INHIBITION OF THE ACTIVITY OF POLY(ADP RIBOSE) SYNTHETASE REDUCES ISCHEMIA-REPERFUSION INJURY IN THE HEART AND SKELETAL-MUSCLE

Reperfusion of the ischemic myocardium results in the generation of ox ygen-derived free radicals, NO, and presumably peroxynitrite, These, i n turn, may cause strand breaks in DNA, which activate the nuclear enz yme poly(ADP ribose) synthetase (PARS), This results in a rapid deplet ion of intracellular NAD and ATP. When this reaction is excessive, the re is ultimately cell death. Here we demonstrate that 3-aminobenzamide (and several other, chemically distinct, inhibitors of PARS activity) reduces the infarct size caused by ischemia and reperfusion of the he art or skeletal muscle of the rabbit, Inhibition of PARS activity also attenuates the myocardial dysfunction caused by global ischemia and r eperfusion in the isolated, perfused heart of the rabbit. In skeletal muscle, inhibition of the activity of neuronal NO synthase reduces inf arct size, indicating that the formation of NO contributes to the acti vation of PARS there. There is no significant neuronal NO synthase act ivity in the heart, and hence NO synthase inhibitors did not reduce my ocardial infarct size. Thus, activation of PARS contributes to the cel l death caused by ischemia-reperfusion, and PARS inhibitors may consti tute a novel therapy for ischemia-reperfusion injury.