CYTOCHROME-P-450-DEPENDENT VASODILATOR RESPONSES TO ARACHIDONIC-ACID IN THE ISOLATED, PERFUSED KIDNEY OF THE RAT

Pretreatment of phenylephrine (0.5-mu-M)-preconstricted, isolated perfused kidneys of the male rat with indomethacin (2.8-mu-M) or BM 13.177 (20-mu-M) abolished the vasoconstrictor response to arachidonic acid (AA), uncovering a vasodilator response. BW 755C (25-mu-M), a dual cyclooxygenase/lipoxygenase inhibitor, did not modify the vasodilator effect of AA, whereas 5,8,11,14-eicosatetraynoic acid (10-mu-M), which blocks all pathways of AA metabolism, abolished AA-induced vasodilation, thus suggesting the involvement of nonlipoxygenase AA metabolites. Clotrimazole (0.7-mu-M) and 7-ethoxyresorufin (1-mu-M), 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-mu-g). 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.