EICOSANOIDS BLOOD VESSELS AND HYPERTENSION

类花生酸血管和高血压

• 批准号: 3338028
• 负责人: PATRICK Y-K WONG
• 金额: $ 20.9万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-01 至 1994-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3338028
• 关键词: antihypertensive agents; arachidonate; blood vessels; cardiovascular disorder prevention; chemical structure function; cytochrome P450; eicosanoid metabolism; familial hypertension; fatty acid biosynthesis; gas chromatography; genetic regulation; genetic transcription; high performance liquid chromatography; homeostasis; isozymes; kidney circulation; leukotrienes; mass spectrometry; phospholipase A2; prostacyclins; spontaneous hypertensive rat; thin layer chromatography; thromboxanes

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.

本申请的总体目标是研究合并， 血管衍生物的释放、代谢和生物活性 细胞色素P450（Cyto P-450）花生四烯酸（AA）L 14，15- 二十碳三烯酸（14，15-EET）。 实验旨在进一步 描述其血管和肾脏作用以及在 调节血压。 最近的报告表明，14，15 EET 是掺入组织磷脂的优选EET。 因为 事实上，含氧磷脂是磷脂酶A2的更好底物， （PLA 2），将14，15-EET掺入PL中可以代表储存 在膜PLs隔室中AA的细胞P-450代谢物的形式， 可在组织损伤和激素或细胞因子刺激时释放。 14，15-EET及其代谢产物具有很强的生物活性， 活动 它抑制血小板聚集，血管加压素（AVP）诱导的 抗利尿和释放肾素。 它还降低了血压， 正常和高血压大鼠。 因为它抑制了环氧化酶的活性 14，15-EET可引起AA代谢向脂氧合酶的分流 或细胞P-450通路。 关于其机制知之甚少， 通过其他加氧酶调节雌二醇的次级代谢， 可能与谷胱甘肽结合。 14，15-EET的次级代谢 将在组织和细胞中研究血管和肾脏中的 程度. 14，15-EET及其代谢产物的内源性水平， 将通过GC/MS鉴定组织。 将研究lyso-PAF用于产生14，15-EET-PAF。 14，15-EET生物活性代谢产物的合成化合物 14，15-EET-PAF可用于研究。 有可能14， 15-EET或其代谢物可能通过其自身的受体或 将研究其他介质的受体。 结果进行 研究将提供有关基本概念的新信息， 储存、释放、转化及其生理功能 AA在血管系统和肾脏系统中的细胞P-450代谢物。