Matsuno H, Kozawa O, Niwa M, Uematsu T
Department of Pharmacology, Gifu University School of Medicine, Japan.
Circulation. 1997 Aug 19;96(4):1299-304. doi: 10.1161/01.cir.96.4.1299.
Aurintricarboxylic acid (ATA) prevents von Willebrand factor binding to platelet glycoprotein (GP) Ib, with higher-molecular-weight ATA more effective than the lower-molecular-weight compound. We investigated the effects of high-molecular-weight ATA (Mr=7500), obtained by fractionating commercial ATA, in the injured hamster carotid artery.
Platelet aggregation was induced in vitro with ADP (2.5 micromol/L) or botrocetin (5 microg/mL) in hamster platelet-rich plasma. IC50 values were 348.6+/-22.4 and 8.2+/-3.2 microg/mL, respectively. The endothelium of hamster carotid artery was denuded with a modified catheter. Continuous administration of high-molecular-weight ATA (10, 30, and 100 microg x kg(-1) x h(-1)) with an infusion pump produced antithrombotic effects in a dose-dependent manner, as evaluated by prolongation of time to occlusion. Neointima formation was observed 2 weeks after catheterization, and proliferating smooth muscle cells (SMCs) were identified by the thymidine analogue 5-bromo-2-deoxyuridine (BrdU). Continuous treatment with the compound (100 microg x kg(-1) x h(-1)) with a 2ML1 Alzet infusion pump resulted in a reduction of neointimal area by 38.0+/-8.8% and decreased the BrdU index on days 1 and 7 significantly. DNA synthesis in DDT1MF2 hamster SMCs was also decreased by the compound in a dose-dependent manner. In histological observation, the process of endothelial healing was improved by this treatment with the compound.
Inhibition of platelet adhesion by von Willebrand factor binding to platelet GP Ib by high-molecular-weight ATA results in the prevention of thrombus formation and the suppression of neointima lesion. In addition, high-molecular-weight ATA has an inhibitory effect on SMC proliferation. This inhibition of both platelet adhesion and SMC proliferation markedly reduced vascular stenosis.
金精三羧酸（ATA）可阻止血管性血友病因子与血小板糖蛋白（GP）Ib结合，高分子量的ATA比低分子量化合物更有效。我们研究了通过对市售ATA进行分级分离得到的高分子量ATA（Mr = 7500）对损伤的仓鼠颈动脉的影响。
在富含仓鼠血小板的血浆中，用ADP（2.5微摩尔/升）或蛇毒凝血酶（5微克/毫升）体外诱导血小板聚集。IC50值分别为348.6±22.4和8.2±3.2微克/毫升。用改良导管剥脱仓鼠颈动脉内皮。用输液泵持续给予高分子量ATA（10、30和100微克·千克⁻¹·小时⁻¹）产生剂量依赖性的抗血栓作用，通过闭塞时间延长来评估。导管插入术后2周观察到新生内膜形成，通过胸腺嘧啶类似物5-溴-2-脱氧尿苷（BrdU）鉴定增殖的平滑肌细胞（SMC）。用2ML1 Alzet输液泵持续给予该化合物（100微克·千克⁻¹·小时⁻¹）导致新生内膜面积减少38.0±8.8%，并在第1天和第7天显著降低BrdU指数。该化合物还以剂量依赖性方式降低了DDT1MF2仓鼠SMC中的DNA合成。在组织学观察中，该化合物的这种处理改善了内皮愈合过程。
高分子量ATA通过抑制血管性血友病因子与血小板GP Ib结合来抑制血小板黏附，从而预防血栓形成并抑制新生内膜病变。此外，高分子量ATA对SMC增殖有抑制作用。对血小板黏附和SMC增殖的这种抑制作用显著减轻了血管狭窄。
