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

Vijay Kumar Kutala, Mahmood Khan, Rajarsi Mandal, Latha P. Ganesan, Susheela Tridandapani, T. Kalai, K. Hideg, Periannan Kuppusamy

Research output: Contribution to journalArticle

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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-ΦNH (TMZ-NH with a phenyl substitute) were infused (50 μM) 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-ΦNH significantly enhanced the recovery of heart function and decreased infarct size. The I/R-induced activation of Akt was further enhanced by TMZ-ΦNH. The present study demonstrated that TMZ-NH and TMZ-ΦNH 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.

Original languageEnglish
Pages (from-to)921-928
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume317
Issue number3
DOIs
Publication statusPublished - Jun 2006

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Trimetazidine
Myocardial Reperfusion Injury
Reperfusion Injury
Myocardial Ischemia
Antioxidants
Reperfusion
Ischemia
Extracellular Signal-Regulated MAP Kinases
Recovery of Function
Angina Pectoris
p38 Mitogen-Activated Protein Kinases
Ventricular Pressure

ASJC Scopus subject areas

  • Pharmacology

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Attenuation of myocardial ischemia-reperfusion injury by trimetazidine derivatives functionalized with antioxidant properties. / Kutala, Vijay Kumar; Khan, Mahmood; Mandal, Rajarsi; Ganesan, Latha P.; Tridandapani, Susheela; Kalai, T.; Hideg, K.; Kuppusamy, Periannan.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 317, No. 3, 06.2006, p. 921-928.

Research output: Contribution to journalArticle

Kutala, Vijay Kumar ; Khan, Mahmood ; Mandal, Rajarsi ; Ganesan, Latha P. ; Tridandapani, Susheela ; Kalai, T. ; Hideg, K. ; Kuppusamy, Periannan. / Attenuation of myocardial ischemia-reperfusion injury by trimetazidine derivatives functionalized with antioxidant properties. In: Journal of Pharmacology and Experimental Therapeutics. 2006 ; Vol. 317, No. 3. pp. 921-928.
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