The theme of the Program Project emphasizes the study of neural and neuroendocrine mechanisms regulating blood pressure and volume and potentially implicated in the etiology and/or maintenance of hypertension in animal models of hypertension and in man. The studies of the program project will focus on cardiovascular receptors and receptor-mediated mechanisms. The program is multidisciplinary with studies at the clinical, animal, cell and molecular level using techniques of molecular pharmacology and biology together with physiological methods to probe organ system responses to receptor activation and/or neural activity. The thesis underlying this program project is that knowledge of the regulation and expression of cardiovascular receptors together with an understanding of their mechanisms yielding functional responses is essential towards an understanding of the basis of hypertension and its cardiovascular sequelae. The research units and cores are highly integrated and have been interacting together for several years. The research proposed for the program project includes the following studies: mechanisms of regulation of the renin- angiotensin system by steroid hormones focused on angiotensinogen and the angiotensin receptor in neural and neuroendocrine tissues: regulation and expression of adrenergic receptors in the kidney of normotensive and hypertensive rats; regulation of chromogranin synthesis and secretion and relationship to adrenal exocytotic mechanisms; distribution and relevance of mineralocorticoid receptors in the rat brain and isolated cells; coupling between adrenergic receptor activation and changes in intracellular calcium in smooth muscle and related cell systems; interrelationship and regulation of angiotensin and adrenergic receptors in the brain of hypertensive rats; the role of renal adrenergic effector mechanisms on glomerular and tubular function; the influence of centrally administered angiotensin on the peripheral microvasculature of hypertensive rats and role of adrenergic receptor modulation. Cores are proposed to support the activities of the research units and facilitate integration and cost-effective utilization of programmatic resources. The proposed studies should contribute significantly to our knowledge of the mechanisms whereby cardiovascular receptor are regulated so as to modify blood pressure and volume and further our understanding of the etiology of hypertension.
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