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: 6109761
• 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: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6109761
• 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.

这是一项研究细胞色素 P450 (P450) 衍生的提案 类二十烷酸作为花生四烯酸 (AA) 诱导的血管舒张介质 并作为血管收缩反应的调节剂并确定其 有助于调节肾功能和血压。在 大鼠离体灌注肾，内皮依赖性血管扩张剂 AA的作用可以在缩颈形成时显现出来 内过氧化物被吲哚美辛阻断并且灌注压升高 与去氧肾上腺素。这种血管舒张作用会被抑制剂减弱 P450 并相应地通过诱导和减少而增加和减少 P45O 耗尽。同样，缓激肽的肾血管扩张作用 (BK) 表现出一种独立于一氧化氮的成分，该成分减少 P450抑制剂。此外，AA 和 AA 均具有肾血管扩张作用。 K+ 通道抑制剂可降低 BK。作为环氧化物，除 14 外， 15EET 是大鼠肾脏的血管扩张剂，据报道 激活血管平滑肌中的 K+ 通道，我们假设 AA 是 通过 P450 转化为介导肾血管扩张剂的环氧化物 AA 通过激活 K+ 通道发挥作用。因此，首要目标是 确定环氧化物是否可以承担超极化的作用 因素。因此，我们将 AA 的肾血管舒张活性关联起来。 通过 GC-MS 测量环氧化物的释放，以及 环氧化酶抑制剂以及解决肾血管影响 EET 的区域异构体和立体异构体以及 K+ 通道的作用。第二个 目标将测试环氧化物的假设，响应释放 血管活性激素，刺激的中度血管收缩作用 激素。因此，17-ODYA 增强肾血管对去氧肾上腺素的反应。 我们将测定环氧化物向血管紧张素 II、精氨酸加压素的释放 和去氧肾上腺素并测试环氧化物和环氧化酶的作用 肾血管收缩剂对这些激素反应的抑制剂。第三个 目的，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的观察 与 WKY 大鼠相比，SHR 大鼠对 AA 和 BK 的反应大大增强。 因此，我们将确定对 AA 的环氧化物释放，肾 对环氧化物的反应性和环氧化酶的体内作用 对肾功能、血压和升压反应性的抑制 高血压和正常血压大鼠。这些研究将描述一个 新型血管舒张系统并确定其表达和功能 对正常血压和高血压有重要意义。