Aurintricarboxylic acid in a canine model of coronary artery thrombosis.
Platelet thrombus formation occurs at sites of severe arterial narrowing where shear stress is elevated. Shear stress appears to induce platelet aggregation in vitro by means of initiation of von Willebrand factor binding to platelet glycoprotein Ib. Recent in vitro studies have demonstrated that aurintricarboxylic acid can inhibit shear stress-induced platelet aggregation. This effect is mediated by aurintricarboxylic acid binding to von Willebrand factor; this binding results in inhibition of von Willebrand factor interaction with glycoprotein Ib. In this study, we examined the effect of aurintricarboxylic acid on platelet-dependent cyclic flow reductions (CFRs) in a canine coronary stenosis model. In dose-response experiments, six animals received 4 mg/kg aurintricarboxylic acid by bolus infusion, followed by 1 mg/kg every 10 minutes. Total inhibition of CFRs was observed in all animals after 6.7 mg/kg aurintricarboxylic acid; CFRs could not be reinitiated by the thromboxane A2 analogue U46619. Continuous infusion of epinephrine (0.4 micrograms/kg/min) caused CFRs to return; however, 3.7 mg/kg additional aurintricarboxylic acid again induced total inhibition of CFRs. In addition, five animals received a bolus infusion of 10 mg/kg aurintricarboxylic acid, which caused total inhibition of CFRs. The average area of stenosis in the constricted vessels was 83%, and shear stress at the site of constriction averaged 350 dynes/cm2. Aurintricarboxylic acid did not alter hemodynamics, thrombin time, platelet count, or ADP/epinephrine-induced platelet aggregation. These data indicate that platelet glycoprotein Ib-von Willebrand factor interactions are important during coronary occlusion and that aurintricarboxylic acid can inhibit coronary thrombosis associated with coronary constriction.
Strony
J
J
Hunter Holmes McGuire Veterans Administration Medical Center, Medical College of Virginia, Richmond 23249.
Phillips
M
M
Brands
D
D
Moake
J
J
Adelman
B
B
D000818:Animals; D001312:Aurintricarboxylic Acid / Q000627:therapeutic use*; D001783:Blood Flow Velocity / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D003327:Coronary Disease / Q000188:drug therapy*; D003328:Coronary Thrombosis / Q000188:drug therapy*; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
D003509:Cyclohexanecarboxylic Acids; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D014841:von Willebrand Factor; D001312:Aurintricarboxylic Acid