Role of guanylyl cyclase and cytochrome P-450 on renal response to nitric oxide.
The present study evaluated whether inhibition of guanylyl cyclase (GC) with 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 butyl-2-methyl phenyl)formamidine (HET0016) alters the renal tubular and vascular 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 (RBF) by 30 and 15%, respectively; glomerular filtration rate (GFR) by 26 and 18%, respectively; and sodium and water excretion by approximately 35%. In rats pretreated with nitro-L-arginine methyl ester (37 nmol. kg(-1). 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 RBF (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 natriuretic effect. These results indicate that both activation of GC and inhibition of CYP450 enzymes contribute to the renal vascular actions of NO, whereas the natriuretic and diuretic actions of NO appear to be largely CYP450 dependent.
López
B
B
Departamento de Fisiología, Facultad de Medicina, Campus de Espinardo, 30100-Murcia, Spain.
Moreno
C
C
Salom
M G
MG
Roman
R J
RJ
Fenoy
F J
FJ
D000111:Acetylcysteine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000578:Amidines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006162:Guanylate Cyclase / Q000378:metabolism*; D007263:Infusions, Parenteral; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009318:Natriuresis / Q000187:drug effects; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000494:pharmacology*; D010069:Oxadiazoles / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology
C116907:1H-(1,2,4)oxadiazolo(4,3-a)-quiloxalin-1-one; D000578:Amidines; D004791:Enzyme Inhibitors; C000708209:HET0016; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D014230:Triazoles; C033020:1-aminobenzotriazole; D009569:Nitric Oxide; C024940:S-nitroso-N-acetylcysteine; D003577:Cytochrome P-450 Enzyme System; D006162:Guanylate Cyclase; D008751:Methylene Blue; D019331:NG-Nitroarginine Methyl Ester; D000111:Acetylcysteine