Simvastatin for rats with thioacetamide-induced liver failure and encephalopathy.
OBJECTIVE
Nitric oxide (NO) inhibition aggravates hepatic damage and encephalopathy and increases mortality in rats with thioacetamide (TAA)-induced acute liver failure. Statins enhance NO synthase expression beyond their lipid-lowering capability, but the impact on encephalopathy remains unexplored. The aim of this study was to assess the effects of simvastatin on rats with TAA-induced acute liver damage and hepatic encephalopathy.


METHODS
Sprague-Dawley rats received TAA (350 mg/kg/day) or normal saline (NS) by intraperitoneal injection for 3 consecutive days. Two days before injections, each group was divided into three subgroups, taking (i) distilled water; (ii) simvastatin (20 mg/kg/day); or (iii) simvastatin plus N(G)-nitro-l-arginine methyl ester (L-NAME, 25 mg/kg/day) by oral gavage for 5 days. On the fifth day, severity of encephalopathy was assessed and plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin and ammonia were measured.


RESULTS
The TAA subgroups showed higher ALT, AST, bilirubin and ammonia levels and lower motor activity counts as compared with the NS subgroups. Among the TAA-treated subgroups, rats with simvastatin treatment exerted higher motor activity counts and survival rate (P = 0.043), and a trend of lower ALT, AST, bilirubin and ammonia levels than those receiving saline. All rats that underwent simvastatin plus L-NAME treatment died during or after TAA injections.


CONCLUSIONS
Simvastatin improved encephalopathy and survival in TAA-administered rats. The beneficial effect was offset by L-NAME, suggesting the role of NO in liver damage and encephalopathy.
Huang
Hui-Chun
HC
Division of Gastroenterology, Taipei Veterans General Hospital, and National Yang-Ming University School of Medicine, Taipei, Taiwan.
Wang
Sun-Sang
SS
Lee
Fa-Yauh
FY
Chan
Cho-Yu
CY
Chang
Full-Young
FY
Lin
Han-Chieh
HC
Chu
Chi-Jen
CJ
Chen
Yi-Chou
YC
Lee
Shou-Dong
SD
D000410:Alanine Transaminase / Q000097:blood; D000641:Ammonia / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001663:Bilirubin / Q000097:blood; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006501:Hepatic Encephalopathy / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D019821:Simvastatin / Q000494:pharmacology*; D013853:Thioacetamide; D013997:Time Factors
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009566:Nitrates; D009573:Nitrites; D013853:Thioacetamide; D009569:Nitric Oxide; D000641:Ammonia; D019821:Simvastatin; D019001:Nitric Oxide Synthase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001663:Bilirubin; D019331:NG-Nitroarginine Methyl Ester