Effects of electrical stimulation of the hepatic nerves ics in the liver. 3,4 Such a regulation of liver metabolism on acute liver damage were examined using isolated rat by the hepatic nerves appears to be exerted with the aid liver perfused in situ, 24 hours after intraperitoneal injecof propagation of neural signals through gap-junctional tion with D-galactosamine (800 mg/kg). The leakage of laccommunication between hepatocytes. 7,8 Hepatic nerves tate dehydrogenase (LDH) and aspartate aminotransferare, however, not only concerned in physiological reguase (AST) from the liver was used as markers of acute lations of the liver, but also likely to be involved in liver damage. In perfused livers after treatment with gapathological changes in this organ. lactosamine, nerve stimulation (20 V, 20 Hz, 2 ms) in-Although the effects of the alteration of autonomic creased the leakage of LDH and AST about 3-fold over nervous activity on liver disease have not yet been well the basal level accompanied by the decrease in flow rate,
established, it was shown in our previous reports that whereas with control livers the leakage of LDH and AST into the effluent was almost undetectable throughout the footshock stress, which increased sympathetic activity perfusion. The rapid increase in the leakage of LDH and in the liver, accelerated chemically-induced liver injury AST was observed during nerve stimulation even under in rats, 9 and that the electrical stimulation of ventroconditions where perfusion flow was maintained conmedial hypothalamus, a brain site intimately associstant. Such effects of hepatic nerve stimulation on galacated with sympathetic facilitation, also caused an exactosamine-treated livers were mimicked well by infusion erbation of acute liver damage induced by carbon of noradrenaline or phenylephrine, and inhibited by the tetrachloride. 10 These results suggest the involvement a 1 -antagonist bunazosin. Artificial reduction of perfusion of hepatic sympathetic nerves in a potentiation of liver flow alone did not induce the rapid leakage of LDH and injury.
AST into the effluent. On the other hand, low concentra-
To further establish this hypothesis, direct effects of tion (10 nmol/L) of noradrenaline only minimally decreased the flow rate but apparently augmented liver cell hepatic nerve stimulation on liver damage have been damage. The acute liver damage augmented by noradrenstudied using perfused livers after treatment with the aline was dependent on extracellular Ca 2/ . These results hepatotoxic chemical, galactosamine, that provokes indicate that in the liver, already having been injured liver injury analogous to hepatitis in rats. 11 The results slightly, the activation of hepatic sympathetic nerves and of the present study indicate the possible involvement circulating catecholamines exaggerate acute liver damof hepatic sympathetic nerves in the exaggeration of age through an action on liver cells, which depends on acute liver damage.
the influx of extracellular Ca 2/ . (HEPATOLOGY 1996; 23:524-529.)
MATERIALS AND METHODS
Materials.
All chemicals used in this study were of analyti-Sympathetic and parasympathetic innervation of the cal grade. D-Galactosamine hydrochloride, noradrenaline hy- liver is known to be involved in the regulation of liver drochloride, L-phenylephrine hydrochloride, DL-isoproterenol metabolism, such as carbohydrate metabolism, 1-4 prohydrochloride, and bovine serum albumin were purchased tein synthesis 5 and bile secretion, 6 and of hemodynamfrom Sigma (St. Louis, MO). Bunazosin hydrochloride was a generous gift from Eisai Co., Ltd. (Tokyo, Japan). Other materials were from Wako Pure Chemical (Osaka, Japan).
Animals. Male Sprague-Dawley rats (190-220 g; Clea Ja-Abbreviations: LDH, lactate dehydrogenase; AST, aspartate aminotransferpan Inc., Osaka, Japan) were kept on a 12-hour light-dark ase.