Acta Pharmacologica Sinica (2010) 31: 150–159; doi: 10.1038/aps.2009.195

Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA

Aim: To investigate the potential antagonistic activity of the antidiabetic agent glybenclamide for the human platelet thromboxane A₂ receptor (abbreviated as TPR).

Methods: Platelets were obtained from healthy donors.  Aggregation studies were performed in a model 700 aggregometry system.  Radioactivity was counted in a Beckman LS 6000 liquid scintillation counter and calcium imaging was performed using an LS50B PerkinElmer Fluorescence Spectrometer. 

Results: It was found that glybenclamide: 1) inhibited aggregation induced by the TPR agonist U46619 (IC₅₀=2.3±0.31 µmol/L) and by the thromboxane A₂ precursor arachidonic acid (IC₅₀=2.6±0.24 µmol/L); 2) displaced SQ29,548 from its binding sites on platelets; 3) lacked any detectable effects on aggregation stimulated by ADP, or the thrombin receptor activating-peptide 4; 4) blocked calcium mobilization induced by U46619, but not by ADP; and 5) failed to raise cAMP levels.

Conclusion: The findings indicate that glybenclamide exerts inhibitory effects on platelets by interacting with TPR.  Thus, glybenclamide or a rationally designed derivative has the potential to serve as an antithrombotic agent.

Keywords: platelet; thromboxane receptor; thrombosis; drug-repurposing; antagonist