Trimetazidine: In vitro influence on heart mitochondrial function

Abstract

The mechanism of action of the antianginal trimetazidine (TMZ) remains largely unknown. In cultured rat ventricular myocytes in physiologic conditions, TMZ (5 x 10(-4) M) reduced the plateau potential level, the upstroke velocity, and the spontaneous action potential rate. When the cardiomyocytes were submitted to hypoxia (150 or 240 minutes) in a glucose-free medium, treatment with TMZ largely prevented the hypoxia-induced electromechanical alterations, i.e., the decrease in plateau amplitude, in resting membrane potential, in action potential duration, in rate, and in contractility. No hypoxia-induced arrhythmia was observed in the TMZ-treated cells. Moreover, the lactate dehydrogenase leakage was significantly reduced in the TMZ-treated cardiomyocytes (-58% and -36%, after 150 and 240 minutes of hypoxia, respectively). The drug was not efficient in reducing the hypoxia-induced decrease in adenosine triphosphate (ATP) content. The cellular ATP content was slightly lower in the TMZ-treated cells in normoxic conditions and in hypoxic conditions, but only in the glucose-free medium. To investigate further the relation between TMZ and energy metabolism, the respiration parameters were measured in heart mitochondria isolated from control and TMZ-treated rats (6 mg/kg/day, 7 days) with different substrates. This treatment resulted in a slight alteration of pyruvate oxidation, which was observed in the absence and in the presence of TMZ (10(-4) M) in the respiration medium. Conversely, a potent inhibition of palmitoylcarnitine oxidation was measured when TMZ was added to the respiration medium. Neither pretreatment of the rats, nor addition of TMZ to the medium affected the oxidation of glutamate or citrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Protective effects of trimetazidine on hypoxic cardiac myocytes from the rat

“…TMZ at 5.10-J M was very efficient in preventing the shortening of the AP duration induced by substrate-free hypoxia. According to our previous results, however, TMZ at 5.10" M did not significantly attenuate the hypoxia-induced decrease in intracellular ATP content (Fantini et al, 1994;Demaison et al, 1995). Since substrate-free hypoxia causes an intracellular ATP drop in our model (Chevalier et al, 1990), the hypoxia-induced shortening in AP could be linked to the activation of an ATP-sensitive potassium conductance at low ATP levels (Findlay, 1994).…”

“…was able to maintain electrical and contractile activity of isolated cardiac muscle cells submitted to substrate-free hypoxia. It can be suggested that the influence of TMZ (5.10 M ) on cell electrophysiology and contractility may represent the functional correlates of a nonspecific membrane effect (Devynck et al 1993) and/or of its intracellular metabolic effects (Demaison et al, 1995). TMZ displayed indeed a depressive action on the V, , , and apparent calcium and potassium blocking potentialities, which were already apparent in basal normoxic conditions.…”

“…In addition, longterm preservation of isolated arrested rat heart was improved by TMZ, probably by a decrease of adenosine triphosphate (ATP) breakdown and of intracellular acidosis (Aussedat et al, 1993). Moreover, TMZ (5.104 M) was shown to affect the mitochondria1 oxidation of fatty acids (Demaison et al, 1995). An inhibitory action of TMZ was also demonstrated on the Na+, K+-pump in the guineapig ventricular muscle (Hisatome et al, 1991).…”

Extracellular glycerol regulates the cardiac energy balance in a working rat heart model

“…The inhibition of FA oxidation by glycerol, observed in this study, may also result from the inhibition of long-chain 3-ketoacyl-CoA thiolase by the acetyl-CoA derived from glycerol oxidation, which increases intracellular acetylCoA, since glucose oxidation is not affected (5). The cardiac function in ischemic conditions and the functional recovery after reperfusion are known to be improved by decreasing the contribution of FAs to cardiac energy (2,7,11,14).…”

“…**P Ͻ 0.01. ***P Ͻ 0.001. diabetes is associated with the long-chain acyl-CoA stimulation of CPT-1 and the acceleration of the production of NADH and acetyl-CoA with consequent inactivation of PDH (2,7,14). Conversely, the reduction of ␤-oxidation by glycerol may favor PDH activation (5), which may, in turn, improve the coupling between glycolysis and glucose oxidation and decrease cellular protons and acidosis and hence calcium overload (12,17).…”