Inhibition of von Willebrand factor binding to platelet GP Ib by a fractionated aurintricarboxylic acid prevents restenosis after vascular injury in hamster carotid artery.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Matsuno
H
H
Department of Pharmacology, Gifu University School of Medicine, Japan. leuven@cc.gifu-u.ac.jp
Kozawa
O
O
Niwa
M
M
Uematsu
T
T
D000818:Animals; D001312:Aurintricarboxylic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D020212:Carotid Artery Injuries; D017536:Carotid Artery, Common / Q000187:drug effects / Q000648:ultrastructure; D016893:Carotid Stenosis / Q000517:prevention & control*; D002478:Cells, Cultured; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D008297:Male; D008855:Microscopy, Electron, Scanning; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012008:Recurrence; D013927:Thrombosis / Q000517:prevention & control; D017539:Tunica Intima / Q000187:drug effects; D014841:von Willebrand Factor / Q000378:metabolism*
D019038:Platelet Glycoprotein GPIb-IX Complex; D014841:von Willebrand Factor; D001312:Aurintricarboxylic Acid