CYTOCHROME P450 DEPENDENT ARACHIDONATE METABOLITES AND HYPERTENSION

该项目旨在确定血管活性激素， 加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)由细胞色素P450依赖性单加氧酶产生的产物。这些 研究将提供相关的信息，以了解一些 高血压的病理生理机制，并可能提供一个合理的 新疗法的基础。初步研究结果显示，P450衍生的 羟基二十碳四烯酸（HETE）被释放到尿和静脉中， 离体灌流肾流出物和16-; 17; 18-、19-和20- HETE在静脉和泌尿室中变化。在 此外，血管活性激素如血管紧张素II（AII）刺激血管生成， 释放HETE。亚末端HETE的生物学特征表明 这些P450-AA代谢物调节肾转运功能， 以立体特异性方式的血管舒缩。此外，AII刺激了 产生细胞因子（TNF），导致前列腺素E2增加 由亨利氏袢（mTALH）小管的粗升支产生。 研究的目的是：（a）检查血管活性物质的作用， 激素对P450衍生的类花生酸释放的正常 肾脏和经受各种实验扰动的肾脏，（B） 表征P450-AA产物对血管和肾脏的活性， 管状制剂，（c）确定以下物质的相对贡献： 预形成/储存的P450-类二十烷酸与从头合成这种 类花生酸在肾脏对血管活性激素的反应，（d）探讨 血管活性激素、TNF产生、一氧化氮和 在mTALH中合成环氧合酶和P450衍生类花生酸 小管

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.