The objectives of the proposed research are to study the regulation of biosynthesis and metabolism of certain characterized C-18 and C-16 oxygenated 21C and 19C adrenal steroids and to examine the mechanisms by which they exhibit mineralocorticoid activity. Direct mineralocorticoid receptors in adrenalectomized rat renal cytosol preparation and indirect or augmented mineralocorticoid activity will be assessed by examining alterations in aldosterone binding to mineralocorticoid receptors in the presence of these steroids (recruitment or positive cooperativity) and we will assess alterations in overall metabolic clearance rate of aldosterone induced by these steroids. Lastly, indirect mineralocorticoid expression through the hyperproduction of deoxycorticosterone due to inhibition of 11-beta-hydroxylase activity by C-19, 16-hydroxylated steroids will be examined. The association of the newly isolated steroids, 19-OH-deoxycorticosterone and 19-Nor-DOC progesterone, with systemic arterial hypertension will be examined. Aberrations in the abnormal regulation of secretion and intermediary metabolism of these compounds will be assessed in hypertensive disorders. The significance of 19-hydroxylation of steroids and oxidative conversion to 19-Nor steroids will be examined.
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