Contractile dysfunction in experimental cardiac allograft rejection: role of the poly (ADP-ribose) polymerase pathway

Recent studies suggested that the peroxynitrite-poly (ADP-ribose) polymerase (PARP) pathway is activated during acute allograft rejection. We investigated whether PARP inhibition improves transplant function during cardiac rejection. Isogeneic Lewis-to-Lewis and allogeneic Dark Agouti-to-Lewis rat cardiac transplants were studied under treatment with placebo or with the PARP-inhibitor INO-1001 (1 mk/kg/day), Functional, biochemical and histological analysis were performed 3 and 5 days after transplantation. After 3 days, baseline left ventricular pressure-volume relationships did not differ between the groups. However, coronary blood flow (4.3 +/- 0.5 vs. 2.2 +/- 0.2 vs. 4.1 +/- 0.3 ml/min/g, P < 0.05) and contractile response to dobutamine (Delta+dP/dt: 98 +/- 11 vs. 57 +/- 7 vs. 88 +/- 8%, P < 0.05) decreased significantly in the placebo group, which was abolished by INO-1001. Vasodilatory response to acethylcholine was reduced in the placebo group (78 +/- 6 vs. 36 +/- 9 vs. 72 +/- 7%, P < 0.05). After 5 days, baseline systolic and diastolic pressure-volume relationships were impaired (P < 0.05) in the placebo group and the response to dobutamine and to acethylcholine deteriorated further which was abolished by INO-1001. Histology confirmed mild to moderate rejection after 3 days and severe acute rejection after 5 days in the allogeneic groups. Thus, contractile and vasomotor dysfunction occur in a typical time dependent manner during cardiac rejection, which can be reduced by PARP-inhibition.