Attenuation of myocardial ischemia-reperfusion injury by trimetazidine derivatives functionalized with antioxidant properties

J Pharmacol Exp Ther. 2006 Jun;317(3):921-8. doi: 10.1124/jpet.105.100834. Epub 2006 Feb 8.

Abstract

Trimetazidine (TMZ), an anti-ischemic metabolic drug, is used to treat chest pain (angina pectoris). We hypothesized that derivatives of TMZ with antioxidant functions may improve the cardiac dysfunction caused by ischemia-reperfusion (I/R) above that observed with TMZ alone. Isolated rat hearts perfused with Krebs-Henseleit buffer according to the Langendorff method were subjected to 30 min of global ischemia followed by 45 min of reperfusion. Trimetazidine, TMZ-NH (TMZ modified with a pyrroline moiety), or TMZ-PhiNH (TMZ-NH with a phenyl substitute) were infused (50 microM) for 1 min before the onset of ischemia. Untreated (control) hearts at the end of 45 min of reperfusion showed a significant decrease in the recovery of coronary flow (42%), left ventricular-developed pressure (22%), and rate-pressure product (25%) compared with preischemic baseline values. The I/R hearts also showed markedly increased lactate dehydrogenase and creatine kinase activities in the coronary effluent, significant myocardial infarction (46% of risk area), and activation of Akt, extracellular signal-regulated kinase, and p38 mitogen-activated protein kinase. Pretreatment of hearts with TMZ-NH or TMZ-PhiNH significantly enhanced the recovery of heart function and decreased infarct size. The I/R-induced activation of Akt was further enhanced by TMZ-PhiNH. The present study demonstrated that TMZ-NH and TMZ-PhiNH significantly protected hearts against I/R-mediated cardiac dysfunction and injury. The protective effect of the TMZ derivatives could be due to the combined effects of antioxidant and anti-ischemic activities as well as enhanced pro-survival Akt activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cardiotonic Agents / chemistry
  • Cardiotonic Agents / pharmacology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Free Radical Scavengers / chemistry
  • Free Radical Scavengers / pharmacology*
  • Hemodynamics / drug effects*
  • In Vitro Techniques
  • Molecular Structure
  • Myocardial Infarction / etiology
  • Myocardial Infarction / prevention & control
  • Myocardial Reperfusion Injury / complications
  • Myocardial Reperfusion Injury / physiopathology
  • Myocardial Reperfusion Injury / prevention & control*
  • Myocardium* / enzymology
  • Myocardium* / metabolism
  • Myocardium* / pathology
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Superoxides / metabolism
  • Trimetazidine / chemistry
  • Trimetazidine / pharmacology*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Cardiotonic Agents
  • Free Radical Scavengers
  • Superoxides
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Trimetazidine