Karlheinz Beckh

Regulation of liver metabolism by the hepatic nerves

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)

Regulation of oxygen consumption and microcirculation by α-sympathetic nerves in isolated perfused rat liver

In isolated rat liver perfused at constant flow with erythrocyte‐free Krebs‐Henseleit bicarbonate buffer containing 5 mM glucose and 2 mM lactate, perivascular stimulation of the hepatic nerves caused a rapid decrease of oxygen uptake, a decrease of the periportal and, after a transient rise, of the perivenous tissue p o2 of surface acini, an increase of portal pressure, and an enhancement of glucose output. Furthermore, nerve stimulation changed the intrahepatic distribution of the perfusate drastically. Infusion of trypan blue 20 s after nerve stimulation resulted in a heterogeneous staining of the liver both at the surface and in cross‐sections, while it led to a homogeneous distribution in non‐stimulated controls. It is concluded that the major component in the mechanism of the nerve‐dependent decrease of oxygen uptake is the microcirculatory change rather than a metabolic effect.

Activation of glycogenolysis and norepinephrine overflow in the perfused rat liver during repetitive perivascular nerve stimulation

During in situ perfusion of rat liver stimulation of nerve bundles around hepatic artery and portal vein resulted in an increase of glucose output, a switch from lactate uptake to output and in a decrease of portal flow. These effects remained essentially the same during 3 stimulation periods at 20 min intervals; norepinephrine overflow, however, was strongly decreased during the second and third period. The metabolic and hemodynamic effects were not correlated to norepinephrine overflow during repetitive stimulations and during stimulations in the presence of norepinephrine, phentolamine, propranolol or desipramine.

Regulation of oxygen consumption in perfused rat liver: decrease by α-sympathetic nerve stimulation and increase by the α-agonist phenylephrine

In livers perfused with Krebs-Henseleit bicarbonate buffer containing bovine red cells, 5 mM glucose and 2 mM lactate, electrical stimulation round the hepatic artery and the portal vein caused via α-receptors a decrease in oxygen consumption and portal flow, an increase in glucose output and a switch from lactate uptake to output.In livers perfused with erythrocyte- and substrate-free buffer both in a volume- or pressure-constant system stimulation of the liver nerves resulted in similar changes. Infusion of the α-agonist phenylephrine mimicked the metabolic and hemodynamic nerve effects, but led to an increase in oxygen uptake. The converse effects of α-sympathetic nerve stimulation and α-agonist infusion on oxygen consumption indicate either a different mode of action or a complex mechanism with opposing metabolic and hemodynamic components.

Modulation by insulin and glucagon of the activation of glycogenolysis by perivascular nerve stimulation in the perfused rat liver

Activation of the sympathetic nervous system results in an increase of hepatic glycogenolysis [1-3]. In intact animals pre-ganglionic stimulation of the splanchnic nerve [4-8] and post-ganglionic stimulation of the hepatic nerves [9-13] was found to increase glucose output by the liver in rabbit [4-7], cat [8-11], dog ]8,12], pig [8], sheep [8] and man [13]. In these in vivo systems it is difficult if not impossible to decide whether the nerves regulated metabolism directly or indirectly via glucagon from the endocrine pancreas and/or catecholamines from the adrenal medulla. In perfused liver preparations pre-ganglionic [14] and post-ganglionic [15,16] nerve stimulation was also shown to enhance glucose output in toad [14], mouse [15] and rat [16]. In these isolated in vitro systems the nerves must have affected metabolism directly. Thus the metabolism of carbohydrates, especially of glycogen in hepatocytes can be regulated not only by circulating hormones such as insulin and glucagon [17,18] but also by the direct autonomic innervation. The relative importance and the mutual dependence of hormonal and neuronal control is unknown. It was the object of the present investigation to study the influence of insulin and glucagon and the activation of hepatic glycogenolysis by perivascular nerve stimulation. In the in situ perfused rat liver infusion of insulin had by itself no effect on the glucose and lactate balance; yet it reduced the nerve-mediated increase of glucose output to 30% and of lactate output only slightly to -75%. Infusion of glucagon led by itself to an enhancement of glucose output and of lactate uptake. Nerve stimulation in the presence of glucagon increased the output of glucose further and reduced the enhanced lactate uptake. The results demonstrate that metabolic changes caused by the hepatic nerves can be modulated by circulating insulin and glucagon.

Inhibition of Ketogenesis by Stimulation of the Hepatic Sympathetic Nerves in the Perfused Rat Liver

In der isoliert perfundierten Leber der Ratte fuhrte Elektrostimulation der Lebernerven um Portalvene und Leberarterie neben einer Erhohung der Glucose-Abgabe, einer Umschaltung von Lactat-Aufnahme in -Abgabe und einer Flusverminderung zu einer Hemmung der Ketonkorper- freisetzung, sowohl bei der basalen als auch der Oleat- stimulierten Ketogenese. Die verminderte Ketogenese be-ruhte auf einer Hemmung der Acetoacetat- bei konstanter s-Hydroxybutyrat-Freisetzung. Gabe des L - Blockers Phentolamin hob die nach Neurostimulation beobachteten Effekte vollstandig auf. Infusion von Nitroprussid- Natrium verhinderte die durch Nervenreize ausgeloste Verminderung des Perfusionsflusses, nicht die der Ketogenese Infusion von Noradrenalin (0,1 µM) imitierte die Effekte des Nervenreizes auf die untersuchten Stoffwechsel- prozesse bei nur geringer Veranderung der Flusrate. Die Ergebnisse deuten an, das neben der Glykogenolyse auch die Ketogenese einer direkten Regulation durch das sympathische Nervensystem unterliegt, Veranderungen der Hamodynamik scheinen eine untergeordnete Rolle zu spielen.