INTERACTION OF KININS AND CYT P450 IN HYPERTENSION

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），花生四烯酸可以被 通过环氧合酶、脂氧合酶和细胞色素P450（P450）代谢， 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， 血管舒张反应的组分依赖于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 演示。 在心脏中，血管扩张剂对BK的反应是独立的， 但通过磷脂酶抑制剂减少， P450。 此外，BK的肾脏和冠状动脉效应与 通过GC-MS测量的P450-AA代谢物的释放。此外， 缓激肽和肾血管扩张剂的冠状血管扩张作用 AA作用依赖于连接P450-AA的K+通道的激活， 超极化 由于环氧化物（EETS）已被证明可以激活K+ 通道，总体目标是检验假设，即Ehrs作为 介导NO非依赖性肾脏和冠状动脉的超极化因子 BK和AA的血管舒张反应，并确定其功能 高血压和糖尿病患者对BK和AA反应改变的意义。 因此，通过该途径衍生的血管扩张剂类二十烷酸的形成可能具有 在控制血管张力、局部血流 从而影响血压 因此，冠状动脉和肾脏释放的 在离体大鼠中，Ehrs与BK和AA的血管舒张作用相关。 灌注的心脏和肾脏以及抑制剂和诱导剂的作用 P450确定。 血管扩张活动的区域和 立体异构体和钾离子通道在反应中的作用将 也被调查。 最终，释放的EET区域异构体的分布图 将由BK和AA确定。 在研究的第二部分， 主要研究者将讨论EET介导的重要性 血管舒张系统对肾功能和血压调节的作用及其机制 对高血压血管反应性改变的贡献， 糖尿病

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.