Glybenclamide Exhibits Thromboxane Receptor‐Dependent Antiplatelet Effects

Abstract

BackgroundProper platelet function is vital as they are the main cellular agents of hemostasis. Conversely, inappropriate activation of platelets is featured in occlusive disease such myocardial infarction, and stroke. While the thromboxane A2 pathway of platelet activation has been identified as an attractive target for pharmacological intervention, no thromboxane receptor (TPR) antagonists are available for clinical use. Given the structural similarity between the antidiabetic sulfonylurea agent Glybenclamide (Glyb) and the TPR antagonist SQ29548, we hypothesize that Glyb exhibits antiplatelet effects via interaction with TPR.ObjectiveCharacterize the potential antiplatelet capacity of Glyb.MethodsIsolate platelets from healthy donors who denied taking medication in the last 10 days and then investigate the effects of Glyb on platelet aggregation induced by the TPR agonist U46619, the thromboxane A2 precursor arachidonic acid (AA), ADP, as well as the protease‐activated receptor peptide (PAR4) using optical aggregometry.ResultsGlyb was found to dose‐dependently inhibit U46619/AA‐ (i.e., TPR‐) mediated platelet aggregation, but had no detectable effects on that triggered by ADP or PAR4.ConclusionOur findings suggest a therapeutic role for Glyb in thrombotic diseases via blockade of TPRs, and may lay the foundation for the design of therapeutic agents for selective targeting of TPR.