Some Biochemical Aspects of the Protective Effect of Trimetazidine on Rat Cardiomyocytes During Hypoxia and Reoxygenation

doi:10.1006/jmcc.1994.1116

Journal of Molecular and Cellular Cardiology

Volume 26, Issue 8, August 1994, Pages 949-958

https://doi.org/10.1006/jmcc.1994.1116 Get rights and content

Abstract

This study was undertaken to evaluate the direct cardioprotective effect of trimetazidine (TMZ), an anti-anginal drug devoid of haemodynamic action, on isolated myocytes. Cultured rat ventricular myocytes were treated with the drug 16 h and 1 h before the experiments. The drug-treated cells and control cells were placed in a substrate free medium and submitted in a specially designed device to either normoxia (N4), or hypoxia (150 min. H2.5, or 240 min, H4), or 150 min hypoxia followed by 90 min reoxygenation (HR). The treatment of the cells with TMZ (5 × 10^-4 M) resulted in a significant decrease of lactate dehydrogenase (LDH) leakage (-58% in H2.5, -36% in H4 and -37% in HR). The LDH release provoked by oxidizing agents, H₂O₂ and 13-s-HpOTrE (13(S)-hydroperoxyoctadecatrienoic acid) during post-hypoxic reoxygenation was also lowered by TMZ. However, this effect reflected the beneficial action of TMZ during hypoxia since the drug was not efficient in altering the LDH leakage induced by the oxidizing agents in normal conditions. Moreover, the hypoxia-induced decreased of ATP content was not affected by TMZ, and resynthesis of ATP during substrate-free reoxygenation was similar in TMZ-treated and control cells. The respiration parameters have been studied in rat heart mitochondria isolated from control and TMZ-treated rats, in the presence or absence of TMZ in the respiration medium (10^-4 M). The main result was a rapid and potent inhibition of palmitoylcarnitine oxidation, when TMZ was added to the respiration medium. The chronic treatment only resulted in a slight alternation of pyruvate oxidation. In conclusion, a pre-treatment of ventricular myocytes with TMZ resulted in an increased cell resistance to hypoxic stress, as evidenced by LDH leakage. This cytoprotective effect to TMZ should not be mediated through an antioxidant activity, but could be related to a modification of lipid metabolism.

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Citation Excerpt :
Increased metabolic rate that accompanies heart failure can be interpreted as the need of additional energy required to counteract the impending breakdown of the homeostatic equilibrium that is characteristic of this chronic morbidity. In this context TMZ, by inhibiting oxidative phosphorylation and by shifting energy production from FFA to glucose oxidation, increases utilization of glucose and lactate, which are more efficient fuels for aerobic respiration, improving cardiac cell efficiency by 16% up to 26% [12,13,41]. Another benefit is the improvement in endothelial function [42] due, at least in part, to direct antioxidant effect of TMZ, which may translate into reduced afterload [43].
The aim of this cohort study was to retrospectively evaluate, in patients with chronic heart failure (CHF), the long term effect of trimetazidine (TMZ) on morbidity and mortality.
Previous small studies in patients with CHF have shown that TMZ can improve left ventricular function, exercise capacity and NYHA class compared to placebo. However, no data on the effects of TMZ on survival in patients with CHF have ever been produced.
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TMZ is effective in reducing mortality and event-free survival in patients with CHF. The addition of TMZ on top of optimal medical therapy improves long term survival in CHF patients.
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Original ArticleSome Biochemical Aspects of the Protective Effect of Trimetazidine on Rat Cardiomyocytes During Hypoxia and Reoxygenation

Abstract

Original Article
Some Biochemical Aspects of the Protective Effect of Trimetazidine on Rat Cardiomyocytes During Hypoxia and Reoxygenation