Abolition of cyclic flow variations in stenosed, endothelium-injured coronary arteries in nonhuman primates with a peptide fragment (VCL) derived from human plasma von Willebrand factor-glycoprotein Ib binding domain.
Abolition of cyclic flow variations in stenosed, endothelium-injured coronary arteries in nonhuman primates with a peptide fragment (VCL) derived from human plasma von Willebrand factor-glycoprotein Ib binding domain.
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使用源自人血浆冯维勒布兰德因子-糖蛋白 Ib 结合域的肽片段 (VCL) 消除非人灵长类动物狭窄、内皮损伤的冠状动脉中的循环血流变化。
DOI：
10.1161/01.cir.90.6.2976
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发表时间：
1994
期刊：
影响因子：
37.8
通讯作者：
Willerson,JT
中科院分区：
文献类型：
--
作者：
McGhie,AI;McNatt,J;Ezov,N;Cui,K;Mower,LK;Hagay,Y;Buja,LM;Garfinkel,LI;Gorecki,M;Willerson,JT
血小板在急性冠状动脉综合征的病理生理中起重要作用。血小板糖蛋白Ib受体和血管性血友病因子之间的相互作用是一个关键事件，允许血小板粘附和聚集，并随后在高剪切率和受损内皮的血管中形成血栓。因此，我们测试的假设，VCL，血管性血友病-糖蛋白Ib结合域的拮抗剂，（1）减弱/废除在狭窄，内皮损伤的冠状动脉在非人灵长类动物的循环流量变化和（2）减少botrocetin诱导的血小板聚集在体外静脉内体内administration.METHODS和ESTSCyclic流量变化建立在麻醉，开胸狒狒（n = 18）。狒狒被分成三组。一组（n = 8）接受VCL推注（4 mg/kg IV），然后输注（6 mg.kg-1. h-1）90分钟（方案A）。另一组（n = 6）接受2 mg/kg推注，随后以3 mg.kg-1. h-1输注90分钟（方案B）。第三组接受生理盐水的安慰剂输注。在给药方案A下，在33 +/- 18分钟后，8只狒狒中有7只的循环流量变化消失，1只明显减弱。循环流量变化的频率从对照期间的每小时18 +/- 9.4下降到VCL输注后的每小时1 +/- 2.5，P <0.002。停止输注后，7只动物中有5只的循环流量变化保持消除> 3小时，7只动物中有2只在2至2.5小时后恢复。在计划B下，6只狒狒中有3只的循环流量变化被消除，其余狒狒的循环流量变化显著减少。循环流量变化的数量从对照期间的每小时17 +/- 4.8下降到VCL输注后的每小时5 +/- 4.9，P <0.001。在该给药方案下，循环流量变化在38 +/- 40分钟时自发恢复。安慰剂输注生理盐水对循环血流频率或严重程度没有影响。VCL给药与出血时间轻微延长和Botrocetin诱导的血小板聚集减少相关。出血时间分别从对照组的88 +/- 32秒增加到276 +/- 204秒，P <0.03，从142 +/- 28秒增加到176 +/- 36秒，P = 0.056。VCL降低Botrocetin诱导的血小板聚集（20微克/毫升），从对照值66 +/- 30.3到33 +/- 31.3 Ω，P <0.05，从64 +/- 23.5到46 +/- 15.8 Ω，P = 0.006，分别用于给药方案A和B。结论因此，给予对应于von Willebrand-糖蛋白Ib结合结构域的肽片段（1）可有效消除狭窄的、内皮损伤的冠状动脉中的循环流动变化，和（2）减少非人灵长类动物体内响应于肉毒素的血小板聚集。
BACKGROUNDPlatelets 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.METHODS AND RESULTSCyclic 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.CONCLUSIONSTherefore, 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.