In isolated rat liver single pass perfused via both the hepatic artery (80 mmHg, 30% flow) and the portal vein (10 mmHg, 70% flow), norepinephrine (NE) was infused either singly or jointly via the hepatic artery or the portal vein in the absence or presence of the alpha 1-blocker prazosin or the beta 2-blocker butoxamine. Arterial NE caused an increase in glucose output and a shift from lactate uptake to release that was slower in onset and smaller in peak height but longer in duration than the alterations affected by portal NE. The sum of the metabolic changes by arterial and portal NE was not equal to the changes by jointly applied arterial plus portal NE. The metabolic alterations by arterial NE were mediated via alpha 1-receptors, with beta 2-receptors probably having a permissive function, but those by portal NE were transmitted only via alpha 1-receptors. Arterial NE caused a strong decrease in arterial flow and contralaterally also a smaller reduction of portal flow. Portal NE decreased portal flow but did not significantly influence arterial flow. The sum of the alterations in flow by arterial and portal NE was not equal to the changes by jointly applied NE. The hemodynamic alterations in the artery by arterial NE were the results of actions via alpha 1-receptors and counteractions via beta 2-receptors, whereas the changes in the portal vein by arterial NE and portal NE were mediated via alpha 1-receptors. About 65% of arterial and only 30% of portal NE was extracted during a single path. The results indicate that the hepatic artery and the portal vein can function as independent sites of hormonal signal input, which interact by complex but still undefined mechanisms in the regulation of metabolism and hemodynamics.