AT2 RECEPTOR MECHANISMS IN ANG II DEPENDENT HYPERTENSION

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The overall objective is to test the hypothesis that the angiotensin II (ANG II) subtype-2 (AT2) receptor plays an important counter-regulatory role in the control of blood pressure in ANG II-dependent hypertension through the renal generation of vasodilator substances. The specific aims will test two hypotheses in ANG II-dependent hypertension: (1) that the AT2 receptor mediates enhanced renal production of bradykinin (BK) and/or nitric oxide (NO) and (2) that AT1 and AT2 receptors regulate renal prostaglandin E2 (PGE2), both leading to counter-regulatory renal vasodilation. The investigators have developed a rat model of renovascular hypertension, the 2-kidney, 1-wrap (Grollman) hypertensive rat and have demonstrated that the hypertension is ANG II-dependent. In this model, the investigators have demonstrated that AT2 receptor blockade prevents the hypotensive response to AT1 receptor blockade, indicating that the AT2 receptor mediates counter-regulatory vasodilation. Using a novel renal interstitial fluid (RIF) microdialysis technique, the investigators have demonstrated in the normal rat that the AT2 receptor mediates ANG II induced renal NO production. The proposed experiments represent a systematic approach to the role of the AT2 receptor in the renal production of BK, NO and PGE2 and their roles in renal vasodilation in ANG II-dependent hypertension. RIF levels of these mediators will be determined in response to AT2 receptor blockade, and distal pathways will be dissected to determine the mechanisms by which AT2 receptors mediate counter-regulatory changes. The proposed studies will provide for the first time in any form of hypertension an understanding of the relevance and mediators of AT2 receptors in the long term control of blood pressure and kidney function.