Glybenclamide: an antidiabetic with in vivo antithrombotic activity.
While proper platelet function is a vital component of hemostasis, their inappropriate activation contributes to thrombotic disorders. One pathway for platelet activation involves their synthesis of the lipid mediator thromboxane A₂ (TXA₂). Although TXA₂ acts by binding to a seven-transmembrane receptor (i.e., the prostanoid TP receptor) that participates in the genesis of thrombosis, currently, there are no antagonists available for clinical use. Since the only available drug targeting this pathway (aspirin) is associated with inherent limitations/serious side effects, developing prostanoid TP receptor antagonists is clearly warranted. To this end, we have previously employed the "repurposing old drugs for new uses" approach to identify prostanoid TP receptor antagonists and showed that the antidiabetic agent glybenclamide selectively inhibited human platelet prostanoid TP receptors (in vitro). On this basis, we hypothesized that glybenclamide exhibits in vivo antiplatelet potential, and therefore, may protect against thrombosis development. Using murine platelets, it was found that glybenclamide injections: 1) inhibited platelet aggregation induced by the prostanoid TP receptor agonist U46619 and the TXA₂ precursor arachidonic acid, under ex vivo experimental settings, concentration-dependently; 2) lacked any detectable effects on aggregation stimulated by ADP, or the thrombin receptor activating-peptide 4; 3) impaired hemostasis by prolonging tail bleeding time; and 4) delayed the development of occlusive thrombi in a carotid artery injury model. Taken together, these findings indicate that glybenclamide does indeed exert, ex vivo and in vivo, prostanoid TP receptor-dependent inhibitory effects on platelet function. Thus, glybenclamide has the potential to be applied in the management of thromboembolic disorders.
Ting
Harold J
HJ
Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, 309 E. Second Street, Pomona, CA 91766, USA.
Khasawneh
Fadi T
FT
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D001760:Bleeding Time; D002341:Carotid Artery Thrombosis / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D058492:Drug Repositioning; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D005905:Glyburide / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006487:Hemostasis / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D009994:Osmolar Concentration; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D017482:Receptors, Thromboxane / Q000819:agonists / Q000037:antagonists & inhibitors; D013923:Thromboembolism / Q000517:prevention & control; D013927:Thrombosis / Q000517:prevention & control*; D013997:Time Factors
D005343:Fibrinolytic Agents; D007004:Hypoglycemic Agents; D010975:Platelet Aggregation Inhibitors; D017482:Receptors, Thromboxane; D016718:Arachidonic Acid; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D005905:Glyburide