Suppression of poly (ADP-ribose) polymerase activation by 3-aminobenzamidein a rat model of myocardial infarction: long-term morphological and functional consequences

1 Recent studies demonstrated that inhibition or genetic inactivation of th e enzyme poly (ADP-ribose) polymerase (PARP) is beneficial in myocardial re perfusion injury. PARP activation in the reperfused myocardium has been ass umed. but not directly demonstrated. Furthermore, the issue whether pharmac ological PARP inhibition affords long-term functional benefit in the reperf used myocardium has not been explored. Thew questions were addressed in the present study. 2 In a rat model of myocardial ischemia (1 h) and reperfusion (up to 24 h), there was a marked and significant activation of PARP in the ischemic bord erzone. as determined by poly(ADP-ribose) (PAR) immunohistochemistry. PAR l ocalized to the nuclei of myocytes and infiltrating mononuclear cells. In t he core of the infarction, necrotic tissues and diffuse PAR staining were o bserved. PARP activation remained markedly detectable 24 It after reperfusi on. The PARP inhibitor 3-aminobenzamide (20 mg kg(-1) intraperitoneally 10 min before reperfusion, and every 2 h thereafter for 6 h) markedly reduced the activation of the enzyme in myocytes. 3 3-aminobenzamide significantly protected against myocardial morphological and functional alterations at 24 h post-reperfusion. Notably, infarct size was reduced. circulating creatine kinase activity was attenuated, and myoc ardial contractility (dP dt(-1)) was restored by 3-aminobenzamide. 4 Our results demonstrate a significant and prolonged activation of PAR-P i n the reperfused myocardium, localizing to the necrotic area and the ischat emic borderzone. Furthermore, the studies demonstrate that PARP inhibition affords long-term beneficial morphological and functional effects in the re perfused myocardium. These data strengthen the notion that pharmacological PARP inhibition is a viable novel experimental approach for protection agai nst myocardial reperfusion injury.