The fraction of glucose passing through glycolysis that is oxidized is low in hypertrophied hearts, a pattern of glucose use associated with poor postischemic contractile function. We tested the hypothesis that trimetazidine, a partial 3-ketoacyl coenzyme A thiolase inhibitor, would stimulate glucose oxidation and, thereby, improve fractional glucose oxidation and postischemic function of hypertrophied hearts. Function, glycolysis, and oxidation of glucose, lactate, and palmitate were measured before and after global no-flow ischemia in isolated working hearts from sham-operated (control) and aortic-constricted (hypertrophied) male Sprague-Dawley rats in the presence or absence of 1 M trimetazidine. Heart function was significantly improved by trimetazidine after ischemia, but only in hypertrophied hearts, with function improving to values in untreated control hearts. This effect occurred in association with relatively minor changes in oxidative metabolism. However, trimetazidine reduced glycolysis by ϳ30% but did so only in hypertrophied hearts, an unexpected novel action of this agent that resulted in a larger fractional oxidation of glucose, effectively normalizing it in hypertrophied hearts. Thus, trimetazidine normalizes postischemic function and fractional glucose oxidation in hypertrophied hearts, mainly by reducing glycolysis. These data extend the potential usefulness of trimetazidine and provide support for its use as a means to improve postischemic function of pressure overload hypertrophied hearts.

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.

The present study investigated the tolerance of the isolated rat heart to ischemia-reperfusion after administration of trimetazidine (TMZ) at different experimental phases, as well as the possible involvement of p38 MAPK and JNKs in this response. Isolated rat hearts were perfused in Langendorff mode. Untreated hearts after stabilization (S) were subjected to 20 min of zero-flow global ischemia (I) and 45 min of reperfusion (R), (NORM), n = 9. TMZ (10(-5) M) was administered (in the perfusate): a) only at S phase, (TMZ-STAB), n = 8, b) only at R, (TMZ-REP), n = 8 and c) during both S and R, (TMZ-STAB+REP), n = 8. Recovery of left ventricular developed pressure at 45 min of R (Rec) was significantly higher in TMZ-STAB and TMZ-STAB+REP and LDH release was lower in TMZ-STAB+REP and TMZ-STAB than NORM, [1153.2 (121.0) and 1152.1 (86.8) vs 1573.5 (138.2), P < 0.05]. TMZ induced cardioprotection did not involve p38 MAPK and JNKs. Phospho-p38 MAPK and JNKs levels after I/R were not changed with TMZ treatment. In TMZ-REP, Rec and LDH release were similar to NORM, but the rate of functional recovery (ratio of Rec at 10 min of R to Rec) was 86.7% (13.3) for TMZ-REP vs 53.8% (7.7) for NORM, P < 0.05. This effect was associated with decreased myocardial lactate content early at reperfusion. In conclusion, preischemic administration of TMZ protects against I/R injury while TMZ given only at reperfusion accelerates recovery of function without reducing the extent of injury.

TMZ limited ischemia-induced electrical dysfunction leading to cardiac susceptibility to VF by decreasing lipid peroxidation and maintaining ionic homeostasis. TMZ could therefore provide protection against ischemia-induced VF.

The present study investigated the ability of trimetazidine (TMZ) to maintain cardiac mitochondrial function during the development of insulin deficiency and hyperinsulinaemia. The anti-ischaemic drug TMZ is known to increase phospholipid synthesis in cardiac membranes and to have a cardioprotective effect. Insulin deficiency was obtained by streptozotocin injection and hyperinsulinaemia was achieved via a fructose diet. Trimetazidine was incorporated into the diet (7.8 mg/day) and mitochondrial function was evaluated in skinned cardiac fibres. Insulin deficiency decreased mitochondrial affinity for ADP and the index of creatine kinase functional activity. This last alteration was partially prevented by TMZ treatment. Insulin deficiency strongly decreased n-3 polyunsaturated fatty acids, especially the docosahexaenoic acid (DHA) content, in cardiac and mitochondrial membranes, inducing a strong increase in the n-6/n-3 ratio. Trimetazidine treatment limited the increase in the n-6/n-3 ratio and prevented the decrease in DHA content in mitochondrial membranes. Insulin deficiency decreased glutamate- and palmitoylcarnitine-supported respiration. Hyperinsulinaemia affected neither mitochondrial affinity for ADP nor the index of creatine kinase functional activity. Hyperinsulinaemia slightly and significantly affected mitochondrial fatty acid composition, by a small increase the n-6/n-3 ratio. Trimetazidine did not modify membrane-bound mitochondrial function but increased the n-6/n-3 ratio. Moreover, hyperinsulinaemia decreased glutamate-supported respiration. In conclusion, modification of membrane homeostasis with TMZ partially prevented the alterations in fatty acid composition and function in cardiac mitochondria induced by insulin deficiency. Three months of hyperinsulinaemia did not modify membrane-bound mitochondrial function and had only slight effects on fatty acid composition.