INTERACTION OF KININS AND CYT P450 IN HYPERTENSION

描述：（改编自摘要）缓激肽（BK）刺激

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.