CAROTID BODY CHEMOTRANSDUCTION& CARDIOPULMONARY CONTROL

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The carotid body plays an important role in many of the cardiovascular, respiratory, and endocrine responses to hypoxia, hypercapnia and acidosis. However, the mechanisms responsible for the conversion of arterial hypoxia, hypercapnia, or acidosis into increased neural activity in the carotid body are only poorly understood. The morphology of the carotid body, the presence of several neurotransmitters in the Type I cells of the carotid body, and recent electrophysiological findings in the Type I cells suggest that chemotransduction can be reasonably modelled after ganglionic transmission. The neurotransmitter-containing Type I cell is analogous to the presynaptic neuron while the neuron apposed to Type I cell is analogous to the postsynaptic neuron. The broad, long-term objective of this proposal is to explore the various components and relationships of this model. The overall hypothesis calls for hypoxia, hypercapnia, or acidosis to depolarize the Type I cells, allowing an activation of voltage-gated calcium channels (VGCC) with subsequent release of neurotransmitters from these cells. The specific aims of this proposal focus on the role of the Type I cells in the genesis of increased neural activity during hypoxia, hypercapnia, and acidosis. The specific aims are three: (1) To determine the electrical activity of Type I cells and how it is influenced by hypoxia, hypercapnia, and acidosis; (2) To determine the presence and characteristics of the subtypes of VGCC (T, L, N) in the Type I cell and their role in chemotransduction during the above natural stimuli; (3) To determine the role of the CO2/HCO3 system in the genesis of neural activity during the chemotransduction of natural stimuli. These aims will be pursued: (1) in whole animals experiments in which the carotid body in situ is selectively and intermittently perfused with various solutions while recording carotid sinus nerve activity; (2) in freshly dissociated or short-term cultured carotid body Type I cells in which specific ion conductances and membrane potentials are recorded using the patch clamp technique. Intracellular free calcium and pH of the Type I cells are also measured using fluorescent dyes. Our preliminary data suggest that VGCC play a key role for hypoxic and hypercapnic chemotransduction, and that the presence of CO2/HCO3 is essential for chemotransduction of hypoxia and acidosis. The proposal consciously attempts to utilize the results of the in vitro experiments to give a deepened understanding to the results of the in vivo experiments. These results from the adult can serve as a benchmark for similar studies in the fetus, newborn, and developing animal where the carotid body influences cardiopulmonary control even more strongly and exercises significant control over the muscles of the upper airways. Such studies pertain directly to Sudden Infant Death Syndrome and to the respiratory instability so prevalent in the newborn.