AT2 RECEPTORS IN BLOOD PRESSURE AND RENAL FUNCTION

描述（由申请人提供）：总体目标是测试 血管紧张素2型（AT 2）受体在这一过程中起重要作用的假说 在控制血压和肾功能，通过产生 缓激肽（BK）、一氧化氮（NO）和环磷酸鸟苷 （cGMP）。具体目的是：（1）验证AT_2受体 刺激介导肾和全身血管舒张和低血压， 增加BK、NO和cGMP的产生;（2）检验假设 AT 2受体的刺激，通过增加肾脏产生的BK，NO和 cGMP诱导尿钠排泄。 研究人员已经证明，AT 2受体表达于 肾、心脏和外周血管系统，并刺激肾BK、NO和cGMP。 首席研究员最近在缺乏AT 2受体的小鼠中进行的研究 （AT 2-ATP）表现出持续的升压和抗心房利尿过敏 血管紧张素Ⅱ（ANG Ⅱ）升高，BK、NO、cGMP明显降低。 这些结果表明，AT 2受体可能作为一个对手的功能， 血管紧张素II对AT 1受体的作用。首席研究员最近 证明了没有功能性AT 1受体的缬沙坦输注大鼠 对血管紧张素II的过度反应被AT 2受体完全阻断 拮抗剂，PD 123319。建议的实验代表了一种系统的方法 AT 2受体在血管舒张和尿钠排泄中的作用，以及肾脏 缬沙坦输注（AT 1受体阻断）大鼠中这些作用的机制 模型该模型将允许评估AT 2受体的作用， 在没有功能性AT 1干扰的情况下， 受体。 拟议的研究将阐明AT 2受体在对照中的作用。 血压和肾功能。了解的功能， AT 2受体对于评估其在肿瘤中的潜在作用是必要的。 高血压的病理生理学和作为抗高血压治疗的靶点。

DESCRIPTION (provided by applicant): 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.