RENIN-ANGIOTENSIN SYSTEM AND ALDOSTERONE REGULATION

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The purpose of this project is to analyze physiological and pathological aspects of the renin-angiotensin system, with emphasis in the role of AII in the regulation of aldosterone secretion and circulatory homeostasis. AII mediates the increases in aldosterone secretion during sodium restriction, but the adrenal effects of the peptide are dependent on the sensitivity of the glomerulosa cell to AII. The adrenal sensitivity to AII is increased during sodium restriction and decreased during sodium loading through mechanisms involving the dopaminergic system. Previous studies in the rat have indicated the importance of adrenal AII receptor regulation in the changes in adrenal sensitivity to AII. However, in the primate the adrenal sensitivity to AII depends on regulatory changes in 18-hydroxylase activity rather than AII receptor regulation. The recently characterized cardiac peptide, atrial natriuretic factor (ANF) is a potent inhibitor of aldosterone production in vivo and in vitro, being markedly more effective in inhibiting AII- than ACTH-stimulated steroidogenesis. Studies are in progress to determine the possible role of ANF in the regulation of adrenal sensitivity to AII in several physiological conditions. The action of AII is highly calcium-dependent, and studies in the rat using the dihydropyridine calcium channel agonist Bay K 8644 provide further evidence for the involvement of voltage-dependent calcium channels in the mechanism of action of AII, but not of that of ACTH. The participation of calcium-dependent protein kinases in the control of adrenal glomerulosa function was suggested by the preferential location of calcium-calmodulin and calcium-phospholipid dependent protein kinases in the zona glomerulosa of the adrenal cortex, and by the ability of AII to decrease cytosolic calcium-calmodulin dependent protein kinase activity in isolated adrenal glomerulosa cells. Studies are in progress to further characterize the central actions of AII, including the interaction of AII with ANF and localization of AII receptors in the primate brain.