The purpose of this project is to analyze physiological and pathological aspects of the renin-angiotensin system, with emphasis in the role of AII in the regulation of aldosterone secretion and circulatory homeostasis. AII mediates the increases in aldosterone secretion during sodium restriction, but the adrenal effects of the peptide are dependent on the sensitivity of the glomerulosa cell to AII. In addition to the modulatory action of somatostatin and dopaminergic mechanisms as possible regulators of the adrenal sensitivity to AII, atrial natriuretic factor (ANF) is a potent inhibitor of aldosterone secretion. As well as exerting a preferential inhibitory effect on AII-stimnulated aldosterone secretion in vitro, experiments in vivo showed that ANF antagonized the increases in plasma aldosterone following AII infusion and sodium restriction, while ACTH-dependent aldosterone stimulation was unaffected. These actions of ANF are in support of a role for the peptide in the regulation of adrenal responsiveness to AII. Studies on the mechanism of action of AII revealed a novel calcium/calmodulin protein kinase that phosphorylates a 100 kDa cytosolic protein in the adrenal glomerulosa zone. This enzyme is different from myosin light chain kinase and its activity was shown to be regulated by AII. Previous studies demonstrating the presence of AII receptors in the rat brain were extended to the primate. In monkey brain, AII receptors were found in the circumventicular organs and other limbic structures, all related to the regulation of water intake, blood pressure and autonomic function. In the rat pituitary gland, AII stimulates prolactin secretion after binding to specific receptors located in the lactotrophs. In contrast to the adrenal and vascular AII receptors, pituitary receptors were unaffected by changes in sodium diet and plasma AII levels, but were regulated by estrogens. Incubation of pituitary cells with estradiol increased prolactin responses to AII but caused a time and dose dependent decrease in AII receptors, indicating that the major regulatory effects of estrogens are exerted at post-receptor sites.
