Poly(ADP-ribose) polymerase inhibitor PJ-34 reduces mesenteric vascular injury induced by experimental cardiopulmonary bypass with cardiac arrest

The aim of this study was to investigate effects of poly(ADP-ribose) polymerase (PARP) inhibition on mesenteric vascular function and metabolism in an experimental model of cardiopulmonary bypass (CPB) with cardiac arrest. Twelve anesthetized dogs underwent 90-min hypothermic CPB. After 60 min of cardiac arrest, reperfusion was started for 40 min following application of either saline vehicle (control, n = 6) or a potent PARP inhibitor, PJ-34 (10 mg/kg iv bolus and 0.5 mg * [kg.sup.1] * [min.sup.-1] infusion for 20 min, n = 6). PJ-34 led to better recovery of cardiac outpu (2.2 [+ or -] 0.1 vs. 1.8 [+ or -] 0.2 1/min in control) and mesenteric blood flow (175 [+ or -] 38 vs. 83 [+ or -] 4 ml/min, P < 0.05 vs. control) after reperfusion. The impaired vasodilator response of the superior mesenteric artery to acetylcholine, assessed in the control group after CPB (-32.8 [+ or -] 3.3 vs. -57.6 [+ or -] 6.6% at baseline, P < 0.05), was improved by PJ-34 (-50.3 [+ or -] 3.6 vs. -54.3 [+ or -] 4.1% at baseline, P < 0.05 vs. control). Although plasma nitrate/nitrite concentrations were not significantly different between groups, mesenteric nitric oxide synthase activity was increased in the PJ-34 group (P < 0.05). Moreover, the treated group showed a marked attenuation of mesenteric venous plasma myeloperoxidase levels after CPB compared with the control group (75 [+ or -] 1 vs. 135 [+ or -] 9 ng/ml, P < 0.05). Pharmacological PARP inhibition protects against development of post-CPB mesenteric vascular dysfunction by improving hemodynamics, restoring nitric oxide production, and reducing neutrophil adhesion. endothelial function; nitric oxide; neutrophil adhesion; hemodynamics