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COMMENTARY
HIGHLIGHTED TOPICS
Oxygen Sensing in Health and Disease
In the first featured article, "Acetylcholine release from the carotid body by hypoxia: evidence for the involvement of autoinhibitory receptors" (2), Kim and colleagues examined the expression of acetylcholine in the glomus cell, the putative oxygen-sensing element of the carotid body. Along with examining glomus cells, these investigators also explored the effect of hypoxia on acetylcholine release and the cellular mechanisms associated with that response. Using an antibody specific to acetylcholine, Kim and colleagues analyzed glomus cells from the rabbit carotid body and showed, for the first time, that a majority of glomus cells express acetylcholine. By analyzing acetylcholine with a highly sensitive HPLC combined with an electrochemical detection system, these investigators showed that acute hypoxia inhibits the basal release of acetylcholine from the rabbit carotid body. However, in the presence of atropine, a general blocker of the muscarinic receptor, or domperidone, a dopamine D2 receptor antagonist, hypoxia facilitates acetylcholine release. It is possible that hypoxia initially (within a few minutes) facilitates the release of acetylcholine in the rabbit carotid body but that subsequent activation of the muscarinic autoinhibitory receptors leads to a decrease in acetylcholine release during prolonged hypoxia.
The findings of this study are of considerable significance because they offer a rational and viable explanation for the apparent initial discrepancy reported in the effects of hypoxia on acetylcholine release from the carotid body in both the rabbit and the cat. It seems that irrespective of species, hypoxia initially facilitates acetylcholine release from the carotid body, thus supporting its role as a neurotransmitter involved in the sensory response of the carotid body to hypoxia. However, as reported in the cat and now in the rabbit carotid body, the differences observed in acetylcholine release during prolonged hypoxia may arise from and be governed by differences in the expression of autoexcitatory and autoinhibitory receptors on glomus cells in these species.
In the second featured article of this Highlighted Topics series, "Autonomic microganglion cells: a source of acetylcholine in the rat carotid body" (1), Gauda and colleagues discuss the "cholinergic hypothesis," which points to acetylcholine as the major excitatory neurotransmitter participating in hypoxic chemosensitivity. The resurgence of this hypothesis has initiated an important unresolved debate as to whether acetylcholine originates from type I cells in the carotid body. Gauda and colleagues used semi-quantitative in situ hybridization histochemistry and immunohistochemistry to determine the effects of development and acute hypoxic exposure on the expression patterns of definitive cholinergic markers within the carotid body, the nodose/petrosal/jugular ganglion complex, and the superior cervical ganglion of the rat. In tissue sections, these investigators demonstrated that the pattern of distribution of both vesicular acetylcholine transport (VAChT) and choline acetyltransferase (ChAT) markers is similar but that the level of VAChT mRNA is uniformly greater than that of ChAT. In younger animals, these investigators observed multiple ganglion cells expressing both VAChT mRNA and VAChT immunoreactivity in the nodose/petrosal/jugular complex. However, although VAChT mRNA and immunoreactivity was not observed within the carotid body, microganglion cells embedded in nerve fibers innervating the carotid body expressed VAChT mRNA and were intensely positive for VAChT immunoreactivity. Of particular note, VAChT was not colocalized with tyrosine hydroxylase immunoreactivity in the carotid body or in the superior cervical ganglion. Although VAChT mRNA levels in the nodose/petrosal/jugular complex decreased coincident with maturation, neither maturation nor hypoxic exposure altered the pattern and level of acetylcholine traits in the carotid body or superior cervical ganglion. These data indicate that cholinergic and catecholaminergic traits are not colocalized within the carotid body. Furthermore, these findings implicate microganglion cells and cholinergic nerve terminals in the carotid body, not type I cells, as the source of acetylcholine mediating hypoxic chemosensitivity. Determining the hypoxic stimulus response of microganglion cells within peripheral arterial chemoreceptors may provide new insights as to how acetylcholine might mediate hypoxic chemosensitivity.
REFERENCES
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