I4, a new synthetic sulfonylurea compound, inhibits the action of TXA2in vivo and in vitro on platelets and aorta vascular smooth muscle

Introduction1-[4-[2-(4-Bromobenzene-sulfonamino)ethyl]phenylsulfonyl]-3-(trans-4-methylcy-clohexyl)urea(I4, CAS865483-06-3); a totally synthetic new sulfonylurea compound, combining the hypoglycemic active structure of Glimepiride (CAS 93479-97-1) and anti-TXA2 receptor (TP) active structure of BM-531(CAS 284464-46-6), was designed and synthesized. Its effects on TXA2 synthesis and TP have not been reported yet.AimTo study the inhibitory effects of I4 and its mechanisms of action on TXA2 and TP.MethodsPlatelet 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 TXA2, CAS 56985-40-1). Plasma TXB2 and 6-keto-prostaglandin F1α (6-keto-PGF1α) were used as markers to determine the effect of I4 on thromboxane synthesis. Fluo-3-AM was used to measure the cytosolic Ca2 + concentrations ([Ca2 +]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 I4 on platelet aggregation induced by U-46619.ResultsI4 exhibited a higher inhibitory potency than Glimepiride on U-46619 induced platelet aggregation in vitro and in vivo. I4 increased the ratio of plasma PGI2/TXA2 and decreased [Ca2 +]i release from platelet internal stores. In addition, I4 presented a vasorelaxant activity on isolated rat aorta contraction induced by U-46619.Oral administration of I4 (1 ~ 10 mg/kg) markedly and dose-dependently inhibited platelet aggregation in both normal rats and type 2 diabetic rats.ConclusionI4 significantly inhibited platelet aggregation induced by U-46619 in vitro and in vivo, and rat aorta contraction. It probably acts by partly blocking TXA2 action, decreasing the platelet intracellular Ca2 +, and increasing the PGI2/TXA2 ratio.