Inhibitors of inducible nitric oxide (NO) synthase are more effective than an NO donor in reducing carbon-tetrachloride induced acute liver injury

Abstract

The exact functional role of nitric oxide (NO) in liver injury is currently a source of controversy. NO is enzymatically synthesized by nitric oxide synthase (NOS). In this study, we assessed the role of inducible NOS (iNOS) in carbon tetrachloride (CCl4)- induced acute liver injury using inhibitors of iNOS, and wani thN Oor dwointhoor.utA thdeu litN IOCSR imnhiicbei tworesr e(5 i-nmjeecthteydl iswoitthhi oCuCrela4 hemisulfate [SMT] and l-N6-(1-iminoethyl)-lysine [LNIL]) and an NO donor (Sodium Nitroprusside [SNP]). Blood and liver tissues were collected for analysis. Immunohistochemistry (IHC), serum alanine aminotransferase (ALT), serum total 8-isoprostane analysis, RT-PCR, Western Blotting (WB) and EMSA were done. Our results showed increased levels of ALT, andecmroinsiiss,t rtoattaiol n8.- iisNopOroSs tiannhei baintdo rnsi tarontdy rSosNinPe aabftreorg CaCteld4 these effects but the effect was more pronounced with SMT and L-NIL. RT-PCR, WB and IHC in CCl4–treated mice demonstrated upregulation of TNF-a, iNOS, and COX-2. The administration of iNOS inhibitors with CCl4 diminished the expression of these proinflammatory mediators. NF-kB was also upregulated in CCl4-treated mice and was reversed in mice pretreated with iNOS inhibitors. SNP pretreated mice also showed a lower expression of COX-2 when compared with CCl4 treated mice but TNF-a, iNOS and NF-kB activity were unaffected. We propose that a high level of nitric oxide is associated with CCl4-induced acute liver injury and the liver injury can be ameliorated by decreasing the NO level with iNOS inhibitors and an NO donor with the former more effective in reducing CCl4-induced liver injury.