Experimental carotid thrombosis in the guinea pig.
The aim of our study was to develop a new carotid thrombosis model with an arterial shear rate close to that prevailing in affected arteries of patients with transient ischemic attacks (TIAs) and moderate carotid stenosis and to test various antithrombotic principles. In anaesthetized guinea pigs, carotid blood flow was monitored by a Doppler flow probe and the vessel was damaged by 2 or 3 brief pinches by a surgical forceps. The intravenous effects of aspirin (20 mg/kg), heparin (200 U/kg) and hirudin (500 micrograms/kg) or Ro 44-9883 (0.2 to 1 mg/kg), a new selective non-peptidic GP IIb-IIIa inhibitor were tested. After the damage, blood flow progressively decreased to zero and could regularly and reproducibly be restored by a mechanical shaking of the artery. The occlusive thrombus consisted mainly of platelet aggregates. The estimated shear rate in the damaged carotid artery was in the range of 1500 to 2800 s-1. The resulting cyclic flow variations (CFVs) were obtained in all the guinea pigs and were abolished in 10%, 20% and 60% of the animals treated with heparin, hirudin and aspirin, respectively. Ro 44-9883 abolished dose dependently the CFVs with 100% abolition at 1 mg/kg. Thus reproducible thrombosis without additional stenosis can be generated in the carotid artery of the guinea pig at a lower shear rate than that prevailing in the classical thrombosis models. GPIIb-IIIa blockade showed a higher curative efficacy than inhibition of the cyclooxygenase pathway or that of thrombin generation either through an antithrombin III dependent or independent mechanism.
Roux
S
S
F. Hoffmann-La Roche, Ltd, Basel, Switzerland.
Carteaux
J P
JP
Hess
P
P
Falivene
L
L
Clozel
J P
JP
D000085:Acetates / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D001241:Aspirin / Q000627:therapeutic use; D001696:Biomechanical Phenomena; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002341:Carotid Artery Thrombosis / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D004195:Disease Models, Animal; D006168:Guinea Pigs; D006493:Heparin / Q000627:therapeutic use; D024764:Hirudin Therapy; D008297:Male; D010314:Partial Thromboplastin Time; D010974:Platelet Aggregation / Q000187:drug effects; D010976:Platelet Count; D014443:Tyrosine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use
D000085:Acetates; D014443:Tyrosine; D006493:Heparin; C084062:lamifiban; D001241:Aspirin