Inhibitory effect of trimetazidine on thrombin-induced aggregation and calcium entry into human platelets

• Published in: Journal of cardiovascular pharmacology Vol. 23; no. 3; p. 401
• Main Authors: Astarie-Dequeker, C, Joulin, Y, Devynck, M A
• Format: Journal Article
• Language: English
• Published: United States 01.03.1994
• Subjects: Blood Platelets - drug effects; Blood Platelets - metabolism; Calcium - blood; Calcium - pharmacology; Cytosol - drug effects; Cytosol - metabolism; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Platelet Activation - drug effects; Platelet Aggregation - drug effects; Protons; Thrombin - antagonists & inhibitors; Thrombin - pharmacology; Trimetazidine - pharmacology
• ISSN: 0160-2446
• DOI: 10.1097/00005344-199423030-00007

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.