Poly(ADP-ribose) polymerase inhibition attenuates biventricular reperfusion injury after orthotopic heart transplantation

Objective: Poly (ADP-ribose) polymerase (PARP) activation plays a key role in free radical induced injury in ischemia/reperfusion. We investigated the effects of INO-1001 a novel PARP inhibitor on postischemic myocardial and endothelial function. Methods: In dogs, 12 orthotopic heart transplantations were performed after 4 h ischemic preservation. At the beginning of reperfusion either saline vehicle (control, n=6, or INO-1001 (1 mg/kg, n=6) was applied. Before explantation and after 120 min of reperfusion we measured biventricular pressure-volume relationships by a combined conductance catheter and the adaptation potential of the right ventricle to acute afterload increase by pulmonary banding. Coronary blood flow (CBF), vasoreactivity, PARP-activation and ATP-content were also determined. Results: INO-1001 led to significantly better recovery of contractility (91 +/- 3 vs. 44 +/- 7%. P<0.05) and CBF (44 +/- 4 vs. 29 +/- 3 ml/min, P<0.05) and higher increase in CBF after acetylcholine (61 +/- 10 vs. 27 8%, P<0.05). In addition, the inotropic adaptation potential of the right ventricle to an increased afterload was better preserved after INO-1001. ATP content was significantly higher in the INO-1001 group (11.0 +/- 2.1 vs. 4.5 +/- 1.1 mumol/g drw). Immunhistology, revealed PARP activation in the control group which was abolished by INO-1001 treatment. Conclusions: PARP inhibition reduces myocardial and enclothelial reperfusion injury after orthotopic heart transplantation. (C) 2004 Published by Elsevier B.V.