Astarie-Dequeker C, Joulin Y, Devynck M A
CNRS URA 1482, Necker Medical School, Paris, France.
J Cardiovasc Pharmacol. 1994 Mar;23(3):401-7.
The antiaggregatory properties of trimetazidine were investigated further by analyzing its effects on cytosolic calcium and proton concentrations, well-known regulators of platelet reactivity. Aggregatory responses of washed platelets were assessed by turbidometry, and cytosolic Ca2+ concentration ([Ca2+]i) and pH (pHi) were determined by their respective fluorescent probes: Fura-2 and BCECF. Preincubation with trimetazidine dose-dependently inhibited platelet aggregation induced by 0.05 U/ml thrombin (p < 0.001). At concentrations < or = 1 mM, trimetazidine did not affect the resting [Ca2+]i value but slightly alkalinized the cytosol by 0.05 +/- 0.03 pH units (p < 0.02, n = 11). In platelets stimulated by 0.05 U/ml thrombin, 0.1 mM trimetazidine did not modify pHi variations but decreased [Ca2+]i variations (p < 0.003, n = 16), blunting by 28 +/- 6% the transient peak of [Ca2+]i (p < 0.006) and decreasing by 6 +/- 2% the equilibrium value (p < 0.005). These inhibitory effects were inversely dependent on thrombin concentrations (p < 0.004, n = 21) and were abolished in the virtual absence of external Ca2+. Trimetazidine therefore attenuates the Ca2+ influx evoked by thrombin, thereby limiting Ca2+ accumulation in stimulated platelets. Such a protective effect may participate in the antiaggregatory properties of trimetazidine.
通过分析曲美他嗪对细胞溶质钙和质子浓度（已知的血小板反应性调节因子）的影响，对其抗聚集特性进行了进一步研究。通过比浊法评估洗涤血小板的聚集反应，并使用各自的荧光探针Fura-2和BCECF测定细胞溶质Ca2+浓度（[Ca2+]i）和pH（pHi）。曲美他嗪预孵育剂量依赖性地抑制了0.05 U/ml凝血酶诱导的血小板聚集（p < 0.001）。在浓度≤1 mM时，曲美他嗪不影响静息[Ca2+]i值，但使细胞溶质轻微碱化0.05±0.03个pH单位（p < 0.02，n = 11）。在由0.05 U/ml凝血酶刺激的血小板中，0.1 mM曲美他嗪不改变pHi变化，但降低了[Ca2+]i变化（p < 0.003，n = 16），使[Ca2+]i的瞬时峰值降低28±6%（p < 0.006），并使平衡值降低6±2%（p < 0.005）。这些抑制作用与凝血酶浓度呈负相关（p < 0.004，n = 21），并且在几乎没有外部Ca2+的情况下被消除。因此，曲美他嗪减弱了凝血酶诱发的Ca2+内流，从而限制了受刺激血小板中Ca2+的积累。这种保护作用可能参与了曲美他嗪的抗聚集特性。
