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

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.

• Authors: Vijay Kumar Kutala, Mahmood Khan, Rajarsi Mandal, Latha P Ganesan, Susheela Tridandapani, Tamas Kalai, Kalman Hideg, Periannan Kuppusamy
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 317 Issue 3 Pg. 921-8 (Jun 2006) ISSN: 0022-3565 [Print] United States
• PMID: 16467453 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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