The objectives of the proposed research are to study the regulation of biosynthesis and metabolism of certain recently 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 activity will be estimated by the binding of labeled steroids to type I mineralocorticoid receptors in adrenalectomized rat renal cytosol preparation. 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 characterized steroids, 16 alpha, 18-diOH-DOC and 17 alpha, 20 alpha-dihydroxy-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. Additional studies of the significance of 18-OH-DOC in systemic arterial hypertension will also be undertaken.
NIH ExPorter
NIH ExPorter