The renin-angiotensin-aldosterone system plays important roles in the regulation of blood pressure and salt and water balance. Thus, the regulations of renin and aldosterone release has important implications in diseases as hypertension and congestive heart failure. While All, ACTH and potassium are the major regulators of aldosterone release, other factors may modulate their actions. The proposed studies will test the hypothesis that aldosterone release is modulated by factors that originate from the zona glomerulosa (ZG) cell per se as well as other cells of the adrenal as endothelial cells which are in close anatomical proximity to ZG cells. These studies are divided in two major sections: 1) ZG cell eicosanoids and 2) endothelial cell factors. 1) We have identified the major arachidonic acid metabolites of adrenal ZG cells as 6-keto PGF1alpha, PGE2, PGF2alpha, PGD2, 12-HETE, 15-HETE, 14, 15-EET, 11, 12-EET, 8,9-EET and 5,6-EET. 12- HPETE and 12-HETE stimulated the release of aldosterone while 11,12-,8,9- and 5,6-EET inhibited release. Additional studies will determine the role of 12-HETE and the EETs in All- and ACTH-induced aldosterone release. Using specific assays for these metabolites, we will quantify their release by All and ACTH and the relationship between metabolite release and steroidogenesis. Additional studies will determine the site and mechanisms of action of these eicosanoids. 2) Several lines of evidence suggest that other cells present in the adrenal may contribute to steroidogenesis. In this regard, we found that the endothelial cells than when ZG cells were incubated alone. This effect could not be duplicated by smooth muscle cells or fibroblast. The steroidogenic factor was present in the media of endothelial cells and could be transferred to ZG cells and promote aldosterone release. We propose to further characterize the properties, action are regulated. These studies will be conducted in vitro with cultured bovine adrenal ZG and endothelial cells and with the perfused adrenal. Finally, endothelial factors also regulate the release of renin. Using cultured juxtaglomerular cells and endothelial cells, we propose to investigate the role of the endothelium in regulating the release of renin by beta-agonists, All, AVP, bradykinin, and histamine. Using inhibitors, we will define which endothelial factors (PGI2, EDRF, endothelin, etc.) are involved. These studies should clarify the role of eicosanoids and provide new insights into the contribution of endothelial cells to aldosterone and renin release.
