This is a proposal to investigate cytochrome P450 (P450) -derived eicosanoids as mediators of arachidonic acid (AA) -induced vasodilation and as modulators of vasoconstrictor responses and to determine their contribute to the regulation of renal function and blood pressure. In the isolated perfused kidney of the rat, an endothelium-dependent vasodilator effect of AA can be uncovered when the formation of constrictor endoperioxides is blocked by indomethacin and perfusion pressure elevated with phenylephrine. This vasodilator effect is attenuated by inhibitors of P450 and correspondingly increased and decreased by induction and depletion of P45O. Similarly, the renal vasodilator effect of bradykinin (BK) exhibits a nitric oxide-independent component that is reduced by inhibitors of P450. Moreover, the renal vasodilator effects of both AA and BK are reduced by inhibitors of K+ channels. As epoxides, except 14, 15EET, are vasodilator in the rat kidney and have been reported to activate K+ channels in vascular smooth muscle, we hypothesize that AA is converted, via P450, to an epoxide that mediates the renal vasodilator effect of AA by activating K+ channels. Thus, the first aim is to determine whether an epoxide can assume the role of an hyperpolarizing factor. Therefore, we shall correlate the renal vasodilator activity of AA to the release of epoxides, measured by GC-MS, and the effects of epoxygenase inhibitors as well as addressing the renal vascular effects of regio- and stereoisomers of EETs and the role of K+ channels.
The second aim will test the hypothesis that epoxides, released in response to vasoactive hormones, moderate vasoconstrictor effects of the stimulating hormone. Thus, 17-ODYA enhances renal vascular responses-to phenylephrine. We shall determine epoxide release to angiotensin II, arginine vasopressin and phenylephrine and test the effects of epoxides and epoxygenase inhibitors on renal vasoconstrictor responses to these hormones.
The third aim, to determine the role of epoxides in altered renal vascular responses to AA in hypertension, is based on observations that renal vasodilator responses to AA and BK are greatly enhanced in SHR versus WKY rats. Consequently, we will determine epoxide release in response to AA, renal responsiveness to epoxides and the in vivo effects of epoxygenase inhibition on renal function, blood pressure-and pressor responsiveness in hypertensive and normotensive rats. These studies will characterize a novel vasodilator system and determine its expression and functional significance in normotension and hypertension.
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