Reduction of myocardial reperfusion injury by an inhibitor of poly (ADP-ribose) synthetase in the pig.
The effect of the Poly (adenosine 5'-diphosphate ribose) synthetase (PARS) inhibitor 3-aminobenzamide on (i) infarct size caused by regional myocardial ischaemia (60 min) and reperfusion (3 h) in the anaesthetised pig, and (ii) on the cell injury/necrosis of human cardiomyoblasts caused by hydrogen peroxide (3 mM) was investigated. Regional myocardial ischaemia and reperfusion resulted in an infarct size of 66+/-3% of the area at risk, which was reduced by 3-aminobenzamide (to 44+/-2%, n=6), but not 3-aminobenzoic acid (66+/-5%, n=4). 3-aminobenzamide also reduced the postischaemic contractile dysfunction. 3-aminobenzamide, but not 3-aminobenzoic acid, abolished the increase in PARS activity as well as the cell injury/necrosis caused by hydrogen peroxide in the cardiomyoblasts. In conclusion, the PARS inhibitor 3-aminobenzamide reduces myocardial reperfusion injury in the pig, and attenuates the cell injury and death associated with oxidant stress in human cardiomyoblasts. We propose that the activation of PARS plays an important role in the injury associated with oxidant stress of the heart.
Bowes
J
J
The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, UK.
Ruetten
H
H
Martorana
P A
PA
Stockhausen
H
H
Thiemermann
C
C
D000818:Animals; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005057:Eukaryotic Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000166:cytology / Q000201:enzymology / Q000473:pathology; D016877:Oxidants / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects; D013552:Swine
D001549:Benzamides; D004791:Enzyme Inhibitors; D016877:Oxidants; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C025160:3-aminobenzamide; D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases