The overall objective is to test the hypothesis that the angiotensin type-2 (AT2) receptor plays an important role in the control of blood pressure and kidney function through the generation of bradykinin (BK), nitric oxide (NO) and guanosine cyclic 3', 5' monophosphate (cGMP).
The specific aims are (1) to test the hypothesis that AT2 receptor stimulation mediates renal and systemic vasodilation and hypotension by increasing the production of BK, NO and cGMP and (2) to test the hypothesis that AT2 receptor stimulation, through increased renal production of BK, NO and cGMP, induces natriuresis. The investigators have demonstrated that the AT2 receptor is expressed in the kidney, heart and peripheral vasculature and stimulates renal BK, NO and cGMP. The principal investigator's recent studies in mice lacking the AT2 receptor (AT2-Null) demonstrate a sustained pressor and antinatriuretic hypersensitivity to angiotensin II (ANG II), accompanied by a marked reduction in BK, NO, cGMP. These results suggest that the AT2 receptor may function as an opponent of the actions of ANG II at the AT1 receptor. The principal investigator has recently demonstrated that valsartan-infused rats without functioning AT1 receptors have hypotensive respoflses to Ang II that are fully blocked by the AT2 receptor antagonist, PD 123319.The proposed experiments represent a systematic approach to the role of the AT2 receptor in vasodilation and natriuresis and the renal mechanisms of these actions in the valsartan-infused (AT1 receptor-blocked) rat model. This model will allow evaluations of the role of the AT2 receptor and its signalling mechanisms in the absence of interference by functional AT1 receptors. The proposed studies will clarify the role of the AT2 receptor in the control of blood pressure and kidney function. An understanding of the function of the AT2 receptor is necessary for an assessment of its potential role in the pathophysiology of hypertension and as a target for antihypertensive therapy.
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