Epoxyeicosatrienoic acid-mediated renal vasodilation to arachidonic acid is enhanced in SHR

We tested the hypothesis that cyclooxygenase-independent vasodilation produ ced by arachidonic acid (AA) is mediated by epoxyeicosatrienoic acids (EETs ) and is blunted in the spontaneously hypertensive rat (SHR). At normal per fusion pressure (PP; 70 to 90 mm Hg), AA constricted the renal vasculature in both SHR and normotensive Wistar-Kyoto rats, an effect abolished by cycl ooxygenase inhibition, and converted to vasodilation when PP was raised to approximate to 200 mm Hg. Unexpectedly, renal vasodilation elicited by AA w as greater in the SHR at high PP; for example, 2.5, 5, and 10 mug of AA pro duced PP declines of 54+/-9, 92+/-10, and 112+/-5 mm Hg, respectively, in S HR compared with 26+/-3, 45+/-5, and 77+/-6 mm Hg in Wistar-Kyoto rats (P < 0.01). However, the renal vasodilator responses to acetylcholine (0.1 <mu> g) and sodium nitroprusside (1 mug) did not differ between strains, indicat ing that vascular responsiveness to AA was independent of intrinsic changes in vascular smooth muscle. Hyperresponsiveness of the renal vasculature to AA may be unique for the SHR, because it did not occur in Sprague-Dawley r ats with angiotensin II-induced hypertension. 5,8,11,14-Eicosatetraynoic ac id (ETYA; 4 mu mol/L), an inhibitor of all AA pathways, attenuated the vaso dilator responses to AA, as did treatment with stannous chloride, which dep letes cytochrome P450 enzymes, suggesting that a cytochrome P450 AA metabol ite mediated the renal vasodilation. N-Methylsulfonyl-12,12-dibromododec-11 -en-amide (DDMS; 2 mu mol/L), a selective omega -hydroxylase inhibitor, did not affect AA-induced vasodilation, whereas selective inhibition of epoxyg enases with either miconazole (0.3 mu mol/L) or N-methylsulfonyl-6-(2-propa rgyloxyphenyl) hexanamide (MS-PPOH; 12 mu mol/L) did, indicating that one o r more EETs were involved in the renal vasodilator action of AA at high PP. This conclusion was supported by the demonstration that AA greatly enhance d the renal efflux of EETs at high PP but not at basal PP.