EFFECTS OF TRIMETAZIDINE ON ISCHEMIC CONTRACTURE IN ISOLATED-PERFUSEDRAT HEARTS

Trimetazidine (1-[2,3,4-trimethoxibenzyl)]-piperazine, TMZ) is a drug with a proposed metabolically based antiischemic action. Because ische mic contracture is a serious complication of ischemia and is considere d metabolic in origin, we studied the effect of trimetazidine (TMZ) on development of ischemic contracture in experimental low-flow ischemia . TMZ was either added to the perfusion fluid or given as pretreatment to the donor rats. Langendorff-perfused isolated rat hearts were subm itted to 30-min subtotal global ischemia (residual flow = 0.2 ml/min, n = 6 per group) (normal flow = 12.4 +/- 0.8 mi/min, heart fresh weigh t = 0.9 +/- 0.3 g). Ischemic contracture was measured by a water-fille d intraventricular balloon. Thereafter, the hearts were reperfused for 20 min and recovery of intraventricular pressure was monitored. Furth ermore, because the mechanisms of action of TMZ may involve cellular e nergy metabolism, we assessed throughout glycolytic flux by collecting the coronary effluent every 5 min during control perfusion, ischemia, and reperfusion periods. Animals from the pretreated groups received TMZ [3 mg/kg orally (p.o.) twice daily] for 5 days. Animals from the c ontrol group received placebo for the same time period. Concentrations of 10(-6) and 10(-4) M were used when the drug was added to the perfu sate. In our experimental conditions, TMZ pretreat ment alone had no m easurable cardioprotective effect, but addition to the perfusate of TM Z 10(-6) M, approximately a therapeutic concentration in humans, reduc ed ischemic contracture in both pretreated and control groups and impr oved postischemic recovery of developed pressure. Conversely, TMZ exer ted no cardioprotective effect when added to the perfusate at a higher concentration (10(-4) M), which unexpectedly exacerbated ischemic con tracture. Finally, glucose utilization remained unchanged in the diffe rent groups, suggesting that the mechanism of the antiischemic action of TMZ (10(-6) M) was not dependent on an increased rate of glycolytic flux.