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

Abstract

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.

Human obesity is characterized by defective fat storage and enhanced muscle fatty acid oxidation, and trimetazidine gradually counteracts these abnormalities

“…In synthesis, the rate constant identifies tissue-related defects, whereas the flux includes the changes in tissue metabolism due to extrinsic, in addition to intrinsic, causes. Early changes in the rate constants confirm the reciprocal substrate regulation by trimetazidine and are likely to precede a net diversion of FA from oxidation toward esterification in complex lipids, in line with the reported observation that trimetazidine stimulates phospholipid synthesis (38) with potential protective effects on cellular membranes (37,38).…”

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

“…The action of trimetazidine on energy metabolism reported in cultured cells (Fantini et al, 1994) and isolated perfused rat heart (Kantor et al, 2000) could hardly account for the effects reported here. Conversely, the effect on membrane phospholipids may account for the nonspecific improvement of AR density, since the modification of cardiac complex lipid metabolism was reported in vivo in the range 3 to 15 mg/day (Sentex et al, 2001), in accordance with the dose used in this study (7.5 mg/day).…”

“…This procedure was designed to avoid the 120 to 180 injections per rat required by the protocol, but did not allow the determination of a plasma peak concentration of trimetazidine, due to the food intake schedule of the rats. The dose of 7.5 mg/day was determined from the literature (Sentex et al, 2001) and a preliminary study of the dose leading to a plasma trimetazidine concentration close to 0.1 to 0.2 M as determined at 8:00 AM and 8:00 PM. Although different from the usual 1 to 10 M range used in vitro in acute investigations with trimetazidine (Kantor et al, 2000;Sentex et al, 2001), this concentration is relevant as compared with that reported for therapeutic administration in humans, 0.2 to 0.6 M for 60 mg/day (Sellier et al, 1987).…”

“…The dose of 7.5 mg/day was determined from the literature (Sentex et al, 2001) and a preliminary study of the dose leading to a plasma trimetazidine concentration close to 0.1 to 0.2 M as determined at 8:00 AM and 8:00 PM. Although different from the usual 1 to 10 M range used in vitro in acute investigations with trimetazidine (Kantor et al, 2000;Sentex et al, 2001), this concentration is relevant as compared with that reported for therapeutic administration in humans, 0.2 to 0.6 M for 60 mg/day (Sellier et al, 1987). The treatment was initiated 3 to 4 days after surgery and was maintained for an additional period of 8 or 12 weeks, leading the rats to the age of 12 or 16 weeks, respectively, similar to the literature (Sentex et al, 1998(Sentex et al, , 2001).…”

“…This beneficial effect on membrane homeostasis through phospholipid turnover induced a significant increase of the incorporation of long-chain polyunsaturated fatty acids in membrane structures (Sentex et al, 1998). More recently, this effect on lipid metabolism was reported to occur in vitro as well as in vivo in the rat in several organs, such as retina, inner ear, and liver (Sentex et al, 2001). This study was designed to test the hypothesis that trimetazidine through acceleration of phospholipid turnover would result in a delayed development of heart failure in the rat, as investigated through AR down-regulation.…”