Role of guanylyl cyclase and cytochrome P-450 on renal response to nitric oxide

The present study evaluated whether inhibition of guanylyl cyclase (GC) wit h 1H-(1,2,4)oxadiazolo[4,3-a]quinoxaline-1-one (ODQ) and methylene blue (MB ) or inhibition of the renal metabolism of arachidonic acid by cytochrome P -450 (CYP450) enzymes with 1-aminobenzotriazole (ABT) and N-hydroxy-N'-(4 b utyl-2-methyl phenyl)formamidine (HET0016) alters the renal tubular and vas cular effects of a nitric oxide (NO) donor in vivo. Intrarenal infusion of ODQ or MB at a dose of 170 nmol.kg(-1).min(-1) lowered renal blood flow (RB F) by 30 and 15%, respectively; glomerular filtration rate (GFR) by 26 and 18%, respectively; and sodium and water excretion by similar to 35%. In rat s pretreated with nitro-L-arginine methyl ester (37 nmol.kg(-l).min(-1)) to block the endogenous production of NO, intrarenal infusion of the NO donor S-nitroso-N-acetylcysteine (S-NO-NAC; 50 nmol.kg(-1).min(-1)) increased RB F (18%), sodium (73%), and water excretion (61%). ODQ or MB administration blocked the effect of S-NO-NAC on RBF but not the diuretic and natriuretic response. Pretreatment of rats with ABT or HET0016 also abolished the renal vasodilatory response to the NO donor and reduced its diuretic and natriur etic effect. These results indicate that both activation of GC and inhibiti on of CYP450 enzymes contribute to the renal vascular actions of NO, wherea s the natriuretic and diuretic actions of NO appear to be largely CYP450 de pendent.