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

Abstract

We tested the hypothesis that cyclooxygenase-independent vasodilation produced by arachidonic acid (AA) is mediated by epoxyeicosatrienoic acids (EETs) and is blunted in the spontaneously hypertensive rat (SHR). At normal perfusion pressure (PP; 70 to 90 mm Hg), AA constricted the renal vasculature in both SHR and normotensive Wistar-Kyoto rats, an effect abolished by cyclooxygenase inhibition, and converted to vasodilation when PP was raised to ≈200 mm Hg. Unexpectedly, renal vasodilation elicited by AA was greater in the SHR at high PP; for example, 2.5, 5, and 10 μg of AA produced PP declines of 54±9, 92±10, and 112±5 mm Hg, respectively, in SHR 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 μg) and sodium nitroprusside (1 μg) did not differ between strains, indicating 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 rats with angiotensin II-induced hypertension. 5,8,11,14-Eicosatetraynoic acid (ETYA; 4 μmol/L), an inhibitor of all AA pathways, attenuated the vasodilator responses to AA, as did treatment with stannous chloride, which depletes cytochrome P450 enzymes, suggesting that a cytochrome P450 AA metabolite mediated the renal vasodilation. N-Methylsulfonyl-12,12-dibromododec-11-en-amide (DDMS; 2 μmol/L), a selective ω-hydroxylase inhibitor, did not affect AA-induced vasodilation, whereas selective inhibition of epoxygenases with either miconazole (0.3 μmol/L) or N-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH; 12 μmol/L) did, indicating that one or more EETs were involved in the renal vasodilator action of AA at high PP. This conclusion was supported by the demonstration that AA greatly enhanced the renal efflux of EETs at high PP but not at basal PP.