Aldosterone is the most important hormone involved in the maintenance of bodily sodium concentrations and a target for hypertensive therapy. Atrial natriuretic peptide (ANP) suppresses the synthesis of aldosterone, and it is thought that this is one way in which ANP lowers blood pressure. The effect of ANP on aldosterone generation is believed to be mediated by the natriuretic peptide-A receptor (NPR-A) which is a membrane-associated guanylyl cyclase. ANP binding to the NPR-A results in a stimulation of guanylyl cyclase activity and elevations of intracellular cGMP concentrations. It is thought that most of the effects of ANP are facilitated through the NPR-A. However, ANP effects on aldosterone synthesis have been dissociated from cGMP production in some studies, and an effect of the natriuretic peptide clearance receptor (NPR-C) on steroidogenesis is not definitively ruled out. The proposed study will use molecular biological expression techniques to directly test the hypothesis that guanylyl cyclase mediates the effect of ANP on adrenocortical steroidogenesis in the human H295R cell-line and in primary cultures of rat zona glomerulosa (ZG) cells. The first specific aim is to determine whether the NPR-A mediates an inhibitory effect on ANP on agonist-evoked aldosterone synthesis. The second specific aim will be to determine the specific involvement of the catalytic domain of guanylyl cyclase in mediating an inhibition of aldosterone generation. The third specific aim will be to determine whether the NPR-C mediates an inhibitory effect on ANP on agonist-evoked steroidogenesis. If the results do not support the involvement of either the NPR-A or NPR-C on aldosterone production, a search for the novel ANP receptor and associated signaling mechanism will be initiated. This work will more clearly elucidate the mechanism by which ANP alters the synthesis of the important cardiovascular hormone, aldosterone. A clear understanding of the effect of the natriuretic peptide receptors on aldosterone synthesis is important for the development of novel treatments for essential hypertension as well as that caused by syndromes of excess aldosterone production (i.e., hyperadrenalism and primary hyperaldosteronism).
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