title: Trimetazidine demonstrated cardioprotective effects through mitochondrial pathway in a model of acute coronary ischemia.
abstract: Myocardial ischemia affects mitochondrial function leading to ionic imbalance and susceptibility to ventricular fibrillation. Trimetazidine (TMZ), a metabolic agent, is clinically used as an anti-anginal therapy. This study was conducted to compare the effect of TMZ 20 mg immediate release (IR) and TMZ 35 mg modified release (MR), two bioequivalent marketed formulations of TMZ, on cardioprotection during acute ischemia in pigs. A 4-day oral treatment with TMZ 20 mg IR (800 mg, tid) or TMZ 35 mg MR (1,400 mg, bid) had no effect on ventricular fibrillation threshold (VFT) prior to ischemia but significantly prevented the decrease in VFT observed in placebo-treated groups after a 1-min left anterior descending coronary artery occlusion. This effect occurred without modifying cardiac hemodynamic and conduction parameters. In both TMZ-treated groups, a significant reduction of the ischemic area as well as a protection of cardiomyocytes were observed. Cardiac enzymatic activity (phosphorylase, succinate dehydrogenase, ATPase) was increased in TMZ-treated groups. Both formulations preserved mitochondrial structure and improved mitochondrial function as demonstrated by a twofold increase of oxidative phosphorylation, by a reduction of reactive oxygen species (ROS) production (>30 %) and by a trend to increase the mitochondrial calcium retention capacity. In this model of ischemia, both TMZ formulations, leading to equivalent TMZ plasma exposures, demonstrated similar cardioprotective effects. This protection could be attributed to a preservation of mitochondrial structure and function, which plays a central role in ATP and ROS production and consequently could be considered as a target of cardioprotection.
authors.affiliation: EA4612 Neurocardiologie, Université Claude Bernard - Lyon1, 8 avenue Rockefeller, 69373, Lyon cedex 08, France.
authors.forename: L
authors.initials: L
authors.lastname: Dehina
authors.forename: F
authors.initials: F
authors.lastname: Vaillant
authors.forename: A
authors.initials: A
authors.lastname: Tabib
authors.forename: B
authors.initials: B
authors.lastname: Bui-Xuan
authors.forename: Ph
authors.initials: P
authors.lastname: Chevalier
authors.forename: N
authors.initials: N
authors.lastname: Dizerens
authors.forename: C
authors.initials: C
authors.lastname: Bui-Xuan
authors.forename: J
authors.initials: J
authors.lastname: Descotes
authors.forename: V
authors.initials: V
authors.lastname: Blanc-Guillemaud
authors.forename: L
authors.initials: L
authors.lastname: Lerond
authors.forename: Q
authors.initials: Q
authors.lastname: Timour
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D054058:Acute Coronary Syndrome / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D003692:Delayed-Action Preparations; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D006339:Heart Rate / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013552:Swine; D014292:Trimetazidine / Q000008:administration & dosage / Q000627:therapeutic use*; D014693:Ventricular Fibrillation / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D002316:Cardiotonic Agents; D003692:Delayed-Action Preparations; D017382:Reactive Oxygen Species; D014292:Trimetazidine