The renin-angiotensin system (RAS) is a major physiological regulator of body fluid volume, electrolyte balance, and arterial pressure. Majority of the biological actions of angiotensin II (Ang II), the principal effector peptide of the RAS, are attributed to its action at the type 1 (AT1) Ang II receptor. Until recently the physiologic functions of the angiotensin type 2 (AT2) receptor has been unknown. Date from our laboratory and confirmed by others indicate that the AT2 receptor stimulates vasodilatation by an autocrine cascade including bradykinin, nitric oxide and cyclic GMP. In addition, we demonstrated that part of the blood pressure lowering effect of the AT1 receptor blockade is mediated by the AT2 receptor. While AT1 receptor has been shown to regulate the RAS activity and Ang II production, the contribution of the AT2 receptor to the regulation of this system is unknown, Preliminary data presented in this application suggest that AT2 receptor inhibits renal renin synthesis and decreases renal cellular uptake of Angiotensin II. This proposal will expand on these preliminary studies and confirm the involvement of the AT2 receptor in the regulation of the RAS.
The specific aims for this proposal are:(1) To test the hypothesis that AT2 receptor reduces renal production of Angiotensin II through the inhibition of renin synthesis.(2) To test the hypothesis that nitric oxide and cyclic GMP generated in response to AT2 receptor stimulation inhibit renin synthesis(3) To test the hypothesis that AT2 receptor inhibits renal cellular uptake of Angiotensin II. Data obtained from this proposal will lead to increased understanding of the pathophysiology of hypertension and development of novel therapies for its management.
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