Nitric oxide formation lowers norepinephrine-induced intrahepatic resistance without major effects on the metabolism in the perfused rat liver.
Nitric oxide (NO) and norepinephrine are potent vasoactive agents that are involved in the control of portal blood flow. We have studied NO and norepinephrine in a non-recirculated rat liver perfusion to analyze their influence on portal flow and hepatic metabolism. Animals were either pretreated with endotoxin (4 hours; 10 mg/kg intraperitoneally) to activate the inducible NO synthase (NOS2), or used without pretreatment for the constitutive NO synthase (NOS3). In both groups, portal flow, bile flow, bile secretion, and the sinusoidal bile acid uptake were reduced by norepinephrine with a simultaneous increase of glucose and lactate output. The addition of the substrate for NO synthesis, L-arginine (0.5 mmol/L), to the perfusate markedly inhibited the effect of 0.1 micromol/L norepinephrine on portal flow from -2.6 +/- 0.32 to 0.3 +/- 0.1 mL/g/10 min in endotoxin-treated animals, and from -2.9 +/- 0.45 to 0.77 +/- 0.29 mL/g/10 min in the untreated ones. In contrast, neither NO formation after L-arginine supplementation nor inhibition of NO synthesis via the structural analogue (N(G)-monomethyl-L-arginine [L-NMMA]) changed cholestatic and glycogenolytic effects caused by norepinephrine. Only the sinusoidal bile acid uptake was reduced following increased NO formation. Thus, we conclude that endogenous NO formation prevents alpha-catecholaminergic-increased intrahepatic resistance without a major influence on the metabolic effects.
Weidenbach
H
H
Department of Internal Medicine, University of Ulm, Germany.
Nussler
A K
AK
Shu
Z
Z
Adler
G
G
Beckh
K
K
D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001646:Bile / Q000187:drug effects; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D005947:Glucose / Q000378:metabolism; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D017082:Portal Pressure; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D019323:omega-N-Methylarginine / Q000494:pharmacology
D008070:Lipopolysaccharides; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019344:Lactic Acid; D001120:Arginine; D019001:Nitric Oxide Synthase; D005947:Glucose; D009638:Norepinephrine