nitroarginine and Chemical-and-Drug-Induced-Liver-Injury

Little is known about the changes in hepatic blood flow associated with acute hepatic injury. The aim of this study was to investigate the effect of nitric oxide (NO) on hepatic blood flow and the severity of hepatic injury in rats with carbon tetrachloride (CCl4)-induced acute hepatic injury.. Rats were pretreated with CCl4 to induce acute hepatic injury. Hepatic blood flow was measured using a radioactive microsphere method. The role of NO in the regulation of hepatic blood flow and the severity of hepatic injury was investigated by administering NG-nitro-L-arginine (L-NNA) and aminoguanidine (AG). Plasma nitrite/nitrate levels, hepatic NO synthase (NOS) activity, and expression of hepatic NOS messenger RNA (mRNA) were measured, and histological examinations were performed.. Hepatic arterial and portal venous blood flow was increased significantly by CCl4, without any change in mean arterial pressure or cardiac output. L-NNA and AG dose-dependently decreased hepatic arterial blood flow, with the highest dose resulting in complete blockade of hepatic arterial dilation, but failed to change portal venous blood flow. Histologically, administration of AG aggravated the hepatic injury in CCl4-treated rats. Plasma nitrite/nitrate levels and hepatic NOS activity were increased significantly by CCl4 treatment. Inducible NOS mRNA was detected in CCl4-treated rats but not in the controls.. The results of this study suggest that the increased hepatic arterial blood flow in CCl4-induced acute hepatic injury is mediated by excessive NO production and up-regulated by inducible NOS, which plays a role in reducing hepatic injury.

Topics: Acute Disease; Animals; Carbon Tetrachloride; Chemical and Drug Induced Liver Injury; Enzyme Inhibitors; Guanidines; Hepatic Artery; Liver; Liver Circulation; Liver Diseases; Male; Nitrates; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitrites; Nitroarginine; Rats; Rats, Sprague-Dawley; Regional Blood Flow; RNA, Messenger

Intravascular coagulation is involved in the development of certain types of liver injury, including that induced by dimethylnitrosamine. Nitric oxide inhibits platelet aggregation and adhesion; however, its role in protecting against intravascular coagulation has not been clarified. We therefore investigated the effect of blocking the production of NO in a dimethylnitrosamine-induced liver injury model. Wistar male rats received dimethylnitrosamine (50 micrograms/kg) intraperitoneally, and were treated with N omega-nitro-L-arginine, an inhibitor of nitric oxide synthase, or N omega-nitro-D-arginine, an inactive isomer. Each arginine derivative (40 mg/kg) was injected intraperitoneally every 6 h. Twenty-four hours after dimethyl-nitrosamine administration, we observed a significant increase in the serum level of alanine aminotransferase in the N omega-nitro-L-arginine group compared with the N omega-nitro-D-arginine group. The N omega-nitro-L-arginine-treated group also exhibited a significant reduction in platelet count, a prolongation of prothrombin time, and an elevation of plasma soluble fibrin monomer complex levels. Sinusoidal congestion, intravascular coagulation, and coagulation necrosis around the central veins were prominent in the N omega-nitro-L-arginine group. In conclusion, the inhibition of nitric oxide production exacerbated the hepatic damage induced by dimethylnitrosamine, mediated by the acceleration of intravascular coagulation.

Topics: Animals; Arginine; Chemical and Drug Induced Liver Injury; Dimethylnitrosamine; Enzyme Inhibitors; Male; Microcirculation; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Wistar