Abstract

There is good evidence that haemorrhagic shock is associated with the generation of reactive oxygen species (ROS) including superoxide anions and hydrogen peroxide [1]. It has been suggested that the activation of PARP plays a role in the cardiovascular failure associated with haemorrhagic shock [2], but there is little information regarding the role of PARP in the pathophysiology of the organ dysfunction/injury associated with haemorrhagic shock. Here we investigate the effects of several PARP inhibitors on the circulatory failure and the organ injury and dysfunction caused by severe haemorrhage and resuscitation in the anaesthetised rat. Male Wistar rats were anaesthetised with thiopentone sodium (120 mg/kg i.p.) and instrumented for the measurement of mean arterial pressure and heart rate. Haemorrhage (to lower blood pressure to ~50 mmHg for 90 min) and resuscitation (with blood and an equivalent volume of Ringers Lactate solution), resulted within 4 h in a delayed fall in blood pressure as well as in renal dysfunction, liver injury and dysfunction, pancreatic injury, and neuromuscular injury. Treatment of rats subjected to haemorrhage and resuscitation with the PARP inhibitors 3-aminobenzamide (10 mg/kg), nicotinamide (10 mg/kg), or 1,5 dihydroxyisoquinoline (ISO, 3 mg/kg) attenuated the multiple organ injury and dysfunction caused by haemorrhage and resuscitation. However, treatment with the vehicle for ISO (10% v/v DMSO) had a similar effect. As the beneficial effects of ISO (the most potent and specific PARP inhibitor) were, in part, due to its vehicle, further studies with the potent, specific and water soluble inhibitor of PARP activity, 5-aminoisoquinolinone (5-AIQ), were performed to ensure that the reduction by the agents of the multiple organ failure in haemorrhagic shock is indeed due to their ability to inhibit PARP activity. Administration (5 min prior to resuscitation of 5-AIQ (0.03 mg/kg i.v, or 0.3 mg/kg i.v.) reduced (in a dose-related fashion) the multiple organ injury and dysfunction, but did not affect the circulatory failure, associated with haemorrhagic shock. In conclusion, this study demonstrates that chemically distinct inhibitors of PARP activity attenuate the renal dysfunction, the hepatocellular injury and the pancreatic injury associated with severe haemorrhage and resuscitation. References: 1.Redl H, Gasser H, Schlag G, Marzi I: Involvement of oxygen radicals in shock related cell injury. Br Med Bull, 1993; 49: 556-65 2.Szabo C: Potential role of peroxynitrite-poly (ADP-ribose) synthetase pathway in a rat model of severe hemorrhagic shock. Shock, 1998; 9: 341-344

Keywords: PARP, haemorrhage, multiple organ injury, Shock