Effects of inhibitors of the activity of poly (ADP‐ribose) synthetase on the organ injury and dysfunction caused by haemorrhagic shock

Abstract

1 Poly (ADP-ribose) synthetase (PARS) is a nuclear enzyme activated by strand breaks in DNA, which are caused by reactive oxygen species (ROS). Here we investigate the e ects of the PARS inhibitors 3-aminobenzamide (3-AB), nicotinamide and 1,5-dihydroxyisoquinoline (ISO) on the circulatory failure and the organ injury/dysfunction caused by haemorrhage and resuscitation in the anaesthetized rat. 2 Haemorrhage (su cient to lower mean arterial blood pressure to 50 mmHg for 90 min) and subsequent resuscitation with shed blood resulted (within 4 h after resuscitation) in a delayed fall in blood pressure to 66+4 mmHg (control, n=13). This circulatory failure was not a ected by administration (5 min prior to resuscitation) of 3-AB (10 mg kg 71 i.v., n=7), nicotinamide (10 mg kg 71 i.v., n=6) or ISO (3 mg kg 71 i.v., n=6). 3 Haemorrhage and resuscitation also resulted in rises in the serum levels of urea and creatinine. This renal dysfunction was attenuated by 3-AB and nicotinamide, but not by nicotinic acid (n=7), an inactive analogue of nicotinamide. Although ISO (n=6) also attenuated the renal dysfunction caused by haemorrhage and resuscitation, its vehicle (10% DMSO, n=4) had the same e ect. 4 Haemorrhagic shock resulted in enhanced serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lipase, indicating the development of hepatocellular and pancreatic injury, respectively. Similarly, haemorrhagic shock also resulted in an increase in the serum levels of creatine kinase (CK) indicating the development of neuromuscular injury. This was attenuated by 3-AB and nicotinamide, but not by nicotinic acid. Although ISO also attenuated the liver, pancreatic and neuromuscular injury caused by haemorrhagic shock, its vehicle had the same e ect. 5 Thus, activation of PARS contributes to the organ injury and dysfunction caused by haemorrhage and resuscitation in the rat.

Effects of nicotinamide, an inhibitor of PARS activity, on gut and liver O2 exchange and energy metabolism during hyperdynamic porcine endotoxemia

“…The experimental data suggests that this ªPARS suicide mechanismº is involved in many of fundamental disturbances of endotoxic shock, including endothelial dysfunction [4], loss of vascular energetic and contractile failure [5,6], pulmonary endothelial and intestinal mucosal hyperpermeability [7], and impairment of mitochondrial respiration [8,9]. Moreover, strategies aimed at inhibiting PARS activity have exerted beneficial effects in various experimental models, including myocardial [10], renal [11], and splanchnic [12] ischemia-reperfusion injury or hemorrhagic shock [13]. In a rat model of endotoxic shock treatment with the PARS inhibitor, nicotinamide prevented the delayed vascular failure and restored the endotoxin (LPS)-induced loss of vascular contractility [5].…”

Protection against hemorrhagic shock in mice genetically deficient in poly(ADP-ribose)polymerase

“…These observations indicate that all of the conditions required for PARP activation are present in HS. Previous studies testing pharmacological inhibitors of PARP in experimental HS suffered from problems with the limited selectivity of the inhibitor for PARP and their relatively low potency (12,13). In the present study, we have investigated in more detail the potential role PARP activation may play in HS by using genetically engineered animals lacking the PARP gene.…”

Poly(ADP-ribose) polymerase triggers the microvascular mechanisms of hepatic ischemia-reperfusion injury

“…Inhibitors of PARP attenuated the hepatic damage after hemorrhagic shock (17,36) but did not reduce liver injury after I/R (4). Although detection of cleaved PARP (89 kDa) is used for the assessment of apoptosis in the liver (38), hepatocellular PARP has been recently shown to be resistant to caspase-induced proteolytic cleavage (9).…”