EICOSANOIDS BLOOD VESSELS AND HYPERTENSION

本申请的总体目标是研究公司成立， 血管衍生素的释放、代谢和生物活性 花生四烯酸代谢产物细胞色素P450(Cyto P-450)L 14，15- 二十碳三烯酸(14，15-EET)。实验的目的是进一步 描述他们的血管和肾脏活动以及在 调节血压。最近的报告显示，14，15个EET 是整合到组织磷脂中的首选EET。因为 含氧磷脂酶是磷脂酶A2较好的底物 (PLA2)，将14，15-EET并入PLS可表示存储 AA的细胞P-450代谢物在细胞膜PPS隔室中的形式 可在组织损伤和激素或细胞因子刺激下释放。 14，15-EET及其代谢物已被发现具有很强的生物学活性 活动。抑制血管加压素(AVP)诱导的血小板聚集 解尿和肾素释放。它还能降低高血压患者的血压 正常大鼠和高血压大鼠。因为它抑制了环氧合酶的活性 14，15-EET可能导致AA代谢向脂氧合酶分流 或与细胞P-450途径有关。人们对这种机制知之甚少，而且 其他加氧酶对EETs次生代谢的调节 可能与谷胱甘肽结合。14，15-EET的次生代谢 将在血管和肾脏的组织和细胞中进行研究 级别。14，15-EET及其代谢物的内源水平 组织将通过GC/MS鉴定。14，15-EET掺入 将对生成14，15-EET-PAF的Lyso-PAF进行研究。 14，15-EET生物活性代谢物的合成 14，15-EET-PAF将可用于研究。14岁的可能性， 15-EET或其代谢产物可能通过其自身的受体或 将对其他介体的受体进行调查。这些措施的结果 研究将提供有关基本概念的新信息 它的储存、释放、转化及其生理功能 AA在血管和肾脏中的代谢产物Cyto P-450。

The overall objective of this application is to study the incorporation, release, metabolism and biological activities of a vascular derived cytochrome P450 (Cyto P-450) metabolite of arachidonic acid (AA)L 14, 15- eicosatrienoic acid (14, 15-EET). Experiments are designed to further characterize their vascular and renal actions and potential role in the regulation of blood pressure. Recent reports demonstrated that 14, 15 EET was the preferred EET that incorporated into tissue phospholipids. Because of the fact that oxygenated PLs are better substrates for Phospholipase A2 (PLA2), the incorporation of 14, 15-EET into PLs may represent a storage form of cyto P-450 metabolites of AA in the membrane PLs compartment which can be released upon tissue injury and hormonal or cytokines stimulation. 14, 15-EET and its metabolite had been found to have potent biological activities. It inhibits platelet aggregation, vasopressin (AVP) induced antiduresis and renin release. It also lowered the blood pressure of normal and hypertensive rats. Since it inhibits the cycloxygenase activity 14, 15-EET may cause shunting of the metabolism of AA to the lipoxygenases or to the cyto P-450 pathway. Little is known about the mechanism and modulation of the secondary metabolism of EETs by other oxygenases and the possible conjugation with glutathione. Secondary metabolism of 14, 15-EET in blood vessels and kidney will be studied in the tissue and cellular levels. The endogenous level of 14, 15-EET and its metabolites in these tissues will be identified by GC/MS. The incorporation of 14, 15-EET into lyso-PAF for the generation of 14, 15-EET-PAF will be investigated. Synthetic compounds of the biologically active metabolites of 14, 15-EET and 14, 15-EET-PAF will be available for study. The possibility that 14, 15-EET or its metabolites may function through its own receptors or receptors of other mediators will be investigated. Results of these studies will provide new information on fundamental concepts on the storage, release, transformation and the physiological functions of this cyto P-450 metabolite of AA in vasculature and renal system.