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-aminoisoquinolinone [5-aminoisoquinolin-1(2H)-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 in the rat. Exposure of H9c2 cells to hydrogen peroxide (H2O2, 1 mM) caused a significant increase in poly (adenosine 5'-diphosphate ribose) polymerase 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'-diphosphate ribose) polymerase activity (IC50: approximately 4.5 microM, n=6-9) and cell injury (EC50: approximately 4.45 microM, n=9). In a rat model of myocardial infarction, left anterior descending coronary artery occlusion (25 min) and reperfusion (2 h) resulted in an infarct size of 50+/-3%. Administration (1 min before reperfusion) of 5-aminoisoquinolinone reduced myocardial infarct size in a dose-related fashion. Thus, 5-aminoisoquinolinone is a potent inhibitor of poly (adenosine 5'-diphosphate ribose) polymerase activity in cardiac myoblasts and reduces myocardial infarct size in vivo.
Wayman
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The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, St. Bartholomew's Hospital, Charterhouse Square, EC1M 6BQ, London, UK.
McDonald
M C
MC
Thompson
A S
AS
Threadgill
M D
MD
Thiemermann
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C
D000818:Animals; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D006861:Hydrogen Peroxide; D007546:Isoquinolines / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000473:pathology; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009580:Nitroblue Tetrazolium; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D013194:Staining and Labeling
C411425:5-aminoisoquinolinone; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009580:Nitroblue Tetrazolium; D006861:Hydrogen Peroxide