INO-1001, a novel poly(ADP-ribose) polymerase inhibitor reduces myocardial and endothelial reperfusion injury after orthotopic heart transplantation

Abstract

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. 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 (1 mg/kg, n = 6) was applied. Left ventricular pressure-volume relationships were measured by a combined pressure-conductance catheter and the slope of the end-systolic pressure volume relationship (Ees) was calculated as a load-independent index of myocardial contractility 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. 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 in the INO-1001 group (11.0 ± 2.1 vs. 4.5 ± 1.1 μmol/g drw). Immunhistology revealed PARP activation in the control group which was abolished by INO-1001 treatment. Thus, PARP inhibition reduces myocardial and endothelial reperfusion injury after orthotopic heart transplantation.