CYTOCHROME P450 DEPENDENT ARACHIDONATE METABOLITES AND HYPERTENSION

细胞色素 P450 依赖性花生四烯酸代谢物与高血压

• 批准号: 6109759
• 负责人: JOHN C MC GIFF
• 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/6109759
• 关键词: angiotensin II; arachidonate; chemical structure function; cytochrome P450; cytokine; enzyme linked immunosorbent assay; hormone metabolism; hormone regulation /control mechanism; hypertension; isolation perfusion; kidney function; laboratory rabbit; laboratory rat; lipopolysaccharides; mass spectrometry; nitric oxide synthase; northern blottings; oxygenases; renal tubule; vasoactive agent; vasomotion; western blottings

This project aims at defining the mechanism by which vasoactive hormones, oxygenases and cytokines interact within the kidney - at organ, cellular and molecular levels - to regulate renal function through arachidonate (AA) products generated by cytochrome P450-dependent monooxygenases. These studies will provide information relevant to understanding some of the pathophysiological mechanisms of hypertension, and may provide a rational basis for novel treatments. Preliminary findings show that P450-derived hydroxyeicosatetraenoic acids (HETEs) are released into urinary and venous effluents of isolated perfused kidneys and that the profile of 16-; 17; 18-; 19- and 20- HETE varies in the venous and urinary compartments. In addition, vasoactive hormones such as angiotensin II (AII) stimulate the release of HETEs. The biological profile of subterminal HETEs suggests that these P450-AA metabolites modulate renal transport function and vasomotion in a stereospecific manner. Further, AII stimulates the production of cytokines (TNF) resulting in enhanced prostaglandin E2 production by thick ascending limb of the loop of Henle (mTALH) tubules. The goals of the research are: (a) to examine the effect of vasoactive hormones on the profile of P450-derived eicosanoids released from normal kidneys and kidneys subjected to various experimental perturbations, (b) to characterize the activity of P450-AA products on vascular and renal tubular preparations, (c) to determine the relative contribution of preformed/stored P450-eicosanoids versus de novo synthesis of such eicosanoids in the renal response to vasoactive hormones, (d) to explore interactions among vasoactive hormones, TNF production, nitric oxide and synthesis of cyclooxygenase- and P450-derived eicosanoids in mTALH tubules.

该项目旨在确定血管活性激素的机制， 氧酶和细胞因子在肾脏内相互作用 - 在器官、细胞 和分子水平 - 通过花生四烯酸调节肾功能 (AA) 细胞色素 P450 依赖性单加氧酶产生的产物。这些 研究将提供与理解一些相关的信息 高血压的病理生理机制，并可能提供合理的解释 新疗法的基础。初步研究结果表明，P450 衍生的 羟基二十碳四烯酸（HETE）被释放到尿液和静脉中 分离的灌注肾脏的流出物和16-的轮廓； 17； 18-; 19- 和 20- HETE 在静脉室和尿室中有所不同。在 此外，血管活性激素如血管紧张素 II (AII) 会刺激 HETE 的释放。亚末端 HETE 的生物学特征表明 这些 P450-AA 代谢物调节肾脏转运功能 以立体特异性方式进行血管舒缩。此外，AII 还刺激 细胞因子 (TNF) 的产生导致前列腺素 E2 增强 由亨利管袢（mTALH）粗升肢产生。 研究的目标是： (a) 检查血管活性物质的作用 激素对正常人释放的 P450 衍生类二十烷酸分布的影响 肾脏和遭受各种实验扰动的肾脏，（b） 表征 P450-AA 产品对血管和肾脏的活性 管状制剂，(c) 确定的相对贡献 预先形成/储存的 P450-类二十烷酸与此类物质的从头合成 类二十烷酸在肾脏对血管活性激素的反应中的作用，(d) 探讨 血管活性激素、TNF 产生、一氧化氮和 mTALH 中环氧合酶和 P450 衍生的类二十烷酸的合成 小管。