Rote W E, Davis J H, Mousa S A, Reilly T M, Lucchesi B R
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0626.
J Cardiovasc Pharmacol. 1994 Apr;23(4):681-9. doi: 10.1097/00005344-199404000-00025.
The platelet glycoprotein IIb/IIIa receptor (GPIIb/IIIa, fibrinogen receptor) represents the final common pathway for platelet aggregation. Inhibition of GPIIb/IIIa with antibodies or peptides containing the RGD sequence has been reported to prevent arterial thrombosis. We examined DMP 728 [(cyclic[D-2-amino-butyryl-N2-methyl-L-arginyl-glycyl-L-aspartyl-3-(a min o- methyl-benzoic acid], methanesulfonic acid salt], a cyclic peptidomimetic, GPIIb/IIIa receptor antagonist, for prevention of thrombosis and rethrombosis in a canine model of carotid artery thrombosis. Dogs were anesthetized, and both carotid arteries were instrumented with an electrode, a flow probe, and a stenosis. A 300-microA current was applied to the intimal surface in the right carotid artery (RCA, control) through the electrode; time to occlusive thrombus formation and thrombus mass was noted. The RCA served as the control vessel; the left carotid artery (LCA) served as the test vessel after DMP 728 administration (0.1 or 1. mg/kg, intravenously, i.v.). As compared with controls, occlusive thrombus formation was reduced by both doses of DMP 728 (control 100% n = 12; 0.1 mg/kg i.v. 17%, p < 0.05, n = 6; 1.0 mg/kg i.v. 0%, p < 0.05, n = 6), time to occlusion was increased (p < 0.05), and thrombus weight was reduced (p < 0.05). Ex vivo platelet aggregation was inhibited in all groups. In a second group of animals, a carotid artery thrombus was formed and lysed with anisoylated plasminogen activator complex (APSAC; 0.05 U/kg intraarterially, i.a.) with or without DMP 728.(ABSTRACT TRUNCATED AT 250 WORDS)
血小板糖蛋白IIb/IIIa受体（GPIIb/IIIa，纤维蛋白原受体）代表血小板聚集的最终共同途径。据报道，用抗体或含RGD序列的肽抑制GPIIb/IIIa可预防动脉血栓形成。我们研究了环肽模拟物DMP 728（环[D-2-氨基丁酰基-N2-甲基-L-精氨酰基-甘氨酰基-L-天冬氨酰基-3-（氨基甲基苯甲酸），甲磺酸盐]），一种GPIIb/IIIa受体拮抗剂，在犬颈动脉血栓形成模型中预防血栓形成和再血栓形成的作用。犬只麻醉后，双侧颈动脉均植入电极、血流探头并造成狭窄。通过电极向右侧颈动脉（RCA，对照组）内膜表面施加300微安电流；记录形成闭塞性血栓的时间和血栓质量。RCA作为对照血管；左颈动脉（LCA）在静脉注射（i.v.）DMP 728（0.1或1.毫克/千克）后作为受试血管。与对照组相比，两种剂量的DMP 728均减少了闭塞性血栓形成（对照组100%，n = 12；0.1毫克/千克静脉注射组17%，p < 0.05，n = 6；1.0毫克/千克静脉注射组0%，p < 0.05，n = 6），延长了闭塞时间（p < 0.05），并减轻了血栓重量（p < 0.05）。所有组的体外血小板聚集均受到抑制。在第二组动物中，形成颈动脉血栓并用茴香酰化纤溶酶原激活剂复合物（APSAC；0.05单位/千克动脉内注射，i.a.）溶解，同时给予或不给予DMP 728。（摘要截短于250字）
