The effects of early and late administration of inhibitors of inducible nitric oxide synthase in a thioacetamide-induced model of acute hepatic failure in the rat

Background/Aims: Nitric oxide (NO) is a pivotal mediator of inflammation. Its role in acute hepatic failure (AHF) is controversial. We investigated the role of NO, and the hypothesis that inhibition of inducible NO synthase (iNOS) activity would improve outcome in liver failure in rats, using the iNOS inhibitors -NAME and aminoguanidine (AMG). Methods: AHF was induced by two intraperitoneal injections of thioacetamide (TAA). Seven groups (n=10) were studied. Group I: TAA alone. Groups II, III and IV were additionally pre-treated with the NO precursor -arginine (300 mg/kg i.p.), or iNOS inhibitors AMG (100 mg/kg s.c.), or NG-nitro- -arginine methyl ester ( -NAME) (100 mg/kg s.c.) for 5 days, respectively. Groups V, VI and VII received -arginine, AMG or -NAME commencing immediately after TAA administration. Clinical and biochemical parameters were assessed serially, and mortality investigated in further similar cohorts for each regime. Results: AMG, pre-treatment but not post-treatment, significantly improved outcome including mortality (10 vs. 70%, P<0.005). The less selective iNOS inhibitor -NAME was not beneficial. Arginine pre-and post-treatment, and iNOS inhibition post-treatment, worsened clinical parameters of TAA-induced liver failure. Conclusions: Administration of the iNOS inhibitor AMG prior to insult reduces the severity of damage and improves mortality.