Cardioprotective effect of trimetazidine in severe ischemic cardiomyopathy

Bricaud, H; Brottier, L; Jl, Barat; Combe, Christian; Boussens, B; Bonnet, Jacques

doi:10.1007/bf00051293

Cited by 19 publications

(11 citation statements)

References 5 publications

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“…has shown beneficial effects on ischemic injury. Bricaud et al ( 1990) demonstrated the bene-ficial effect of TMZ in long-term treatment of ischemic cardiomyopathy without associated adverse effect. Bricaud et al ( 1990) demonstrated the bene-ficial effect of TMZ in long-term treatment of ischemic cardiomyopathy without associated adverse effect.…”

Section: Introductionmentioning

confidence: 94%

“…In clinical studies, this drug displayed antianginal properties in improving exercise capacity, total work performed, and electrocardiographic signs of ischemia (Timour et al, 1991;Detry et al, 1994). Bricaud et al ( 1990) demonstrated the bene-ficial effect of TMZ in long-term treatment of ischemic cardiomyopathy without associated adverse effect. Several studies were designed to explain the mechanism of action of this drug.…”

Section: Introductionmentioning

confidence: 99%

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Protective effects of trimetazidine on hypoxic cardiac myocytes from the rat

Fantini¹,

Athias²,

Demaison

et al. 1997

Fundamemntal Clinical Pharma

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The electrophysiological effects of the antianginal drug trimetazidine (TMZ) were investigated in cultured rat ventricular myocytes using a substrate-free hypoxia model of ischemia. The transmembrane potentials were recorded with glass microelectrodes and the contractions were simultaneously monitored with a video motion detector. The cardiomyocytes were treated with TMZ (1-5.10(-4) M final concentration) in the bath. The untreated and the drug-treated cells were submitted either to 150 min normoxia or to 150 min hypoxia followed by 90 min reoxygenation in the absence of oxidizable substrate. In normoxic conditions, TMZ did not affect the maximal diastolic potential (MDP) but significantly lowered the plateau potential level (OS) and decreased the upstroke velocity (Vmax) and the spontaneous action potential rate (APR). Conversely, TMZ significantly increased action potential duration at 80% repolarization (APD80). Under substrate-free hypoxia, the untreated cells displayed a progressive contractile failure and an important decrease in OS and APD. In parallel, early postdepolarizations triggering high rate spikes were observed. Prolonging oxygen depletion led to the cessation of the spontaneous electrical activity and thereafter to a gradual decrease in MDP. Near normal rhythmic action potentials and contractions resumed after reoxygenation. Comparatively, the treatment by 5.10(-4) M TMZ almost completely prevented the decrease in plateau amplitude, resting membrane potential, Vmax, APD80, and rate caused by substrate-free hypoxia. Moreover, the hypoxia-induced arrhythmias and the cessation of spontaneous electromechanical activities did not occur in the presence of TMZ (5.10(-4) M). After reoxygenation, the TMZ-treated cells exhibited a higher action potential amplitude than that of the untreated cells, although the TMZ-induced depressive effects on the spontaneous frequency and the Vmax persisted. In conclusion, this study shows that TMZ (5.10(-4) M) is efficient in protecting the isolated cardiac myocytes against the functional alterations induced by substrate-free hypoxia and led thus to a better recovery upon reoxygenation. The cytoprotective action may be linked, at least in part, to apparent ion channel blocking effects of the drug, which appeared in basal conditions at concentrations used in this study.

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Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Protective effects of trimetazidine on hypoxic cardiac myocytes from the rat

Fantini¹,

Athias²,

Demaison

et al. 1997

Fundamemntal Clinical Pharma

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“…Bricaud et al. [4] demonstrated the beneficial effect of a long‐term TMZ treatment in ischemic cardiopathy without associated adverse effects. In vitro, the beneficial properties of the molecule were reported in isolated perfused heart models, which confirmed that the mechanism of the beneficial effect was not associated to any haemodynamic component [5,6].…”

Section: Introductionmentioning

confidence: 99%

Influence of Trimetazidine on the synthesis of complex lipids in the heart and other target organs

