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1. The nervous control of hepatic urea and glutamine release and of ammonia uptake was studied in the rat liver perfused in situ.2. Electrical stimulation of the nerve bundles around the hepatic artery and the portal vein resulted in a reduction of urea release, of glutamine output and of ammonia uptake. At the same time, as observed before Eur. J. Biochem. 123, 521 -5261, nerve stimulation led to a decrease of portal flow as well as to an increase of glucose release and a shift of lactate uptake to output.3. Noradrenaline infusion mimicked the nerve-dependent metabolic and hemodynamic changes in a first approximation only at the highly unphysiological concentration of 0.1 pM. It was without effect at 0.01 pM, which might be reached in the sinusoids as a result of overflow from the vasculature.4. In the presence of sodium nitroprusside nerve stimulation no longer reduced urea output, glutamine release and ammonia uptake or portal flow, yet it still increased glucose and lactate release.5. Phentolamine clearly reduced the alterations after nervous stimulation of urea output, ammonia uptake and portal flow, while propranolol was essentially not effective. The nerve-stimulation-dependent reduction of glutamine release was almost abolished in the presence of phentolamine and lowered to 50% by propranolol.6. Glucagon stimulated urea output but had no influence on glutamine release, ammonia uptake and portal flow. Nerve stimulation antagonized the glucagon-stimulated urea release.7. The present results suggest that in the perfused liver wsympathetic hepatic nerves regulate urea release, glutamine output and ammonia uptake predominantly by an indirect mechanism via hemodynamic alterations, but glucose release by a direct mechanism also in the absence of circulatory changes.The liver is innervated by sympathetic and parasympathetic nerves [l-31. It was shown previously that in the isolated perfused rat liver electrical stimulation of the nerve bundles around the hepatic artery and the portal vein resulted in an increase of glucose output, a switch from lactate uptake to output and a decrease of portal flow [4] combined with a change of the intrahepatic microcirculation [5, 61, a reduction of oxygen uptake [5,7] and an overflow of noradrenaline into the hepatic vein [8]. All nerve actions were predominantly aadrenergic. It was observed recently that hepatic nerve stimulation decreased ketogenesis [9]. Possible effects of nerve stimulation on hepatic 'nitrogen' metabolism have not been studied so far either in vivo or in the isolated perfused organ. Therefore it was the object of the present investigation to clarify whether the hepatic nerves can also regulate urea, glutamine and ammonia metabolism besides glucose and lactate exchange. A preliminary report on some of the findings has appeared previously [lo].

In rat liver perfused in situ stimulation of the nerve plexus around the hepatic artery and the portal vein caused an increase in glucose output and a shift from lactate uptake to output. The effects of nerve stimulation on some key enzymes, metabolites and effectors of carbohydrate metabolism were determined and compared to the actions of glucagon, which led to an increase not only of glucose output but also of lactate uptake.1. Nerve stimulation caused an enhancement of the activity of glycogen phosphorylase a to 300% and a decrease of the activity of glycogen synthase I to 40%, while it left the activity of pyruvate kinase unaltered. Glucagon, similarly to nerve action, led to a strong increase of glycogen phosphorylase and to a decrease of glycogen synthase; yet in contrast to the nerve effect it lowered pyruvate kinase activity clearly.2. Nerve stimulation increased the levels of glucose 6-phosphate and of fructose 6-phosphate to 200% and 170%, respectively; glucagon enhanced the levels to about 400% and 230%, respectively. The levels of ATP and ADP were not altered, those of AMP were increased slightly by nerve stimulation. 3.Nerve stimulation enhanced the levels of the effectors fructose 2,6-bisphosphate and cyclic AMP only slightly to 140% and 125%, respectively; glucagon lowered the level of fructose 2,6-bisphosphate to 15% and increased the level of cyclic AMP to 300%.4. In calcium-free perfusions the metabolic responses to nerve stimulation showed normal kinetics, if calcium was re-added 3 min before, but delayed kinetics, if it was re-added 2 min after the onset of the stimulus. The delay may be due to the time required to refill intracellular calcium stores. The hemodynamic alterations dependent on extracellular calcium were normal in both cases.The activation of glycogen phosphorylase, the inhibition of glycogen synthase and the increase of glucose 6-phosphate can well explain the enhancement of glucose output following nerve stimulation. The unaltered activity of pyruvate kinase and the marginal increase of fructose 2,6-bisphosphate cannot be the cause of the nervestimulation-dependent shift from lactate uptake to output. The very slight increase of the level of cyclic AMP after nerve stimulation cannot elicit the observed activation of glycogen phosphorylase. This finding and the delayed metabolic response of calcium-depleted/repleted livers to nerve stimulation suggest that activation of the enzyme after nerve stimulation is mediated by an increase of cytosolic calcium, which would be in accord with the observed a-mechanism.

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