ATRIAL NATRIURETIC PEPTIDE & ALDOSTERONE SECRETION

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Atrial natriuretic peptide (ANP), a potent diuretic and natriuretic hormone, has receptors throughout the body, including the central nervous system, the kidney, smooth muscle and the adrenal cortex. An understanding of the mechanism of action of this peptide will provide insight into the major counter-regulatory effectors determining volume and blood pressure homeostasis in humans. This study focuses on elucidating the mechanism of action of ANP in the adrenal glomerulosa where it inhibits the synthesis and secretion of aldosterone. This inhibitory action itself has important physiological implications since aldosterone is the major regulator of salt and water reabsorption in the kidney, and derangements in its secretion have been associated clinically with high blood pressure and edematous states such as congestive heart failure and liver cirrhosis. Occupation of the ANP receptor(s) induces an increase in cGMP via a unique guanylate cyclase-containing receptor and a decrease in cAMP via a receptor/G-protein interaction. In the glomerulosa cell the targets of these second messengers remain unknown, although the differential modulation of voltage- dependent Ca2+ channels by ANP and their critical importance to the maintenance of steroidogenesis indicate that Ca2+ channels may be sites of regulation. The specific aims of this project are to determine: the mechanism by which ANP modulates Ca2+ channels, the association of other Ca2+-dependent protein kinases, and the relationship of cGMP and membrane potential to the ANP-induced inhibition of steroidogenesis. These studies will involve patch-clamp analysis of voltage-gated channels, electrophysiological and spectrofluorometric determinations of membrane potential, the use of kinase activation assays and Western blotting techniques, and radioimmunoassays for cyclic nucleotides and aldosterone. As a result this project will elucidate the mechanism(s) by which ANP alters the generation of the Ca2+ influx signal and its reception by Ca2+- dependent effectors and will contribute to our understanding of hypo- nad hypervolemic states.