TY - JOUR
T1 - Protection against myocardial ischemia and reperfusion injury by 3- aminobenzamide, an inhibitor of poly (ADP-ribose) synthetase
AU - Zingarelli, Basilia
AU - Cuzzocrea, Salvatore
AU - Zsengellér, Zsuzsanna
AU - Salzman, Andrew L.
AU - Szabó, Csaba
N1 - Funding Information:
This work was supported by the American Heart Association (Ohio Section) to Dr. Zingarelli and by a Grant from the Children’s Hospital Medical Center of Cincinnati (‘‘Trustees Grant’’) to Dr. Szabó. The authors would like to thank Michael O’Connor and Alvin Denenberg for technical assistance.
PY - 1997/11
Y1 - 1997/11
N2 - Objective: Peroxynitrite and hydroxyl radical, reactive oxidants produced during reperfusion, are potent triggers of DNA single strand breakage. DNA injury triggers the activation of the nuclear enzyme poly (ADP- ribose) synthetase (PARS), which contributes to cellular energetic depletion. Using 3-aminobenzamide, an inhibitor of PARS, we investigated the role of PARS in the pathogenesis of myocardial reperfusion injury in a rat model. Methods and results: Occlusion of the left main coronary artery (one hour) followed by reperfusion (one hour) in the anesthetized rat caused severe cardiac necrosis, neutrophil infiltration, and increased plasma creatine phosphokinase activity. There was significant peroxynitrite production during reperfusion, as indicated by a massive increase in nitrotyrosine in the necrotic myocardium. Reperfusion was also associated with a significant loss of myocardial ATP. In vivo administration of the PARS inhibitor 3- aminobenzamide (10 mg/kg i.v.) to rats subjected to myocardial ischemia and reperfusion, reduced myocardial infarct size and blunted the increase in plasma creatine phosphokinase activity and myeloperoxidase activity in infarcted hearts. In addition 3-aminobenzamide partially preserved the myocardial ATP levels. In vitro, pharmacological inhibition of PARS also ameliorated peroxynitrate-induced cytotoxicity in rat cardiac myocytes and human endothelial cells. Conclusion: 3-aminobenzamide has significant protective effects in myocardial reperfusion injury. We hypothesize that activation of PARS activation plays a role in the pathophysiology of acute myocardial infarction.
AB - Objective: Peroxynitrite and hydroxyl radical, reactive oxidants produced during reperfusion, are potent triggers of DNA single strand breakage. DNA injury triggers the activation of the nuclear enzyme poly (ADP- ribose) synthetase (PARS), which contributes to cellular energetic depletion. Using 3-aminobenzamide, an inhibitor of PARS, we investigated the role of PARS in the pathogenesis of myocardial reperfusion injury in a rat model. Methods and results: Occlusion of the left main coronary artery (one hour) followed by reperfusion (one hour) in the anesthetized rat caused severe cardiac necrosis, neutrophil infiltration, and increased plasma creatine phosphokinase activity. There was significant peroxynitrite production during reperfusion, as indicated by a massive increase in nitrotyrosine in the necrotic myocardium. Reperfusion was also associated with a significant loss of myocardial ATP. In vivo administration of the PARS inhibitor 3- aminobenzamide (10 mg/kg i.v.) to rats subjected to myocardial ischemia and reperfusion, reduced myocardial infarct size and blunted the increase in plasma creatine phosphokinase activity and myeloperoxidase activity in infarcted hearts. In addition 3-aminobenzamide partially preserved the myocardial ATP levels. In vitro, pharmacological inhibition of PARS also ameliorated peroxynitrate-induced cytotoxicity in rat cardiac myocytes and human endothelial cells. Conclusion: 3-aminobenzamide has significant protective effects in myocardial reperfusion injury. We hypothesize that activation of PARS activation plays a role in the pathophysiology of acute myocardial infarction.
KW - DNA damage
KW - Nitric oxide
KW - Nitrotyrosine
KW - Oxygen radicals
KW - Peroxynitrite
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U2 - 10.1016/S0008-6363(97)00137-5
DO - 10.1016/S0008-6363(97)00137-5
M3 - Article
C2 - 9463632
AN - SCOPUS:0031281259
SN - 0008-6363
VL - 36
SP - 205
EP - 215
JO - Cardiovascular research
JF - Cardiovascular research
IS - 2
ER -