Anti-ischemic effects of trimetazidine: 31P-NMR spectroscopy in the isolated rat heart

Abstract

The effects of trimetazidine (TMZ) on ischemia-induced metabolic damage were evaluated by 31P-NMR spectroscopy in the isolated rat heart. Isolated rat hearts underwent retrograde perfusion (37 degrees C, 9.81 kPa, pH 7.4, bicarbonate buffer) and were subjected to either partial global ischemia (24 min, 0.2 ml.min-1 residual coronary flow) or total global ischemia (12 min, no flow). 31P-NMR spectra (132 accumulations, 45 degrees, 101.3 MHz) were recorded every 3 min. Changes in cardiac ATP, PC and Pi were followed, and intracellular pH was estimated from the chemical shift of Pi. Trimetazidine (TMZ) was added to the perfusion fluid at the beginning of the perfusion. The drug was used at 2 concentrations: 6.10(-7) M, with no effect upon cardiac contractility under normoxic conditions, and 6.10(-4) M, which significantly depresses cardiac work. When TMZ was used at a concentration of 6.10(-7) M, intracellular acidosis at the end of the 24 min low-flow ischemia protocol was lower than in control hearts (6.6 vs 6.0). During reperfusion, restoration of phosphorylation (as expressed by ATP/Pi ratios) was accelerated by the drug. Similar but more pronounced effects were seen following 12 min total ischemia when TMZ was used at a concentration (6.10(-4) M) which brings about a reduction in cardiac work. In this case, myocardial ATP content was also protected during ischemia. It is concluded that restoration of phosphorylation processes upon reperfusion is more rapid under the effects of trimetazidine than in control hearts. Protection of the mechanisms or structures involved in energy transfer could be due to a reduction in ischemia-induced intracellular acidosis under the effect of TMZ.