Department of Pharmaceutical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA.
Acta Pharmacol Sin. 2010 Feb;31(2):150-9. doi: 10.1038/aps.2009.195.
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.
研究抗糖尿病药物格列本脲对人血小板血栓素 A(2)受体（简称 TPR）的潜在拮抗活性。
从健康供体中获得血小板。在模型 700 聚合仪系统中进行聚合研究。使用 Beckman LS 6000 液体闪烁计数器计数放射性，使用 LS50B PerkinElmer 荧光分光光度计进行钙成像。
发现格列本脲：1）抑制 TPR 激动剂 U46619（IC（50）=2.3+/-0.31μmol/L）和血栓烷 A（2）前体花生四烯酸（IC（50）=2.6+/-0.24μmol/L）诱导的聚集；2）从血小板结合部位置换 SQ29,548；3）对 ADP 或凝血酶受体激活肽 4 刺激的聚集没有任何可检测的影响；4）阻断 U46619 诱导的钙动员，但不阻断 ADP；5）未能升高 cAMP 水平。
这些发现表明，格列本脲通过与 TPR 相互作用对血小板发挥抑制作用。因此，格列本脲或合理设计的衍生物有可能成为一种抗血栓形成剂。
