摘要
目的 :研究新型磺酰脲类化合物G0 0 4的抗血栓作用及机制。方法 :考察G0 0 4对体外大鼠主动脉血管收缩、人血小板聚集、小鼠尾静脉出血时间、实验性血栓形成以及对人脐静脉内皮细胞(ECV30 4 )分泌PGI2 和TXA2 的影响 ,并应用Fluo3 AM测定G0 0 4对ECV30 4 [Ca2 + ]i 的影响。结果 :G0 0 4不能拮抗去甲肾上腺素、氯化钾诱导的体外缩血管作用 ,但显著抑制花生四烯酸 (AA)、二磷酸腺苷 (ADP)诱导的体外人血小板聚集 ,延长小鼠尾静脉出血时间 ,对小鼠胶原 -肾上腺素诱发体内血栓有明显的保护作用 ,明显延长电刺激导致的大鼠颈动脉血栓形成时间 ,促进ECV30 4分泌PGI2 ,抑制TXA2 的合成并呈现浓度依赖性 ,对高 [K+ ]引起的钙内流无抑制作用。结论 :G0 0 4具有显著的抗体内血栓作用 ,其机制可能与抑制血小板聚集、降低内皮细胞分泌TXA2 、刺激PGI2 释放有关。
AIM:To study the effects and mechanisms of a novel sulfonylureous compound 1 ｛4 [2 (4 bromobenzenesulfonaminoethyl)phenylsufonyl｝ 3 (trans 4 methylcyclohexyl) urea, G004, on antithrombosis. METHODS: The influence of compound G004 on the vasoconstrictor action, platelet aggregation and thrombosis formation was studied. The effects of compound G004 on the tail vein bleeding time in mice was examined. The influence of compound G004 on the release of prostanglandin I 2 and thromboxan A 2 from ECV304 cells was investigated. The measurement of cytosolic free Ca 2+ in attached ECV304 cells loaded with Fluo3/AM was carried out. RESULTS: Compound G004 did not inhibit the contraction of rat aorta rings induced by norepinephrine or potassium chloride, but potently inhibit human platelet aggregation challenged by arachidonic acid and adenosine diphosphate. Compound G004 significantly prolonged the tail vein bleeding time in mice and occlusion time of carotid artery in experimentally thrombotic rats. Compound G004 reduced mice mortality induced by the collagen plus epinephrine in a dose dependent manner. Compound G004 enhanced PGI 2 release and reduced TXA 2 secretion from ECV304 cells. G004 had no effect on the increase of cytosolic free Ca 2+ induced by patassium chloride. CONCLUSION: The compound G004 has a remarkable antithrombotic effect in vivo. Its active mechanism may be attributed to inhibition of platelet aggregation, enhancing PGI 2 generation and decreasing TXA 2 secretion from human umbilical vein endothelium.
出处
《中国临床药理学与治疗学》
CAS
CSCD
2005年第2期162-167,共6页
Chinese Journal of Clinical Pharmacology and Therapeutics
