The suppression by lipopolysaccharide of cytochrome P450-dependent renal vasodilation in the rat is mediated by nitric oxide.
The isolated perfused kidney of the rat was used to examine the hypothesis that lipopolysaccharide-induced nitric oxide (NO) production inhibits cytochrome P450-dependent vasodilation. The vasodilator responses to arachidonic acid and bradykinin were examined as the response to arachidonic acid is wholly dependent, and that to bradykinin partly dependent on cytochrome P450 metabolism. In endotoxin-treated rats, the vasodilator response to arachidonic acid was inhibited, and those to bradykinin and acetylcholine were enhanced. Following treatment with phenobarbitone, the inducer of certain isoforms of cytochrome P450 enzymes, the vasodilator effects of all three agonists, especially that of arachidonic acid, were amplified. Lipopolysaccharide inhibited the effect of phenobarbitone on the vasodilator effect of arachidonic acid and bradykinin but enhanced that of acetylcholine. The effect of lipopolysaccharide was antagonized by haemoglobin, a NO antagonist, and N omega-nitro-L-arginine, an inhibitor of NO synthase, suggesting that the inhibitory effect of lipopolysaccharide on arachidonic acid- and bradykinin-induced vasodilation was mediated by NO/NO synthase. N omega-Nitro-L-arginine enhanced vasodilation induced by arachidonic acid while that induced by bradykinin or acetylcholine was reduced, implying that endogenous NO inhibits vasodilator cytochrome P450 metabolites in the rat kidney. Pretreatment with dexamethasone, an inhibitor of inducible NO synthase, resulted in inhibition of the lipopolysaccharide modulation of arachidonic acid-induced vasodilation, suggesting that the inducible NO synthase is the target of the inhibitory effect of lipopolysaccharide. The inhibitory effect of lipopolysaccharide was mimicked by nitroprusside, the L-arginine-independent NO donor, and by L-arginine, the biosynthetic precursor of NO. The effect of L-arginine, but not of nitroprusside, was antagonized by N omega-nitro-L-arginine, suggesting a specific role for NO synthase in the inhibitory effect of lipopolysaccharide in the inhibition of cytochrome P450-dependent vasodilation in the rat kidney.
D000109:Acetylcholine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D006454:Hemoglobins / Q000494:pharmacology; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D019335:Nitroarginine; D009599:Nitroprusside / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012077:Renal Artery / Q000187:drug effects* / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects*
D006454:Hemoglobins; D008070:Lipopolysaccharides; D009599:Nitroprusside; D019335:Nitroarginine; D016718:Arachidonic Acid; D009569:Nitric Oxide; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D001120:Arginine; D000109:Acetylcholine; D001920:Bradykinin; D010634:Phenobarbital