Although trauma-hemorrhage produces tissue hypoxia, systemic inflammatory response and organ dysfunction, the mechanisms responsible for these alterations are not clear. Using a potent selective inducible NO synthase (iNOS) inhibitor, N-(3-[aminomethyl] benzyl) acetamidine (1400W), and a non-selective NOS inhibitor, N (G)-nitro-L-arginine methyl ester (L-NAME), we investigated whether iNOS plays any role in producing hepatic injury, inflammation and changes of protein expression following trauma-hemorrhage. To investigate this, male Sprague-Dawley rats were subjected to midline laparotomy and hemorrhagic shock (mean blood pressure 35-40 mmHg for ~90 min) followed by fluid resuscitation. Animals were treated with either vehicle (DMSO) or 1400W (10 mg/kg BW, intraperitoneally), or L-NAME (30 mg/kg, iv) 30 min before resuscitation and sacrificed 2 hrs after resuscitation. Trauma-hemorrhage/resuscitation induced a marked hypotension and increase in markers of hepatic injury (i.e., plasma -GST, tissue myeloperoxidase [MPO] activity and nitrotyrosine formation). Hepatic expression of iNOS, HIF-1, ICAM-1, IL-6, TNF- and neutrophil chemoattractant (CINC-1 and MIP-2) protein levels were also markedly increased following trauma-hemorrhage/resuscitation. Administration of the iNOS inhibitor 1400W significantly attenuated hypotension and expression of these mediators of hepatic injury induced by trauma-hemorrhage/resuscitation. However, administration of L-NAME could not attenuate hepatic dysfunction and tissue injury mediated by trauma-hemorrhage, although it improved MBP as did 1400W. These results indicate that increased expression of iNOS following trauma-hemorrhage plays an important role in the induction of hepatic damage