Sentex¹,

Héliès-Toussaint²,

Rousseau³

et al. 2001

Fundamemntal Clinical Pharma

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Trimetazidine exerts antianginal properties at the cellular level, without haemodynamic effect in clinical and experimental conditions. This cytoprotection was attributed to a decreased utilization of fatty acids for energy production, balanced by an increased incorporation in structural lipids. This study evaluated the influence of Trimetazidine on complex lipid synthesis from [2-(3)H] glycerol, in ventricular myocytes, isolated rat hearts and in vivo in the myocardium and several other tissues. In cardiomyocytes, Trimetazidine increased the synthesis of phosphatidyl-choline (+ 80%), phosphatidyl-ethanolamine (+ 210%), phosphatidyl-inositol (+ 250%) and cardiolipid (+ 100%). The common precursor diacylglycerol was also increased (+ 40%) whereas triacylglycerol was decreased (-70%). Similar results were obtained in isolated hearts with 10 microm Trimetazidine (phosphatidyl-choline + 60%, phosphatidyl-ethanolamine + 60%, phosphatidyl-inositol + 100% and cardiolipid + 50%), the last two phospholipids containing 85% of the radioactivity. At 1 microm, Trimetazidine still stimulated the phospholipid synthesis although the difference was found significant only in phosphatidyl-inositol and cardiolipid. In vivo studies (10 mg/kg per day for 7 days and 5 mg/kg, i.p. before the experiment) revealed significant changes in the intracellular lipid biosynthesis, with increased labelling of phospholipids and reduced incorporation of glycerol in nonphosphorous lipids. Trimetazidine increased the glycerol uptake from plasma to the other tissues (liver, cochlea, retina), resulting in an altered lipid synthesis. The anti-anginal properties of Trimetazidine involve a reorganisation of the glycerol-based lipid synthesis balance in cardiomyocytes, associated with an increased uptake of plasma glycerol that may contribute to explain the pharmacological properties reported in other organs.

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“…Trimetazidine (1-[2,3,4-trimethoxy-benzyl]piperazine 2 HCl; Laboratoires Servier, Courbevoie, France) is an anti-anginal drug devoid of hemodynamic properties. The drug is known for its cardioprotective effects in the treatment of ischemic cardiomyopathy (Bricaud et al, 1990) and was shown to exert its protective effect at the ventricular myocyte level (Lavanchy et al, 1987;Renaud, 1988;Fantini et al, 1994). Several publications reported that the cytoprotective properties of trimetazidine could be partly attributed to an effect on cellular lipid metabolism.…”

mentioning

confidence: 99%

Prevention of Heart Failure in Rats by Trimetazidine Treatment: A Consequence of Accelerated Phospholipid Turnover?

Tabbi-Anneni

Héliès-Toussaint²,

Morin³

et al. 2003

The Journal of Pharmacology and Experimental Therapeutics

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Heart failure is known for alteration of cardiac catecholamine responsiveness involving adrenergic receptor (AR) down-regulation. Trimetazidine, a metabolically active anti-ischemic drug, accelerates the turnover of phospholipids. The present study evaluated the consequences of trimetazidine treatment (supposed to increase phospholipid synthesis) on AR in heart failure in rats. In control rats, trimetazidine (7.5 mg/day supplied in the diet) induced after 8 weeks a significant increase in both ␤-(ϩ54%) and ␣-AR (ϩ30%) density, although after 12 weeks, the receptor density was normalized. Heart failure was obtained by ascending aortic banding. These heart failure rats developed a severe cardiac hypertrophy, mainly affecting the left ventricle, which was significantly reduced in the trimetazidine-treated group. The plasma level of brain natriuretic peptide (BNP), a marker of heart failure severity, was significantly increased in the heart failure group as compared with the sham group (900 and 1200% after 8 and 12 weeks, respectively). In the trimetazidine-treated group, the plasma BNP increase was significantly lower. The development of heart failure was associated with a decrease in ␤-and ␣-AR sites (Ϫ23 and Ϫ36% versus sham, respectively) after 8 weeks and continued to decrease after 12 weeks (Ϫ37 and Ϫ48% versus sham, respectively). This down-regulation was prevented by trimetazidine without alteration in affinity. These results suggest that trimetazidine prevents AR desensitization and cardiac hypertrophy, in a pressure-overload model of heart failure. This cytoprotection suggests that membrane homeostasis preservation may be considered as a therapeutic target in the treatment of heart failure.

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Cardioprotective effect of trimetazidine in severe ischemic cardiomyopathy

Cited by 19 publications

References 5 publications

Protective effects of trimetazidine on hypoxic cardiac myocytes from the rat

Protective effects of trimetazidine on hypoxic cardiac myocytes from the rat

Influence of Trimetazidine on the synthesis of complex lipids in the heart and other target organs

Prevention of Heart Failure in Rats by Trimetazidine Treatment: A Consequence of Accelerated Phospholipid Turnover?

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