I4, a new synthetic sulfonylurea compound, inhibits the action of TXA2 in vivo and in vitro on platelets and aorta vascular smooth muscle.
BACKGROUND
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.


OBJECTIVE
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.


CONCLUSIONS
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.
Department of Pharmacology, China Pharmaceutical University, Nanjing, PR China.
Na
N
Lu
Minxia
M
Zhan
Cong
C
Gao
Guanzhong
G
Wu
Huibing
H
Zhang
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000276:immunology / Q000473:pathology; D006801:Humans; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013453:Sulfonylurea Compounds / Q000737:chemistry* / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000276:immunology
D010975:Platelet Aggregation Inhibitors; D013453:Sulfonylurea Compounds; D013928:Thromboxane A2; D002118:Calcium