AT2 RECEPTOR MECHANISMS IN ANG II DEPENDENT HYPERTENSION

总体目标是测试血管紧张素II的假设 (Ang II)亚型2(AT2)受体发挥重要的反调节作用 血管紧张素Ⅱ依赖型高血压的血压控制作用 通过肾脏产生血管扩张剂物质。具体的 AIMS将检验血管紧张素Ⅱ依赖型高血压的两个假说：(1) AT2受体介导肾脏缓激肽(BK)的增加 和/或AT1和AT2受体调节的一氧化氮(NO)和(2) 肾前列腺素E_2(PGE_2)，两者均导致肾脏逆调节 血管扩张。 研究人员开发了一种大鼠肾血管模型 高血压，2肾1包(Groll Man)高血压大鼠 说明高血压是血管紧张素Ⅱ依赖性的。在这个模型中， 研究人员已经证明，AT2受体的阻断可以阻止 AT1受体阻滞剂的降压反应，表明 AT2受体介导逆调节性血管扩张。用一本小说 肾间质液(RIF)微透析技术 研究人员已经在正常大鼠身上证明了AT2受体 介导Ang II诱导的肾脏NO的产生。拟议中的实验 代表了一种系统的方法来研究AT2受体在 肾脏BK、NO和PGE2的产生及其在肾脏中的作用 血管紧张素Ⅱ依赖型高血压的血管扩张。这些项目的RIF级别 将根据AT2受体阻断的反应确定介体，以及 远端通路将被解剖以确定其机制 AT2受体介导逆调节变化。建议进行的研究 将首次在任何形式的高血压和 血管紧张素转换酶2受体与血管紧张素转换酶的相关性及其介体的认识 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.