In this request, we focus on 3 tightly related themes. The first addresses Central Mediation of the Baroreflex that examines the integrative role of parabrachial nucleus; neurotransmitter functions of excitatory amino acids; and role of the brain serotonin system in renal and cardiovascular adjustments. The second theme addresses Endothelial-- Neural-Vascular Interactions with 3 subprojects that examine paracrine influences on baroreceptors and mechanisms of mechanoelectrical transduction; role of EDRF, nitric oxide (NO), and S-nitrosothiols (NOF) in regulating sympathetic function; and paracrine modulation of vascular tone in a model of atherosclerosis. The third theme addresses Reflex Autonomic Control in Selected Physiologic and Pathologic States with two subprojects in animals on the ontogeny of baroreflex and the differential sympathetic control of functional components of the kidney; and two other subprojects in humans, one on reflex neurovascular control during isometric exercise, and one on mechanisms of abnormal autonomic control with aging and sleep apnea. Three efficiently planned and established Cores will serve the entire program. We believe this application responds directly and fully to the criticisms of Committee A. It has several strengths: 1) it is more focused ion neural control which has been the forte of our research; 2) it brings together several senior investigators with various expertise from six Departments (Medicine, Neurology, Anatomy, Pharmacology, Pediatrics and Ob-Gyn) who have worked together for many years; 3) it is much more integrative extending from work on isolated cells to systems, to animal models and to humans; 4) it highlights the unique ability of this group to bring basic concepts into the arena of human investigation in an excellent scientific interactive environment; 5) it reveals the exceptional track record of the investiga- tors. We are confident the overall outcome will be better than the sum of the parts.
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