EICOSANOIDS, VASCULAR TONE AND BLOOD PRESSURE

描述：（改编自应用程序）的重要性 血管内皮细胞衬里在调节血管 基调已明确确立。 乙酰胆碱，P物质， 和缓激肽在内皮存在时松弛血管， 而不是在它缺席的情况下。 这种弛豫归因于EDRF的释放。 有证据表明存在多个EDRF。 一氧化氮（NO-EDRF） 在 此外，存在由花生四烯酸释放的EDRF（AA-EDRF）， 不是PGI 2，而是脂氧合酶代谢产物。 调查人员发现 该AA-EDRF作为15-脂氧合酶的代谢物 11，14，15-三羟基二十碳三烯酸（11，14，15-THETA）， HPLC和气相色谱/质谱法。 11-H-14，15-EETA被认为是 是11，14，15-θ的前体。 11-H-14，15-EETA和11，14，15-THETA 松弛兔主动脉，一个或两个代表AA-EDRF。 拟议 研究将测试花生四烯酸是由代谢的假设， 内皮对血管扩张剂类二十烷酸11-H，14，15-EETA和11，14，15-THETA 参与调节血管张力，并有助于 血管活性激素的作用。 研究将在分离的血液中进行 血管、平滑肌细胞和EC。 利用化学分析， 生物化学和药理学方法拟议的实验将： 1)确定主动脉和EC是否产生11，14，15-EETA，并确定 11，14，15-θ的立体化学。 实验将比较 THETA和HEETA，它们的立体异构体的血管扩张活性; 2） 开发11，14，15-THETA和可能的11-H-14-15-EETA的测定方法， 研究血管活性剂对其释放的调节。 的 花生四烯酸代谢抑制剂对释放的影响将 测定 这些定量信息将与 生理学和药理学研究，以确定 代谢产物对血管张力和血管活性激素的活性; 3） 研究11，14，15-EETA和11，14，15-THETA的生物合成途径 使用纯化的酶、转染的细胞、抗体和 抑制剂;和4）研究11，14，15-EETA和 11，14，15-THETA扩张平滑肌。

DESCRIPTION: (Adapted from the application) The importance of the endothelial cell lining of the blood vessel in the regulation of vascular tone is clearly established. Hormones such as acetylcholine, substance P, and bradykinin relax blood vessels in the presence of the endothelium but not in its absence. The relaxation is attributed to the release of EDRF. There is evidence for multiple EDRFs. One is nitric oxide, (NO-EDRF). In addition, there is an EDRF released by arachidonic acid (AA-EDRF) that is not PGI2, but a lipoxygenase metabolite. The investigators have identified this AA-EDRF as a metabolite of 15-lipoxygenase 11,14,15-trihydroxyeicosatrienoic acid (11,14,15-THETA) using bioassay, HPLC, and gas chromatography/mass spectrometry. 11-H-14,15-EETA is thought to be a precursor of 11,14,15-THETA. 11-H-14,15-EETA and 11,14,15-THETA relax the rabbit aorta and one or both represent AA-EDRF. The proposed studies will test the hypothesis that arachidonic acid is metabolized by the endothelium to vasodilator eicosanoids 11-H,14,15-EETA and 11,14,15-THETA that are involved in the regulation of vascular tone and contribute to the action of vasoactive hormones. Studies will be conducted in isolated blood vessels, smooth muscle cells and ECs. Using chemical, analytical, biochemical and pharmacological approaches the proposed experiments will: 1) determine if 11,14,15-EETA is produced by the aorta and ECs and determine the stereochemistry of 11,14,15-THETA. Experiments will compare the vasodilator activity of the THETA and HEETA, their stereo isomers; 2) develop an assay for 11,14,15-THETA and possibly 11-H-14-15-EETA and investigate the regulation of their release by vasoactive agents. The effect of inhibitors of arachidonic acid metabolism on release will be determined. This quantitative information will be combined with physiological and pharmacological studies to determine the contribution of the metabolites to vascular tone and the activity of vasoactive hormones; 3) study the biosynthetic pathway for 11,14,15-EETA and 11,14,15-THETA formation using purified enzymes, transfected cells, antibodies and inhibitors; and 4) investigate the mechanism by which 11,14,15-EETA and 11,14,15-THETA dilate smooth muscle.