Protection against myocardial ischemia and reperfusion injury by 3- aminobenzamide, an inhibitor of poly (ADP-ribose) synthetase

Basilia Zingarelli, Salvatore Cuzzocrea, Zsuzsanna Zsengellér, Andrew L. Salzman, Csaba Szabo

Research output: Contribution to journalArticle

205 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)205-215
Number of pages11
JournalCardiovascular Research
Volume36
Issue number2
DOIs
StatePublished - Nov 1997
Externally publishedYes

Fingerprint

Poly Adenosine Diphosphate Ribose
Myocardial Reperfusion Injury
Ligases
Reperfusion Injury
Myocardial Ischemia
Reperfusion
Peroxynitrous Acid
Creatine Kinase
Adenosine Triphosphate
Myocardial Infarction
Myocardial Reperfusion
Enzyme Activation
Neutrophil Infiltration
Cardiac Myocytes
Oxidants
Hydroxyl Radical
Peroxidase
DNA Damage
3-aminobenzamide
Coronary Vessels

Keywords

  • DNA damage
  • Nitric oxide
  • Nitrotyrosine
  • Oxygen radicals
  • Peroxynitrite

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Protection against myocardial ischemia and reperfusion injury by 3- aminobenzamide, an inhibitor of poly (ADP-ribose) synthetase. / Zingarelli, Basilia; Cuzzocrea, Salvatore; Zsengellér, Zsuzsanna; Salzman, Andrew L.; Szabo, Csaba.

In: Cardiovascular Research, Vol. 36, No. 2, 11.1997, p. 205-215.

Research output: Contribution to journalArticle

Zingarelli, Basilia ; Cuzzocrea, Salvatore ; Zsengellér, Zsuzsanna ; Salzman, Andrew L. ; Szabo, Csaba. / Protection against myocardial ischemia and reperfusion injury by 3- aminobenzamide, an inhibitor of poly (ADP-ribose) synthetase. In: Cardiovascular Research. 1997 ; Vol. 36, No. 2. pp. 205-215.
@article{50b5084bf4e444a78a2658703afed018,
title = "Protection against myocardial ischemia and reperfusion injury by 3- aminobenzamide, an inhibitor of poly (ADP-ribose) synthetase",
abstract = "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.",
keywords = "DNA damage, Nitric oxide, Nitrotyrosine, Oxygen radicals, Peroxynitrite",
author = "Basilia Zingarelli and Salvatore Cuzzocrea and Zsuzsanna Zsengell{\'e}r and Salzman, {Andrew L.} and Csaba Szabo",
year = "1997",
month = "11",
doi = "10.1016/S0008-6363(97)00137-5",
language = "English (US)",
volume = "36",
pages = "205--215",
journal = "Cardiovascular Research",
issn = "0008-6363",
publisher = "Oxford University Press",
number = "2",

}

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 - Szabo, Csaba

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

UR - http://www.scopus.com/inward/record.url?scp=0031281259&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031281259&partnerID=8YFLogxK

U2 - 10.1016/S0008-6363(97)00137-5

DO - 10.1016/S0008-6363(97)00137-5

M3 - Article

C2 - 9463632

AN - SCOPUS:0031281259

VL - 36

SP - 205

EP - 215

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 2

ER -