Rote W E, Mu D X, Roncinske R A, Frelinger A L, Lucchesi B R
University of Michigan Medical School, Department of Pharmacology, Ann Arbor.
J Pharmacol Exp Ther. 1993 Nov;267(2):809-14.
Applaggin, an inhibitor of platelet aggregation via binding to the glycoprotein IIb/IIIa receptor, was examined in an anesthetized canine model of arterial thrombosis formation secondary to arterial wall injury. Both carotid arteries were isolated and instrumented with flow probes, intravascular anodal electrodes and adjustable constrictors. The right carotid artery was injured initially and served as the control response to vessel wall injury in each animal, whereas the left carotid was injured after applaggin administration (1.0 mg/kg, i.v.). Arterial occlusion in the control vessel occurred in each of seven animals. Time for occlusive thrombus development was 125.6 +/- 15.2 min. One of the seven left carotid arteries occluded after applaggin. Thrombus weight was greater in control vessels (44.2 +/- 7.0 mg) vs. thrombus weight after applaggin (11.2 +/- 2.4 mg). Cyclic flow variations occurred in all control arteries before development of an occlusive thrombus. In contrast, cyclic flow variations were observed only in two of seven vessels injured after applaggin. One of the latter vessels developed an occlusive thrombus. Platelet counts, heart rate and blood pressure were unaltered over the course of the experimental protocol. Ex vivo platelet aggregation to arachidonic acid was examined before and after applaggin administration. Platelet-rich plasma from animals having initial normal baseline aggregation no longer aggregated 30 min after administration of applaggin. Aggregation returned to normal within 3 hr. Applaggin binds to stimulated and unstimulated platelets and two classes of binding sites were identified. The results demonstrate that applaggin possesses an antithrombotic effect in the experimental model of canine carotid artery thrombosis.
阿普拉金是一种通过与糖蛋白IIb/IIIa受体结合来抑制血小板聚集的物质，在动脉壁损伤继发的动脉血栓形成的麻醉犬模型中进行了研究。分离出双侧颈动脉，安装流量探头、血管内阳极电极和可调节的血管夹。首先损伤右侧颈动脉，作为每只动物对血管壁损伤的对照反应，而左侧颈动脉在静脉注射阿普拉金（1.0mg/kg）后进行损伤。七只动物的对照血管均发生了动脉闭塞。闭塞性血栓形成的时间为125.6±15.2分钟。七只接受阿普拉金处理的左侧颈动脉中有一只发生了闭塞。对照血管中的血栓重量（44.2±7.0mg）大于阿普拉金处理后的血栓重量（11.2±2.4mg）。在闭塞性血栓形成之前，所有对照动脉均出现了周期性血流变化。相比之下，在接受阿普拉金处理后损伤的七只血管中，只有两只观察到了周期性血流变化。其中一只血管形成了闭塞性血栓。在实验过程中，血小板计数、心率和血压均未改变。在给予阿普拉金前后，检测了体外血小板对花生四烯酸的聚集情况。初始基线聚集正常的动物的富含血小板血浆在给予阿普拉金30分钟后不再聚集。聚集在3小时内恢复正常。阿普拉金与受刺激和未受刺激的血小板结合，并鉴定出两类结合位点。结果表明，阿普拉金在犬颈动脉血栓形成的实验模型中具有抗血栓作用。
