EICOSANOIDS BLOOD VESSELS AND HYPERTENSION

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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.