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.
OBJECTIVE
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 L-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 L-arginine (300 mg/kg i.p.), or iNOS inhibitors AMG (100 mg/kg s.c.), or N(G)-nitro-L-arginine methyl ester (L-NAME) (100 mg/kg s.c.) for 5 days, respectively. Groups V, VI and VII received L-arginine, AMG or L-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 L-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.
Rahman
Tony Manibur
TM
Department of Medicine-Hepatology, Royal Free and University College Medical School, Royal Free Campus, Rowland Hill Street, Hampstead, London NW3 2PF, UK.
Hodgson
Humphrey Julian Francis
HJ
D000641:Ammonia / Q000097:blood; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology; D006501:Hepatic Encephalopathy / Q000188:drug therapy / Q000401:mortality; D008099:Liver / Q000201:enzymology / Q000473:pathology; D017114:Liver Failure, Acute / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008111:Liver Function Tests; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017208:Rats, Wistar; D013853:Thioacetamide
D004791:Enzyme Inhibitors; D006146:Guanidines; D013853:Thioacetamide; D009569:Nitric Oxide; D000641:Ammonia; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester