INO-1001, a novel poly-ADP-ribose polymerase (PARP)-Inhibitor protects against myocardial and endothelial reperfusion injury after orthotopic heart transplantation

Objectives: Poly (ADP-ribose) polymerase (PARP) activation plays a key role in free radical induced injury in the context of ischemia/reperfusion. In the present study, we investigated the effects of INO-1001 a novel ultrapotent PARP inhibitor on postischemic myocardial and endothelial function in a canine heart transplantation model.

Material and Methods: After 4 hours of ischemic preservation, 12 orthotopic heart transplantations were performed. At the beginning of reperfusion either saline vehicle (control, n=6), or INO-1001 (1mg/kg, n=6) was applied. Left ventricular pressure-volume relationships were measured by a combined conductance catheter and the slope of the end-systolic pressure volume relationship (Ees) was calculated before explantation and after 120 minutes of reperfusion. Coronary blood flow (CBF), endothelium-dependent vasodilatation to acetylcholine (ACH) and endothelium-independent vasodilatation to sodium nitroprusside (SNP) were also determined. Serial biopsies were taken to determine ATP-content and for immunhistology.

Results: Admimistration of INO-1001 led to significantly better recovery (given as percent of baseline) of Ees (91±3 vs. 44±7%, p<0.05). CBF was significantly higher in the INO-1001 group (44±4 vs. 29±3, ml/min, p<0.05). While the vasodilatatory response to SNP was similar in both groups, ACH resulted in a significantly higher increase in CBF in the INO-1001 group (61±10% vs. 27±8%, p<0.05). ATP content was significantly higher in the INO-1001 group (11.0±2.1 vs. 4.5±1.1µmol/g drw). Immunhistology revealed PARP activation in the control group which was abolished by INO-1001 treatment.

Conclusions: PARP inhibition reduces myocardial and endothelial reperfusion injury after orthotopic heart transplantation.