AT2 RECEPTOR MECHANISMS IN ANG II DEPENDENT HYPERTENSION

总体目标是检验血管紧张素II (ANG II）亚型-2（AT 2）受体在细胞内起重要的反调节作用， 在ANG II依赖性高血压中控制血压的作用 通过肾脏产生血管扩张物质。 具体 目的是检验ANG II依赖性高血压的两个假设：（1） AT 2受体介导缓激肽（BK）的肾产生增强 和/或一氧化氮（NO），以及（2）AT 1和AT 2受体调节 肾前列腺素E2（PGE 2），两者都导致反调节肾 血管舒张 研究人员已经开发了一种肾血管性的大鼠模型， 高血压，2肾，1包（Grollman）高血压大鼠，并有 表明高血压是ANG II依赖性的。在这个模型中， 研究人员已经证明，AT 2受体阻断剂可以防止 对AT 1受体阻断剂的过度反应，表明 AT 2受体介导反调节血管舒张。 使用一种新 肾间质液微透析技术 研究人员已经在正常大鼠中证明， 介导ANG II诱导的肾NO产生。 拟议的实验 代表了一种系统的方法，在AT 2受体的作用， 肾组织BK、NO和PGE_2的产生及其在肾组织中的作用 血管紧张素II依赖性高血压的血管舒张。 RIF水平 将响应于AT 2受体阻断来确定介质，并且 将解剖远端通路以确定 AT 2受体介导反调节变化。 拟议的研究 将首次为任何形式的高血压患者提供 了解AT 2受体在糖尿病中的相关性和介质 长期控制血压和肾功能。

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.