S-15176 reduces the hepatic injury in rats subjected to experimental ischemia and reperfusion

The protective effect of N-[(3,5-di-tertiobutyl-4-hydroxy-1-thiophenyl)]-3- propyl-N'-(2,3,4-trimethoxybenzyl)piperazine (S-15176) on liver injury indu ced by warm ischemia-reperfusion was investigated using a rat model. Animal s were subjected to 2 h of ischemia followed by different reperfusion times . Hepatocyte integrity was assessed by measuring plasma alanine and asparta te aminotransferase activities, and by determining reduced and oxidized glu tathione in plasma and bile. Hepatocyte function was quantitated by determi ning bile flow and liver ATP content. Ischemia-reperfusion resulted in seve re hepatic injury involving a huge increase in alanine and aspartate aminot ransferase activities, a drop in ATP content, and a decrease in bile flow. Plasma and bile reduced (GSH) and oxidized (GSSG) glutathione concentration s were inversely related: plasma levels increased when biliary levels decre ased. This was associated with a decrease in animal survival (-34%). S-1517 6 pretreatment (1.25, 2.5, 5 or 10 mg kg(-1) day(-1)) improved the survival rate and limited tissue damages in a dose-dependent manner. The pretreatme nt also reduced the aminotransferase leakage from hepatocytes and the incre ase in plasma glutathione levels. In addition, normalization of the plasma GSSG/GSH ratio, a good index of an oxidative stress, was observed in groups treated with the higher dosage, suggesting that the antioxidant properties demonstrated for the compound in vitro (IC50 = 0.3 mu M towards lipid pero xidation) could play a role in its protective effect. S-15176 pretreatment also protected the organ from the drop in ATP levels. At the higher dose, A TP content was maintained at a level almost 86% of the sham-operated group after 60 min of reperfusion. This was associated with a restoration of the biliary flow. These data suggest that S-15176 may be a useful drug in liver surgery to prevent ischemia-reperfusion injury. (C) 2000 Elsevier Science B.V. All rights reserved.