McGhie A I, McNatt J, Ezov N, Cui K, Mower L K, Hagay Y, Buja L M, Garfinkel L I, Gorecki M, Willerson J T
Department of Internal Medicine (Cardiology Division), University of Texas-Houston Health Science Center.
Circulation. 1994 Dec;90(6):2976-81. doi: 10.1161/01.cir.90.6.2976.
Platelets play an important role in the pathophysiology of acute coronary syndromes. The interaction between the platelet glycoprotein Ib receptor and von Willebrand factor is a critical event allowing platelet adhesion and aggregation and subsequent thrombus formation in vessels with high shear rates and damaged endothelium. Therefore, we tested the hypotheses that VCL, an antagonist of von Willebrand-glycoprotein Ib binding domain, (1) attenuates/abolishes cyclic flow variations in stenosed, endothelium-injured coronary arteries in nonhuman primates and (2) reduces botrocetin-induced platelet aggregation in vitro after intravenous in vivo administration.
Cyclic flow variations were established in anesthetized, open-chest baboons (n = 18). The baboons were divided into three groups. One group (n = 8) received a bolus of VCL (4 mg/kg IV) followed by an infusion (6 mg.kg-1.h-1) for 90 minutes (schedule A). Another group (n = 6) received a 2-mg/kg bolus followed by an infusion of 3 mg.kg-1.h-1 for 90 minutes (schedule B). The third group received a placebo infusion of normal saline. Under dosing schedule A, cyclic flow variations were abolished in 7 of 8 baboons after 33 +/- 18 minutes and markedly attenuated in 1. The frequency of cyclic flow variations fell from 18 +/- 9.4 per hour during the control period to 1 +/- 2.5 per hour after VCL infusion, P < .002. After cessation of infusion, cyclic flow variations remained abolished in 5 of 7 animals for > 3 hours and returned in 2 of 7 after 2 to 2.5 hours. Under schedule B, cyclic flow variations were abolished in 3 of 6 baboons and markedly reduced in the remainder. The number of cyclic flow variations fell from 17 +/- 4.8 per hour during the control period to 5 +/- 4.9 per hour after the VCL infusion, P < .001. The cyclic flow variations returned spontaneously at 38 +/- 40 minutes under this dosing schedule. Placebo infusion of saline had no effect on cyclic flow frequency or severity. VCL administration was associated with slight prolongation in bleeding time and a reduction in botrocetin-induced platelet aggregation. The bleeding time increased from a control time of 88 +/- 32 to 276 +/- 204 seconds, P < .03, and from 142 +/- 28 to 176 +/- 36 seconds, P = .056, for schedules A and B, respectively. VCL decreased platelet aggregation in response to botrocetin (20 micrograms/mL), from a control value of 66 +/- 30.3 to 33 +/- 31.3 omega, P < .05, and from 64 +/- 23.5 to 46 +/- 15.8 omega, P = .006, for dosing schedules A and B, respectively.
Therefore, administration of a peptide fragment corresponding to von Willebrand-glycoprotein Ib binding domain (1) is effective in abolishing cyclic flow variations in stenosed, endothelium-injured coronary arteries and (2) reduces platelet aggregation in vivo in response to botrocetin in nonhuman primates.
血小板在急性冠状动脉综合征的病理生理学中起重要作用。血小板糖蛋白Ib受体与血管性血友病因子之间的相互作用是一个关键事件，可使血小板在高剪切率和内皮受损的血管中发生黏附、聚集及随后的血栓形成。因此，我们检验了以下假设：血管性血友病因子-糖蛋白Ib结合域拮抗剂VCL，（1）减轻/消除非人类灵长类动物狭窄、内皮损伤冠状动脉中的周期性血流变化；（2）在静脉内体内给药后，减少in vitro中蛇毒巴曲酶诱导的血小板聚集。
在麻醉、开胸的狒狒（n = 18）中建立周期性血流变化。将狒狒分为三组。一组（n = 8）静脉推注VCL（4 mg/kg），随后输注（6 mg·kg-1·h-1）90分钟（方案A）。另一组（n = 6）静脉推注2 mg/kg，随后输注3 mg·kg-1·h-1 90分钟（方案B）。第三组输注生理盐水作为安慰剂。在方案A给药时，8只狒狒中有7只在33±18分钟后周期性血流变化消失，1只明显减轻。周期性血流变化的频率从对照期的每小时18±9.4次降至VCL输注后的每小时1±2.5次，P <.002。输注停止后，7只动物中有5只的周期性血流变化在> 3小时内仍消失，7只中有2只在2至2.5小时后恢复。在方案B下，6只狒狒中有3只的周期性血流变化消失，其余明显减少。周期性血流变化的次数从对照期的每小时17±4.8次降至VCL输注后的每小时5±4.9次，P <.001。在此给药方案下，周期性血流变化在38±40分钟时自发恢复。生理盐水安慰剂输注对周期性血流频率或严重程度无影响。给予VCL与出血时间略有延长及蛇毒巴曲酶诱导的血小板聚集减少有关。方案A和方案B的出血时间分别从对照时间88±32秒增加到276±204秒，P <.03，从对照时间142±28秒增加到176±36秒，P =.056。VCL降低了对蛇毒巴曲酶（20微克/毫升）的血小板聚集反应，方案A和方案B的对照值分别从66±30.3降至33±31.3Ω，P <.05，从64±23.5降至46±15.8Ω，P =.006。
因此，给予对应于血管性血友病因子-糖蛋白Ib结合域的肽片段，（1）可有效消除狭窄、内皮损伤冠状动脉中的周期性血流变化；（2）减少非人类灵长类动物体内对蛇毒巴曲酶的血小板聚集反应。
