Chemotransduction in the Carotid Body

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DESCRIPTION (provided by applicant): The carotid body (CB), located near the internal carotid artery, is the only structure which detects too little O2 (hypoxia) or too much CO2 (hypercapnia) or hydrogen ion in the arterial blood, and signals the brain to produce several respiratory and cardiovascular reflex responses. This application proposes to explore further the mechanisms of CB's transduction of hypoxia and hypercapnia into increased the CB's neural output (CBNO). From a commonly accepted structure of the organ and sequence of events in the chemotransductive process we shall address three issues: (a) What is the relationship between CB acetylcholine (ACh) and CB dopamine (DA)? (b) Where are the pertinent receptors? (c) What is the impact of these agents back on the CB glomus cell (GC)? Experiments test hypotheses deriving from the overall working hypothesis: ACh is a (the) primary excitatory neuroagent for the CBNO's response to hypoxia and hypercapnia in the cat. The cat has exhibited many CB-generated reflex responses as well as serving as the norm for the CB's neurophysiological response characteristics. Nitric oxide (NO), ATP, and adenosine (ADO) are reported to have an effect on the CBNO's response to hypoxia and hypercapnia, and therefore on the role of ACh. SPECIFIC AIMS: (1) to measure the hypoxia-/hypercapnia- induced release of Ach and catecholamines (CAs) along with CBNO from the superfused CB in vitro with HPLC-ECD, and to measure the influence of NO, ATP, and ADO on the hypoxia- and hypercapnia-challenged CB; (2) to locate dopaminegic and purinergic receptors in the CB, the carotid sinus nerve, and in cell bodies of the petrosal ganglion (PG) with RT-PCR and immunocytochemistry; (3) to determine the effect of DA, ATP, and ADO on ACh-induced membrane voltages and currents of GCs with patch clamp, and the impact of these agents on [Ca2+]i with microfluorometry. Patients who have suffered near fatal asthma attacks are known to have hyporesponsive CBs, whereas borderline hypertensives have hyperresponsive CBs. Reduction of obstructive apneas during sleep depends on the CB. Medical management of these situations could be greatly improved with a better understanding of the CB's transductive processes, possibly with genetic manipulation or drugs with highly focused effects.