Norepinephrine–Induced Cholestasis in the Isolated Perfused Rat Liver Is Secondary to Its Hemodynamic Effects

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Abstract
In this study we examined the effect of pharmacological doses of various α–adrenergic agents on hepatic portal perfusion, organic anion uptake and bile secretion using the isolated perfused rat liver. Addition of norepinephrine at portal perfusate concentrations ranging from 0.01 to 100 μmol/L induced a dose–related increase in portal pressure with a twofold increment at the highest concentration. This was accompanied by an inhibition of hepatocellular uptake of taurocholate by 16.8% ± 1.8% and of sulfobromophthalein (BSP) by 32.9% ± 3.0% compared with controls. Moreover, a 22.5% ± 3% decrease in bile flow rate and a 22.8% ± 4% inhibition of biliary excretion of taurocholate were observed. Addition of other α–adrenergic agonists (epinephrine, dopamine and phenylephrine) at similar concentrations produced the same hepatic effects as observed with norepinephrine. During infusion of these α–adrenergic agents, trypan blue infusion revealed a patchy perfusion pattern of the liver surface compared with the homogeneously stained organs in controls. The hemodynamic alterations could be confirmed by electron microscopy examination that demonstrated that increased portal pressure produced by norepinephrine was associated with sinusoidal shunting. All hemodynamic, metabolic and biliary changes induced by norepinephrine could be entirely prevented by concomitant infusion of the α–antagonist phentolamine, thus indicating that norepinephrineinduced hepatic effects were mediated by α–receptors. In contrast, simultaneous addition of papaverine, an unspecific vasodilator, prevented the hemodynamic and the biliary changes of norepinephrine, but failed to modify the metabolic effects of the drug. These results indicate that norepinephrine–induced cholestasis in the isolated perfused rat liver accompanies the hemodynamic changes, thus supporting the concept that the drug has no direct effect on hepatic bile formation. (Hepatology 1990;12:314-321).