Eicosanoids, Vascular Tone and Blood Pressure

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DESCRIPTION (provided by applicant): Endothelial cells (EC) release factors that reduce vascular tone and counteract vasoconstriction including nitric oxide (NO) and PGI2. In the rabbit aorta, endothelium-dependent relaxations to acetylcholine are reduced, but not blocked, by inhibitors of NO and PG synthesis and are attributed to endothelium-derived hyperpolarizing factor (EDHF). They are blocked by inhibitors of phospholipases, lipoxygenases (LOs) and/or cytochrome P450s (CYPs). Arachidonic acid (AA) also causes endothelium-dependent relaxations and hyperpolarizations that are blocked by LO and CYP inhibitors, high [K]o and apamin. Thus, these relaxations and hyperpolarizations are mediated by a LO metabolite of AA. We have identified 2 vasodilator LO metabolites of AA as 11(R),12(S),15(S)- trihydroxy-eicosatrienoic acid (11,12,15-THETA) and a novel dihydro-furan,15-hydroxy-11,14- epoxyeicosatrienoic acid (15-H-11,14-EETA). 11,12,15-THETA relaxes rabbit aorta, hyperpolarizes aortic smooth muscle cells (SMCs), activates a SMC apamin-sensitive K channel and is released by acetylcholine. In young rabbits, the synthesis of these LO metabolites is elevated and treatment with a LO inhibitor increases blood pressure. These LO metabolites may be important in regulating blood pressure and blood flow in young animals and mediating relaxations to acetylcholine and other agonists in older animals. The proposed studies will test the hypothesis that arachidonic acid is metabolized by the endothelium to vasodilator eicosanoids, including 11,12,15-THETA and 15-H- 11,14-EETA, that regulate vascular tone, mediate the action of vasoactive hormones and regulate blood pressure. The proposed experiments will: 1. Compare the natural and synthetic 15-H-11,14- EETA and 11,12,15-THETA for vasorelaxation, chromatographic behavior and mechanism of action and test the hypothesis that 15-H-11,14-EETA and 11,12,15-THETA relax and hyperpolarize SMCs by activating K channels; 2. Characterize the vascular consequences of the co-release of K, 11,12,15- THETA and 15-H-11,14-EETA and test the hypothesis that the co-release of K enhances the relaxations to the THETA and HEETA; 3. Characterize the biosynthetic pathway(s) for 15-H-11,14- EETA and 11,12,15-THETA synthesis and metabolism in aorta, SMCs and ECs; and 4. Investigate the age-dependent changes in the THETA and HEETA synthesis and changes in blood pressure in response to LO inhibition and test the hypothesis that endogenous LO metabolites are important regulators of blood pressure in young rabbits.