5-aminoisoquinolinone, a potent inhibitor of poly (adenosine 5 '-diphosphate ribose) polymerase, reduces myocardial infarct size

This study investigates the effects of a novel, water-soluble inhibitor of the activity of poly (adenosine 5 ' -diphosphate ribose) polymerase, 5-amin oisoquinolinone [5-aminoisoquinolin-1(2 H)-one], on (i) poly (adenosine 5 ' -diphosphate ribose) polymerase activity in rat cardiac myoblasts and (ii) the infarct size caused by regional myocardial ischaemia and reperfusion i n the rat. Exposure of H9c2 cells to hydrogen peroxide (H2O2, 1 mM) caused a significant increase in poly (adenosine 5 ' -diphosphate ribose) polymera se activity and an 80-90% reduction in mitochondrial respiration (cellular injury). Pretreatment of these cells with 5-aminoisoquinolinone (0.003-1 mM ) caused a concentration-dependent inhibition of poly (adenosine 5 ' -dipho sphate ribose) polymerase activity (IC50: similar to 4.5 muM, n = 6-9) and cell injury (EC50: similar to 4.45 muM, n = 9). In a rat model of myocardia l infarction, left anterior descending coronary artery occlusion (25 min) a nd reperfusion (2 h) resulted in an infarct size of 50 +/- 3%. Administrati on (1 min before reperfusion) of 5- aminoisoquinolinone reduced myocardial infarct size in a dose-related fashion. Thus, 5-aminoisoquinolinone is a po tent inhibitor of poly (adenosine 5 ' -diphosphate ribose) polymerase activ ity in cardiac myoblasts and reduces myocardial infarct size in vivo. (C) 2 001 Elsevier Science B.V. All rights reserved.