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 analyz e 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 pretrea tment for the constitutive NO synthase (NOS3). In both groups, portal flow, bile flow, bile secretion, and the sinusoidal bile acid uptake w ere 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 mu mol/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 o f NO synthesis via the structural analogue (N-G-monomethyl-L-arginine [L-NMMA]) changed cholestatic and glycogenolytic effects caused by nor epinephrine, Only the sinusoidal bile acid uptake was reduced followin g increased NO formation. Thus, we conclude that endogenous NO formati on prevents alpha-catecholaminergic-increased intrahepatic resistance without a major influence on the metabolic effects.