Role of Nitric Oxide in Endotoxin-Induced Hepatic Microvascular Dysfunction in Rats Chronically Fed Ethanol

Abstract

Nitric oxide (NO) appears to be involved in the pathogenesis of endotoxin-induced liver injury. However, little is known about how NO acts on the hepatic microcirculation, especially in alcohol-fed animals. We examined the roles of NO in endotoxin-induced hepatic microvascular dysfunction in control and ethanol-fed rats. One lobe of the liver was observed with an intravital microscope. Flow velocity of fluorescein isothiocyanate-labeled erythrocytes in sinusoids was measured with an off-line velocimeter. Portal pressure and mean arterial pressure also were measured. After administration of endotoxin to control, the flow velocity decreased after 30 min. Portal pressure increased after 45 min. However, in ethanol-fed rats, both the flow velocity and portal pressure temporarily increased in the early phase. Thereafter, the flow velocity decreased and portal pressure increased. At 30 min after administration of the endotoxin, pretreatment with 10 mg/kg of an NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA), enhanced the endotoxin-induced decrease in the velocity of erythrocytes in the midzonal region of both control and ethanol-fed rats. Although 0.5 mg/kg of L-NMMA enhanced the endotoxin-induced reduction of erythrocyte velocity in the midzonal region of ethanol-fed rats, L-NMMA enhanced the endotoxin-induced reduction of erythrocyte velocity in the pericentral region of control rats. At 60 min after the endotoxin administration, L-NMMA did not affect the endotoxin-induced decrease of erythrocyte velocity in either control or ethanol-fed rats. Although 10 mg/kg of L-NMMA increased mean arterial pressure both in control and ethanol-fed rats, 0.5 mg/kg of L-NMMA did not change mean arterial pressure in either control or ethanol-fed rats. These results suggest that NO is involved in endotoxin-induced hepatic microvascular dysfunction, which may contribute to the sequential liver injury, especially in alcohol-fed animals.