Repurposing an old drug for a new use: glybenclamide exerts antiplatelet activity by interacting with the thromboxane...

To investigate the potential antagonistic activity of the antidiabetic agent glybenclamide for the human platelet thromboxane A(2) receptor (abbreviated as TPR).

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.

It was found that glybenclamide: 1) inhibited aggregation induced by the TPR agonist U46619 (IC(50)=2.3+/-0.31 micromol/L) and by the thromboxane A(2) precursor arachidonic acid (IC(50)=2.6+/-0.24 micromol/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.

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.