Cytochrome P-450-dependent vasodilator responses to arachidonic acid in the isolated, perfused kidney of the rat.
نویسندگان
چکیده
Pretreatment of phenylephrine (0.5 microM)-preconstricted, isolated perfused kidneys of the male rat with indomethacin (2.8 microM) or BM 13.177 (20 microM) abolished the vasoconstrictor response to arachidonic acid (AA), uncovering a vasodilator response. BW 755C (25 microM), a dual cyclooxygenase/lipoxygenase inhibitor, did not modify the vasodilator effect of AA, whereas 5,8,11,14-eicosatetraynoic acid (10 microM), which blocks all pathways of AA metabolism, abolished AA-induced vasodilation, thus suggesting the involvement of nonlipoxygenase AA metabolites. Clotrimazole (0.7 microM) and 7-ethoxyresorufin (1 microM), both considered to be specific inhibitors of the cytochrome P-450 monooxygenase enzymes, inhibited the vasodilator effect, suggesting that AA-induced renal vasodilation is mediated by one or more cytochrome P-450-derived AA metabolites. None of these interventions affected the vasodilator responses to acetylcholine (100 ng) and nitroprusside (1 microgram). Denudation of the endothelium with CHAPS (10 mg/l) reduced the vasodilator responses to AA, suggesting a requirement of an intact endothelium, whereas inhibition of guanylate cyclase with methylene blue (10(-4) M) was without effect, suggesting that cGMP was not involved in the vasodilator response to AA. The AA-induced renal vasodilation was accompanied by the generation of biologically active material or materials released into the renal effluent, which relaxed endothelium-intact and endothelium-denuded rings of isolated aorta and mesenteric and celiac arteries of the rabbit. These results suggest that in the rat kidney, AA is metabolized by endothelial cytochrome P-450-dependent enzymes to vasodilator metabolites.
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عنوان ژورنال:
- Circulation research
دوره 68 4 شماره
صفحات -
تاریخ انتشار 1991