INTERACTION OF KININS AND CYT P450 IN HYPERTENSION

描述：(摘自摘要)缓激肽(BK)刺激 磷脂酶C和A2释放花生四烯酸(AA) 由环氧合酶、脂氧合酶和细胞色素P450(P450)代谢至 产生可能有助于多肽作用的血管活性产物。 在大鼠肾脏中，药理学证据表明，大量的 血管扩张剂反应的成分依赖于P450-AA的代谢。 类似地，依赖P450的肾血管扩张剂对AA的反应可以是 演示了。在心脏，血管扩张对BK的反应是独立的 NO和前列腺素，但被磷脂酶和前列腺素酶抑制剂减少 P450。此外，BK对肾脏和冠状动脉的影响与 GC-MS检测P450-AA代谢物的释放。此外，肾脏 缓激肽和肾血管扩张剂的冠脉扩张作用 AA的作用依赖于连接P450-AA和 超极化。环氧化物(EET)已被证明能激活K 渠道，总体目标是测试EET作为 介导非独立肾和冠脉的超极化因子 血管扩张剂对BK和AA的反应及其功能 高血压和糖尿病患者对BK和AA反应改变的意义。 因此，通过这一途径衍生的血管扩张剂二十烷类化合物的形成可能具有 血管张力、局部血流控制的重要意义 因此，也就是血压。因此，冠状动脉和肾脏的释放 EETs可能与BK和AA的血管扩张作用有关 心脏和肾脏的灌流及其抑制剂和诱导剂的作用 P450已确定。该区域的血管扩张活性-和 EETs的立体异构体和K通道在反应中的作用将 也要接受调查。最终，EET区域异构体的概况公布 由BK和AA决定。在研究的第二部分， 首席调查员将阐述EET介导的 血管扩张剂系统对肾功能和血压的调节作用及其机制 高血压和高血压患者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.