Introduction: 1-[4-[2-(4-Bromobenzene-sulfonamino)ethyl]phenylsulfonyl]-3-(trans-4-methylcy-clohexyl)urea(I(4), CAS865483-06-3); a totally synthetic new sulfonylurea compound, combining the hypoglycemic active structure of Glimepiride (CAS 93479-97-1) and anti-TXA(2) receptor (TP) active structure of BM-531(CAS 284464-46-6), was designed and synthesized. Its effects on TXA(2) synthesis and TP have not been reported yet.
Aim: To study the inhibitory effects of I(4) and its mechanisms of action on TXA(2) and TP.
Methods: Platelet aggregation studies were performed on human platelet, rat whole blood platelet and rabbit platelet, platelets aggregation was induced by TP agonist U-46619(stable analog of TXA(2), CAS 56985-40-1). Plasma TXB(2) and 6-keto-prostaglandin F(1α) (6-keto-PGF(1α)) were used as markers to determine the effect of I(4) on thromboxane synthesis. Fluo-3-AM was used to measure the cytosolic Ca(2+) concentrations ([Ca(2+)](i)) in rabbit platelet. Aorta rings with and without endothelium were prepared and aorta contraction was induced by U-46619. A model of type 2 diabetes mellitus was established by intraperitoneal injection of low dose of streptozocin to rats fed a high-calorie diet. Both normal rats and type 2 diabetic rats were used to assay the inhibitory effect of I(4) on platelet aggregation induced by U-46619.
Results: I(4) exhibited a higher inhibitory potency than Glimepiride on U-46619 induced platelet aggregation in vitro and in vivo. I(4) increased the ratio of plasma PGI(2)/TXA(2) and decreased [Ca(2+)](i) release from platelet internal stores. In addition, I(4) presented a vasorelaxant activity on isolated rat aorta contraction induced by U-46619.Oral administration of I(4) (1~10mg/kg) markedly and dose-dependently inhibited platelet aggregation in both normal rats and type 2 diabetic rats.
Conclusion: I(4) significantly inhibited platelet aggregation induced by U-46619 in vitro and in vivo, and rat aorta contraction. It probably acts by partly blocking TXA(2) action, decreasing the platelet intracellular Ca(2+), and increasing the PGI(2)/TXA(2) ratio.
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