Experimental Pulmonary Embolus in the Rat: A New in vivo Model to Test Thrombolytic Drugs
Experimental Pulmonary Embolus in the Rat: A New in vivo Model to Test Thrombolytic Drugs
复制标题
大鼠实验性肺栓塞：测试溶栓药物的新体内模型
DOI：
10.1097/00005344-198811000-00004
复制
发表时间：
1988
影响因子：
3
通讯作者：
T. Tschopp
中科院分区：
文献类型：
--
作者：
J. Clozel;P. Holvoet;T. Tschopp
目前，溶栓药物的作用是在需要相对大量药物的狗或兔模型中进行体内测试的。本研究的目的是描述一种新的模型，该模型允许测试具有有限量化合物的药物的体内溶栓作用。为此，我们通过将I125放射性标记的凝块注射到静脉循环中来诱导麻醉大鼠的肺栓塞，并且我们测量了自发发生的或通过增加剂量的野生型组织纤溶酶原激活剂（tPA）（从0.125至2 mg/kg i. v.）或通过链激酶（750，000 I.U./（kg i.v.）或尿激酶（750，000 I.U./ kg i.v.）。在这些大鼠的血浆中，我们还测量了tPA的纤溶酶原激活活性以及纤溶酶原、纤维蛋白原和α2-抗纤溶酶的浓度。自发地，存在时间依赖性血栓溶解（33%/h），可被抑肽酶部分抑制。野生型tPA诱导了剂量相关的血栓溶解，剂量超过0.25 mg/kg时，血浆纤维蛋白原浓度降低有限。链激酶和较小程度的尿激酶诱导了较大的止血分解（如全身纤维蛋白原溶解、纤溶酶原激活和α2-抗纤溶酶消耗所示）。我们的结论是，大鼠肺栓塞模型是适合于测试溶栓药物的溶栓疗效，效力和纤维蛋白特异性，需要比先前描述的体内模型的药物量较少。
Currently, the effects of the thrombolytic drugs are tested in vivo in dog or rabbit models that require a relatively large amount of the drug. The goal of the present study was to describe a new model that would allow one to test the in vivo thrombolytic effect of drugs with a limited amount of compound. For this purpose, we have induced a pulmonary embolus in anesthetized rats by injecting I125 radiolabeled clots into the venous circulation and we have measured the lysis of these clots occurring either spontaneously or induced by increasing doses of wild-type tissue plasminogen activator (tPA) (from 0.125 to 2 mg/kg i.v.) or by streptokinase (750,000 I.U./kg i.v.) or urokinase (750,000 I.U./kg i.v.). In the plasma of these rats, we have also measured the plasminogen activation activity of tPA as well as the concentrations of plasminogen, fibrinogen, and α2-antiplasmin. Spontaneously, there was a time dependent thrombolysis (33%/h) that could be partially inhibited by aprotinin. Wild-type tPA induced a dose-related thrombolysis with a limited decrease of plasma fibrinogen concentration with doses over 0.25 mg/kg. Streptokinase and to a smaller extent urokinase induced a larger hemostatic breakdown (as indicated by systemic fibrinogenolysis, plasminogen activation, and α2-antiplasmin consumption). We conclude that the rat pulmonary embolus model is suitable for testing the thrombolytic efficacy, potency, and the fibrin specificity of thrombolytic drugs and requires a smaller amount of drug than the previously described in vivo models.