VASCULAR CYTOCHROME P450 RELATED ARACHIDONIC ACID PRODUCTS

血管细胞色素P450相关花生四烯酸产品

• 批准号: 6202240
• 负责人: JOHN QUILLEY
• 金额: $ 24.35万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-20 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6202240
• 关键词: antihypertensive agents; arachidonate; cytochrome P450; dietary sodium; eicosanoids; enzyme inhibitors; epoxides; fluconazole; gas chromatography mass spectrometry; high performance liquid chromatography; hormone regulation /control mechanism; isolation perfusion; isomer; kidney circulation; kidney function; laboratory rat; nitroferricyanide; phenylephrine; potassium channel; prostaglandins; radioimmunoassay; renal hypertension; spontaneous hypertensive rat; vasoactive agent; vasodilators

This is a proposal to investigate cytochrome P450 (P450) -derived eicosanoids as mediators of arachidonic acid (AA) -induced vasodilation and as modulators of vasoconstrictor responses and to determine their contribute to the regulation of renal function and blood pressure. In the isolated perfused kidney of the rat, an endothelium-dependent vasodilator effect of AA can be uncovered when the formation of constrictor endoperioxides is blocked by indomethacin and perfusion pressure elevated with phenylephrine. This vasodilator effect is attenuated by inhibitors of P450 and correspondingly increased and decreased by induction and depletion of P45O. Similarly, the renal vasodilator effect of bradykinin (BK) exhibits a nitric oxide-independent component that is reduced by inhibitors of P450. Moreover, the renal vasodilator effects of both AA and BK are reduced by inhibitors of K+ channels. As epoxides, except 14, 15EET, are vasodilator in the rat kidney and have been reported to activate K+ channels in vascular smooth muscle, we hypothesize that AA is converted, via P450, to an epoxide that mediates the renal vasodilator effect of AA by activating K+ channels. Thus, the first aim is to determine whether an epoxide can assume the role of an hyperpolarizing factor. Therefore, we shall correlate the renal vasodilator activity of AA to the release of epoxides, measured by GC-MS, and the effects of epoxygenase inhibitors as well as addressing the renal vascular effects of regio- and stereoisomers of EETs and the role of K+ channels. The second aim will test the hypothesis that epoxides, released in response to vasoactive hormones, moderate vasoconstrictor effects of the stimulating hormone. Thus, 17-ODYA enhances renal vascular responses-to phenylephrine. We shall determine epoxide release to angiotensin II, arginine vasopressin and phenylephrine and test the effects of epoxides and epoxygenase inhibitors on renal vasoconstrictor responses to these hormones. The third aim, to determine the role of epoxides in altered renal vascular responses to AA in hypertension, is based on observations that renal vasodilator responses to AA and BK are greatly enhanced in SHR versus WKY rats. Consequently, we will determine epoxide release in response to AA, renal responsiveness to epoxides and the in vivo effects of epoxygenase inhibition on renal function, blood pressure-and pressor responsiveness in hypertensive and normotensive rats. These studies will characterize a novel vasodilator system and determine its expression and functional significance in normotension and hypertension.

这是一个研究细胞色素P450（P450）衍生的 类花生酸作为花生四烯酸（AA）诱导的血管舒张的介质 和作为血管收缩反应的调节剂，并确定它们的 有助于调节肾功能和血压。在 内皮依赖性血管扩张剂--大鼠离体灌流肾 当收缩肌形成时，AA的作用可以被揭示出来 吲哚美辛阻断内过氧化物，灌注压升高 苯乙醯胺这种血管扩张作用可被以下物质的抑制剂减弱 P450和相应的增加和减少诱导， P45 O的消耗。同样，缓激肽的肾血管舒张作用 (BK)显示出一氧化氮非依赖性成分， P450抑制剂。此外，AA和 BK被K+通道抑制剂还原。作为环氧化物，除了14， 15 EET是大鼠肾脏中的血管扩张剂， 激活血管平滑肌中的K+通道，我们假设AA是 通过P450转化为介导肾血管舒张的环氧化物 AA通过激活K+通道的作用。因此，第一个目标是 确定环氧化物是否可以承担超极化的作用， 因子因此，我们将AA的肾血管舒张活性与AA的肾血管舒张活性相关联。 对环氧化物释放的影响，通过GC-MS测量，以及 环氧合酶抑制剂以及解决肾血管效应 的区域和立体异构体以及K+通道的作用。第二 aim将测试这样一种假设，即环氧化物，在响应 血管活性激素，刺激的中度血管收缩作用 激素.因此，17-ODYA增强肾血管对苯肾上腺素的反应。 我们将测定环氧化物释放到血管紧张素II，精氨酸加压素 并测试环氧化物和环氧合酶的作用 抑制剂对肾血管收缩反应这些激素。第三 目的是确定环氧化物在改变肾血管反应中的作用 高血压中的AA，是基于肾血管扩张剂 SHR与WKY大鼠相比，对AA和BK的反应大大增强。 因此，我们将确定环氧化物释放对AA，肾 对环氧化物的反应性和环氧合酶的体内作用 抑制肾功能、血压和升压反应性 高血压和正常血压大鼠。这些研究将描述一个 新的血管扩张系统，并确定其表达和功能 在正常血压和高血压中的意义。