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INTERACTION OF KININS AND CYT P450 IN HYPERTENSION

激肽和 CYT P450 在高血压中的相互作用

基本信息

批准号：
6322808
负责人：
JOHN QUILLEY
金额：
$ 12.23万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-10 至 2000-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6322808
关键词：
arachidonate bradykinin cytochrome P450 diabetes mellitus disease /disorder model eicosanoid metabolism eicosanoids enzyme inhibitors enzyme mechanism gas chromatography mass spectrometry hypertension laboratory rat potassium channel spontaneous hypertensive rat vasodilation

项目摘要

DESCRIPTION: (Adapted from abstract) Bradykinin (BK) stimulates phospholipases C and A2 to release arachidonic acid (AA) which can be metabolized by cyclooxygenase, lipoxygenase and cytochrome P450 (P450) to yield vasoactive products that may contribute to the action of the peptide. In the rat kidney, pharmacological evidence suggests that a substantial component of the vasodilator response is dependent on P450-AA metabolism. Similarly, a P450-dependent renal vasodilator response to AA can be demonstrated. In the heart, the vasodilator response to BK is independent of NO and prostaglandins but reduced by inhibitors of phospholipase and P450. Moreover, the renal and coronary effects of BK are associated with release of P450-AA metabolites, measured by GC-MS. Furthermore, the renal and coronary vasodilator actions of bradykinin and the renal vasodilator effect of AA are dependent on activation of K+ channels linking P450-AA and hyperpolarization. As epoxides (EETS) have been shown to activate K+ channels, the overall objective is to test the hypothesis that EETs act as hyperpolarizing factors that mediate NO-independent renal and coronary vasodilator responses to BK and AA and to determine their functional significance to altered responses to BK and AA in hypertension and diabetes. Thus, formation of vasodilator eicosanoids derived via this pathway may have important implications in the control of vascular tone, local blood flow and, thereby, blood pressure. Therefore, the coronary, and renal release of EETs will be correlated to the vasodilator effects of BK and AA in isolated perfused hearts and kidneys and the effects of inhibitors and inducers of P450 ascertained. The vasodilator activities of the regio- and stereo-isomers of the EETs and the role of K+ channels in the responses will be also investigated. Ultimately, the profile of EET regioisomers released by BK and AA will be determined. In the second part of the study, the principal investigator will address the significance of an EET-mediated vasodilator system to renal function and blood pressure regulation and its contribution to altered vascular responsiveness in hypertension and diabetes.

描述：（改编自摘要）缓激肽 (BK) 刺激磷脂酶 C 和 A2 释放花生四烯酸 (AA)，可由环氧合酶、脂氧合酶和细胞色素P450（P450）代谢为产生可能有助于肽作用的血管活性产物。在大鼠肾脏中，药理学证据表明，大量血管舒张反应的组成部分取决于 P450-AA 代谢。类似地，P450 依赖性肾血管舒张剂对 AA 的反应可以是证明了。在心脏中，血管舒张剂对 BK 的反应是独立的 NO 和前列腺素，但被磷脂酶抑制剂和 P450。此外，BK 的肾脏和冠状动脉作用与通过 GC-MS 测量 P450-AA 代谢物的释放。此外，肾缓激肽和肾血管扩张剂的冠状血管扩张作用 AA 的作用取决于连接 P450-AA 的 K+ 通道的激活和超极化。环氧化物 (EETS) 已被证明可以激活 K+ 渠道，总体目标是检验 EET 充当的假设介导不依赖于 NO 的肾脏和冠状动脉的超极化因子血管舒张剂对 BK 和 AA 的反应并确定其功能高血压和糖尿病患者对 BK 和 AA 的反应改变具有重要意义。因此，通过该途径衍生的血管舒张类二十烷酸的形成可能具有对控制血管张力、局部血流具有重要意义从而影响血压。因此，冠状动脉和肾脏释放 EET 将与孤立的 BK 和 AA 的血管舒张作用相关。灌注心脏和肾脏以及抑制剂和诱导剂的作用 P450 已确定。该区域的血管舒张活性 EET 的立体异构体以及 K+ 通道在反应中的作用将也受到调查。最终，EET 区域异构体的概况发布由BK和AA确定。在研究的第二部分中，首席研究员将阐述 EET 介导的重要性血管扩张系统对肾功能和血压的调节及其作用高血压和血管反应性改变的贡献糖尿病。