激活血管内皮细胞乙酰胆碱作用靶标的抗血栓作用及其分子机制  

Antithrombosis through activating endothelial target for acetylcholine and its molecular mechanism

作　　者：陈冬梅[1] 慕邵峰[1] 汪海[1] 

机构地区：[1]军事医学科学院毒物药物研究所,北京100850

出　　处：《中国药理学通报》2002年第5期527-531,共5页Chinese Pharmacological Bulletin

基　　金：国家重点基础研究发展规划项目(NoG19980 5 112 );北京赛德维康医药研究院新药研究基金项目资助 (No 19990 0 1)

摘　　要：目的　在角叉菜胶诱发的小鼠尾动脉血栓模型上 ,研究激活血管内皮细胞乙酰胆碱作用靶标对血栓形成的影响并探讨其可能的分子机制。方法　比较既可激活血管内皮乙酰胆碱作用靶标 ,又可激活M受体的槟榔碱和仅可激活M受体的毛果芸香碱对成栓率和血栓长度影响的差异 ,分析激活内皮乙酰胆碱作用靶标对血栓的影响 ;通过测定血小板最大聚集率 ;凝血酶原时间 (PT)、活化部分凝血活酶时间(KPTT)和凝血酶时间 (TT) ;血浆中组织型纤溶酶原激活物(t PA)的含量和纤溶酶原激活物抑制剂 (PAI 1)的活性 ;血浆血栓素A2 (TXA2 )和前列环素 (PGI2 )含量 ,分析其可能的分子机制。结果　槟榔碱在 0 1～ 4 0mg·kg-1(ip)可剂量依赖性地对抗血栓形成 ,而在相同条件下 ,大剂量 (4mg·kg-1)的毛果芸香碱仍无抗血栓作用 ;槟榔碱对TT ,PT和KPTT和血小板最大聚集率 (MAR)均无影响 ;使血浆中t PA的含量升高 ,PAI 1的活性降低 ;使血栓形成过程中升高的TXA2 降低 ,并呈明显的量效关系 ,使血栓形成过程中降低的PGI2 升高。结论　激活血管内皮细胞乙酰胆碱靶标可对抗血栓形成 ,其可能的分子机制不通过直接影响凝血系统和血小板的聚集 ,而通过促进内皮细胞释放t PA和抑制内皮细胞合成并释放的PAI 1的活性 ,间接激活纤溶系统 ,发挥抗血栓?AIM To examine antithrombotic effects of arecoline on the arterial thrombosis induced by carrageenin in mice through modulating the functions of endothelium and determine its mechanisms from hemostatic system, the platelet aggregative functions and the bioactive factors released by vascular endothelial cells. METHODS Kappa carrageenin was given ip in mice and mice were fed at the temperature of 20 to 21 degrees and at the humidity of 30 percent to 50 percent. RESULTS On the foregoing models of thrombosis, arecoline could antagonize the formation of thrombosis through activating the endothelial target for acetylcholine in a dose dependent manner and its antithrombotic potency was 250 to 500 times greater than aspirin; while under the same conditions, pilocarpine could not antagonize the formation of thrombosis. The levels of TT, PT, KPTT and MAR had no prominent changes compaired with control groups. The levels of t-PA became higher greatly than normal and the levels of PAI 1 became lower greatly than normal 2 hours after intravenous injection of arecoline in rats. Arecoline could decrease the higher plasma levels of thromboxane A2 and increase the lower plasma levels of prostacyclin in a dose dependent manner in the mice tail thrombosis induced by carrageenin. CONCLUSION The antithrombotic effects of arecoline are associated with activating the endothelial target for acetylcholine closely, but are not associated with muscarinic receptors,and not relevant to hemostatic systems or functions of platelet aggregation directly.

关 键 词：角叉菜胶 槟榔碱 t—PA PAI-1 激活血管内皮细胞乙酰胆碱靶标 抗血栓作用 分子机制 动物实验 

分 类 号：R972.6[医药卫生—药品] R－332[医药卫生—药学]