In the isolated rat liver perfused as usual via the portal vein, joint electrical stimulation of the nerve fibers around the artery and the portal vein in the liver hilus increased glucose output, shifted lactate uptake to output, decreased urea and glutamine formation as well as ammonia uptake, reduced ketone body production, lowered oxygen uptake and reduced perfusion flow simultaneously changing the intrahepatic flow distribution; it was accompanied by an overflow of noradrenaline into the hepatic vein. All effects were mediated predominantly via alpha-receptors; they were dependent on extracellular calcium. In livers perfused both via the artery and the portal vein, separate stimulation of the plexus at the common hepatic artery or at the portal vein caused similar effects on glucose and lactate balance and on perfusion flow. Arterial stimulation caused the higher metabolic responses and alterations not only in arterial but also 'transhepaticly' in portal flow, and conversely, portal flow elicited the smaller metabolic responses and alterations in both portal and 'transhepaticly' arterial flow. If sympathetic nerve actions were blocked using alpha- and beta-antagonists, the resulting parasympathetic stimulation increased glucose uptake in the presence of insulin and antagonized the glucagon stimulated glucose release, both alone and more strongly in the presence of insulin. The sympathetic nerves may act directly at the parenchymal cells or indirectly via an overflow of neurotransmitter from the vasculature into the sinusoids or via hemodynamic changes. Experiments with the smooth muscle relaxant sodium nitroprusside and with retrograde flow indicate that neither hemodynamic changes nor noradrenaline overflow from the vasculature can play a major role in the mechanism of action of sympathetic liver nerves on glucose and lactate metabolism. Comparative studies with perfused livers of rats, guinea pigs and tupaias are in line with the view that in the rat the sympathetic nerves act via contacts with only a few periportal hepatocytes, from where the signal is propagated through gap junctions, while in guinea pig and tupaia the nerves act via contacts with almost all parenchymal cells. Sympathetic nerve stimulation of the perfused rat liver caused an increase in the activity of glycogen phosphorylase and a decrease of glycogen synthase, but left the activity of pyruvate kinase unaltered; fructose 2,6-bisphosphate and cAMP were only slightly enhanced.(ABSTRACT TRUNCATED AT 400 WORDS)