Abstract

Myocardial ischaemia 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 Vastarel 20 mg IR (immediate release) and Vastarel 35 mg MR (modified release), two bioequivalent marketed formulations of TMZ, on cardioprotection during acute ischaemia in pigs. A 4-day oral treatment with Vastarel 20 mg IR (800 mg three time a day) or Vastarel 35 mg MR (1400 mg twice daily) had no effect on ventricular fibrillation threshold (VFT) prior to ischaemia, 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 haemodynamic and conduction parameters. In both Vastarel-treated groups, a significant reduction of the ischaemic area as well as a protection of cardiomyocytes were observed. Cardiac enzymatic activity (phosphorylase, succino dehydrogenase, ATPase) was increased in Vastarel-treated groups. Both formulations preserved mitochondrial structure and improved mitochondrial function as demonstrated by a twofold increase of oxidative phosphorylation, by a reduction of ROS production (>30%) and by a trend to increase the mitochondrial calcium retention capacity. In this model of ischaemia, both Vastarel 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.