3-AMINOBENZAMIDE, AN INHIBITOR OF POLY (ADP-RIBOSE) SYNTHETASE, IMPROVES HEMODYNAMICS AND PROLONGS SURVIVAL IN A PORCINE MODEL OF HEMORRHAGIC-SHOCK

Hypoxia, energy deficit, and oxidative damage are principal mechanisms of injury in hemorrhagic shock (HS). Oxidant-induced cellular energet ic failure and cell dysfunction is mediated, in part, via the activati on of the nuclear enzyme poly (ADP-ribose) synthetase (PARS). Here we examine the effect of the PARS inhibitor 3-aminobenzamide (3AB) in a s evere HS model. Pigs were bled to a cardiac index of 40 mL/kg/min for 2 h, which was followed by saline resuscitation (20 mL/kg). Hypovolemi a induced decreases in mean arterial blood pressure (to 40-42 mmHg), i n both atrial pressures, in systemic oxygen consumption (by 26-30%), a nd in mixed venous saturation (by 65%). HS also caused lactic acidosis (4.0-5.5 mM). Fluid replacement with saline caused only a partial and transient recovery of blood pressure and cardiac output, with no reco very of stroke work during resuscitation. Fluid replacement did not pr event the progressive hemodynamic decompensation. The PARS inhibitor 3 AB (15 mg/kg) significantly ameliorated the fall in blood pressure, ca rdiac output, and stroke work; slightly increased left atrial pressure during resuscitation; and significantly prolonged survival. PARS inhi bition also prevented the reduction in oxygen consumption and mixed ve nous saturation during resuscitation. Taking these data together, we c onclude that pharmacological inhibition of PARS exerts beneficial effe cts in a porcine model of severe HS. We propose that favorable action of 3AB is related, at least in part, to an improved cardiac performanc e.