Endotoxin-induced nitric oxide synthesis in the perfused rat liver: effects of L-arginine and ammonium chloride.
We used the single-pass-perfused rat liver model to study short-term regulation of endotoxin-inducible nitric oxide synthesis by following the release of nitrite and nitrate, the oxidation products of nitric oxide, into the effluent perfusate. In endotoxin-pretreated livers, the basal nitrite+nitrate release was 5.3 +/- 1.2 nmol.gm liver-1.min-1. Nitrite and nitrate release was stimulated by L-arginine in a dose-dependent and saturable fashion. Maximal nitrite+nitrate release with 1 mmol/L L-arginine infused to the influent perfusate was 10.2 +/- 1.1 nmol.gm liver-1.min-1, with a half-maximal effect at 53 mumol/L L-arginine. In the absence of molecular oxygen, nitric oxide synthesis was inhibited. Ammonium chloride infusion also stimulated nitrite and nitrate release to a maximal rate of 9.2 +/- 0.8 nmol.gm liver-1.min-1 with half-maximal effects at 60 mumol/L ammonium chloride. Ammonium chloride-stimulated nitrite and nitrate release was abolished when urea synthesis was inhibited by bicarbonate-free liver perfusion. Citrulline and ornithine (200 mumol/L each) were without effect on nitrite and nitrate release. L-Nitroarginine methyl ester inhibited both, L-arginine-and ammonium chloride-induced nitrite and nitrate release. Stimulation of nitric oxide synthesis by L-arginine and ammonium chloride addition (1 mmol/L each) was accompanied by a threefold-to-fourfold increase of cyclic GMP release into the effluent perfusate. In livers of endotoxin-pretreated rats the urea production from L-arginine was higher than that in untreated livers, suggesting induction of an L-arginine transport system in hepatocytes by endotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)
Wettstein
M
M
Department of Internal Medicine, University of Freiburg, Germany.
Gerok
W
W
Häussinger
D
D
D000643:Ammonium Chloride / Q000494:pharmacology*; D000818:Animals; D001120:Arginine / Q000378:metabolism / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*; D010100:Oxygen / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D012486:Salmonella typhimurium; D014508:Urea / Q000037:antagonists & inhibitors / Q000378:metabolism
D004731:Endotoxins; D000643:Ammonium Chloride; D009569:Nitric Oxide; D014508:Urea; D001120:Arginine; D006152:Cyclic GMP; D010100:Oxygen