Superoxide dismutase mimetics with catalase activity reduce the organ injury in hemorrhagic shock.

Abstract

Reactive oxygen species (ROS) contribute to the multiple organ failure (MOF) in hemorrhagic shock. Here we investigate the effects of two superoxide dismutase (SOD) mimetics with catalase activity (EUK-8 and EUK-134) on the circulatory failure and the organ injury and dysfunction associated with hemorrhagic shock in the anesthetised rat. Hemorrhage (sufficient to lower mean arterial blood pressure to 45 mmHg for 90 min) and subsequent resuscitation with shed blood resulted (within 4 h after resuscitation) in a delayed fall in blood pressure, liver injury and renal dysfunction as well as pancreatic injury. Treatment of rats on resuscitation with EUK-8 (3 mg/kg i.v. bolus followed by 3 mg/kg/h i.v. infusion) significantly attenuated liver injury, renal dysfunction and pancreatic injury caused by hemorrhage and resuscitation. Administration of EUK-134 (3 mg/kg i.v. bolus followed by 3 mg/kg/h) reduced the liver injury and renal dysfunction (but not the pancreatic injury) caused by hemorrhagic shock. However, neither EUK-8 nor EUK-134 reduced the delayed circulatory failure associated with hemorrhagic shock. Thus, we propose that an enhanced formation of ROS contributes to the MOF in hemorrhagic shock, and that membrane-permeable SOD-mimetics with catalase activity, such as EUK-8 or EUK-134, may represent a novel therapeutic approach for the therapy of hemorrhagic shock.