NEUROPEPTIDASES AND CAROTID BODY FUNCTIONS

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The carotid bodies transduce changes in the levels of arterial oxygen, carbon dioxide and hydrogen ion concentrations into action potential encoded nerve signals. This transduction process is complex and believed to involve several neurochemicals including neuropeptides. Neuropeptidases, viz., neutral endopeptidase (NEP), a soluble endopeptidase (sNEP), and endothelin converting enzyme (ECE)-like activity occur in the carotid body and they involve in the metabolism of neuropeptides in the chemoreceptor tissue. More importantly, inhibition of these enzymes by phosphoramidon both in vivo and in vitro appears to potentiate not only the carotid body activity but also its response to the physiological stimulus, hypoxia. These observations suggest that NEP, sNEP and ECE-like activity may play hitherto undefined important functional roles in the carotid body. This investigation, specifically, addresses the molecular characterization and regulation of NEP, sNEP and ECE and their importance in the functions of the carotid body. Our hypothesis is that: a) Peptidases regulate the synthesis and degradation of neuropeptides in the carotid body, and that the activity and peptidases levels are differentially altered by hypoxia. b) Hypoxia induced alteration of peptidases involves dopaminergic receptors resulting in changes in the peptide levels of the carotid body. c) The changes in neuropeptides, in turn, contribute to the altered sensitivity of the carotid body to hypoxia. Studies proposed in Specific Aim 1 will determine the influence of short-term hypoxia on neuropeptidases of the carotid body. In Specific Aim 2, the cellular mechanism(s) associated with the regulation of neuropeptidases of the carotid body by short-term hypoxia will be investigated. The effect of long-term hypoxia on the activity and expression of NEP, sNEP and ECE- like activities of the carotid body will be examined in studies of Specific Aim 3. In Specific Aim 4, we will determine the influence of dopamine, and dopaminergic antagonists on neuropeptidases and neuropeptide metabolism of the carotid body. It is anticipated that the proposed studies will provide clues as to the role of phosphoramidon- sensitive enzymes in the functions of the carotid body. These studies may also yield new information in the development of enzyme based therapeutic agents in the treatment of hypoxemia, associated with high altitude adaptation and chronic obstructive lung diseases.