The overall goal of this renewal application is to provide evidence for the participation of the amino terminal heptapeptide-angiotensin-(1-7)- in the control of arterial pressure and fluid metabolism. The research plan around the hypothesis that Ang-(1-7) opposes or counter-balances the pressor and trophic actions of Ang II by actions on a novel receptor subtype modulating synthesis and release of prostacyclin and nitric acid in a tissue specific manner. The anti-hypertensive effects of Ang-(1-7) may also involve augmentation of the actions of kinin since (Ang-(1-7) is both a substrate and an inhibitor of angiotensin converting enzyme (ACE). In Project 1 we will determine the contribution of Ang-(1-7) to the regulation of blood pressure in SHR and [mRen-2]27 transgenic hypertensive rats using agents that inhibit Ang-(1-7) synthesis, activity, or binding. Dr. Chapell's project will investigate the biochemical contribution and mechanisms of regulation of Ang-(1-7)- forming and degrading enzymes, neprilysin and ACE. The next project will analyze the tissue-specific pharmacological and functional responses of a novel non-AT1/AT2 Ang-(1-7) receptor in animal models of hypertensive and in mice with genetic deletion of AT1 or AT2 receptors. The next project will characterize by expression cloning the novel Ang-(1-7) [AT(1-7)] receptor mediating antiproliferative responses from rats vascular smooth muscle cells. The last project will characterize the role of Ang-(1-7)- in modulating the vasculo protective effects of estrogen in normal and [mRen-2]27 hypertensive rats. Core Resource Facilities (Cellular and Molecular Biology, Biochemistry, and Transgenic Animals) provide the integrative structure for the conduction of the proposed research plan. The proposed studies address the role of Ang-(1- 7) as a tissue hormone regulating the pressor and trophic action of Ang II and its potential role in acting as an anti-hypertensive factor in conditions of increased renin, angiotensin activity. Ten years after the discovery of the biological activity of Ang-(1-7,) the proposed research has direct implications for unraveling the mechanisms contributing to the development of Ang II-dependent hypertension and the mode of action of ACE inhibitors and Ang II antagonists.
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