RENIN-ANGIOTENSIN SYSTEM AND ALDOSTERONE REGULATION

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The purpose of this project is to analyze physiological and pathological aspects of the renin angiotensin system, including the effects of AII in circulatory homeostasis, pituitary and gonadal function. AII mediates the increase in aldosterone secretion during sodium restriction, but the adrenal effects of the peptide are dependent on the sensitivity of the glomulosa zone to AII. Previous studies in the rat have demonstrated that the adrenal responsiveness to AII depends on the trophic effects of the peptide and the modulatory effect of the other regulators such as dopamine, atrial natriuretic factor (ANF) and somatostatin (SRIF). Studies using the dopaminergic antagonist metoclopramide (MCP), in sodium loaded hypo physectomized rats showed that the sensitizing effect of MCP on the adrenal effects of AII is blunted in the absence of the pituitary. In addition, abundant receptors for AII, which undergo regulatory changes during altered sodium intake, AII and MCP administration, are present in the intermediate lobe of the pituitary suggesting that an intermediate lobe factor is involved in the control of the adrenal responsiveness to AII. Studies on the ontogeny of the AII receptor revealed dramatic changes in receptor concentration and distribution during development. In addition to a marked decrease in AII receptor concentration in the adrenal capsule and smooth muscle with age, in fetal and neonatal rat and mouse there are abundant AII receptors widely distributed in muscular and mesenchymal tissue throughout the body. Other components of the renin-AII system were found in the fetus suggesting a unique role of AII during development. Analysis of the role of the receptor bound AII in adrenal glomerulose cells indicated marked internalization of the ligand following binding of the agonist but not the antagonist. In addition, there was significant accumulation of the internalized agonist in the nucleus suggesting direct actions of AII at the genomic level in addition to the recognized membrane transduction mechanisms.