Antiplatelet aggregation and endothelial protection of I₄, a new synthetic anti-diabetes sulfonylurea compound

Abstract

I₄ is a new synthetic anti-diabetes sulfonylurea compound. The aim of present study was to investigate the preventive effects and primary action mechanisms of I₄ on platelet-mediated arterial thrombosis. Platelet aggregation and 5-hydroxytryptamine (5-HT) secretion ex vivo was detected. The time-to-occlusion (TTO), thrombus weight and content of von Willebrand factor (vWF) in rat model of electrical- and ferric chloride-induced vessel occlusion were determined. Meanwhile, a rat model of type 2 diabetes mellitus (T2DM) was established to evaluate the effect of I₄ on levels of plasma p-selectin, 6-keto-prostaglandin F_1a (6-keto-PGF_1a), thromboxane B₂ (TXB₂), tissue-type plasminogen activator (t-PA) and type-1 plasminogen activator inhibitor (PAI-1). NO synthesis, NOS activity, adhesion of platelet toward endothelial cell and intercellular adhesion molecule-1 (ICAM-1) expression were examined. Results showed that I₄ exhibited a higher inhibitory potency than Glimepiride on ADP-induced platelet aggregation and 5-HT release ex vivo. In addition, I₄ reduced the thrombus weight and content of vWF and markedly prolonged TTO. Oral administration of I₄ (1 ∼ 10 mg/kg) inhibited p-selectin production, elevated the ratio of plasma 6-keto-PGF_1a/TXB₂ and t-PA/PAI-1 in T2DM rats. Furthermore, I₄ significantly improved NO synthesis and NOS activity, lowered adhesion ratio of platelet toward endothelial cells and ICAM-1 expression on HUVECs. These observations suggest that I₄ markedly improves platelet-mediated arterial thrombosis by inhibiting platelet activation and release reaction, ameliorating the endothelial dysfunction such as the suppression of vWF production and the reduction of the overexpression of ICAM-1, displayed its potential in alleviating diabetes-associated vascular complications.

• Endothelial dysfunction I₄
• platelet hyperreactivity
• platelet-mediated thrombosis

Acknowledgements

We appreciated Mr. Carlos A. Chan Cordeiro for language assistance.

Declaration of interest

The authors report no conflicts of interest. This study was supported by National major new drug creation program (2009ZX09103-094) and National Natural Science Foundation (30973638).