides in the carotid body of cats and rats (i.e., substance P, vasoactive intestinal polypeptide [VIP], and enkephalins), suggesting that neuropeptides may play important roles in the transmission of nerve signals. Substance P, a member of the tachykinin group of polypeptides, has been proposed as a general transmitter/modulator for primary afferent fibers sensing nociceptive stimuli. In addition, substance P enhances the discharge of carotid body preparations in vivo and in vitro. These excitatory effects of substance P are dose-dependent, seem to be slow in onset, and last several seconds after intracarotid administration. Hypoxic excitation of the carotid body is markedly attenuated by substance P antagonists. The mechanism(s) for sensing O2 in the carotid body remains unclear. However, hypoxia depolarizes type I cells and increases cytosolic calcium, perhaps through effects on O2-sensitive, voltage-gated potassium channels and cytochrome protein(s) with a low affinity for O2. Depolarization of glomus cells in turn causes neurotransmitter release and activation of sinus nerve afferent terminals.
Efferent discharge to the carotid body from the CNS depresses afferent activity provoked by hypoxia. This efferent inhibition may prevent saturation of the carotid body response, allowing the carotid body to respond to a wider range of PO2 than it could otherwise. In part, efferent control depends on sympathetic nervous regulation of carotid body blood flow. However, other inhibitory efferent fibers that have no effect on the carotid body vasculature are also present.
With hypoxia, ventilation, like carotid body activity, increases hyperbolically (Fig. 6). Also, changes in PCO2 seem to enhance the ventilatory response to hypoxia, and vice versa (i.e., CO2 and hypoxia interact multiplicatively). Single carotid body fibers respond to both CO2 and hypoxia, so that some of the interaction of hypoxia and hypercapnia occurs at the cellular level in the sensor itself. However, other evidence suggests that convergence of input from central and peripheral chemoreceptors at the level of the CNS helps enhance the interaction of hypoxia and hypercapnia as ventilatory stimulants. Experimental studies on the effect of carotid nerve stimulation in different phases of breathing show that carotid body discharge is more effective in stimulating breathing during inspiration than during expiration. Carotid body discharge varies spontaneously during the breathing cycle as a result of variations in PaO2. The relationship between oscillations in carotid body activity and phase of breathing depends on the circulation time between the lungs and the carotid body. Thus, changes in cardiac output theoretically might affect both the level and pattern of breathing. When central chemoreceptor activity and the response to CO2 have been eliminated by destruction of the ventrolateral medullary surfaces, input from the carotid body alone is sufficient to maintain rhythmic breathing. Both central and peripheral chemoreceptors respond proportionally as the level of PCO2 is altered. Some studies suggest that increases in the rate of change of CO2 but not in the rate of change of PO2 also stimulate the carotid body.
FIG. 6. Effect of changing PaCO2 on (A) the ventilatory response to hypoxia and (B) the ventilatory response to hypercapnia.
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