CYTOCHROME P450 DEPENDENT ARACHIDONATE METABOLITES AND HYPERTENSION

该项目旨在确定血管活性荷尔蒙， 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)依赖细胞色素P450的单加氧酶产生的产物。这些 研究将提供相关信息，以了解一些 并可能为高血压的病理生理机制提供合理的 为新的治疗方法奠定基础。初步研究结果显示，P450源于 羟基二十碳四烯酸(HETE)被释放到尿液和静脉中 分离的灌流肾的流出物和16-；17； 18-、19-和20-HETE在静脉室和尿室各有不同。在……里面 此外，血管活性激素，如血管紧张素II(AII)，刺激 释放HETE。亚端HETE的生物学特征表明 这些P450-AA代谢物调节肾脏转运功能和 以立体特异性的方式进行血管运动。此外，所有这些都刺激了 细胞因子(TNF)的产生导致前列腺素E_2升高 由粗大的Henle(MTALH)小管环上升支产生。 这项研究的目标是：(A)检查血管活性的影响 从正常人释放的P450衍生二十烷的激素谱 肾脏和肾脏受到各种实验扰动，(B) P450-AA产物对血管和肾脏的活性表征 管状制剂，(C)确定 预制/储存的P450-二十烷类化合物与从头合成此类化合物的比较 二十烷基类化合物在肾脏对血管活性激素的反应，(D)探讨 血管活性激素、肿瘤坏死因子产生、一氧化氮和 MTALH中环氧合酶和P450衍生二十烷类化合物的合成 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.