EICOSANOIDS, VASCULAR TONE AND BLOOD PRESSURE

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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.