Antithrombotic effects of a platelet fibrinogen receptor antagonist in a canine model of carotid artery thrombosis.
OBJECTIVE
Platelet-fibrin thrombi in the lumen of atherostenotic carotid arteries may underlie transient ischemic attacks and cerebral infarction. For this reason, we investigated the antiplatelet and antithrombotic effects of a novel and potent platelet fibrinogen receptor (glycoprotein IIb/IIIa) antagonist (SK&F 106760).


METHODS
The effects of 0.1-3.0 mg/kg i.v. SK&F 106760 on platelet aggregation were examined ex vivo in canine platelet-rich plasma (n = 20). In addition, the antithrombotic effects of SK&F 106760 were compared with those of aspirin in an acute canine model of extracranial carotid artery thrombosis with high-grade stenosis. Sham-operated (n = 4), vehicle-treated (n = 6), SK&F 106760-treated (n = 8), aspirin-treated (n = 9), and SK&F 106760+aspirin-treated (n = 5) dogs were examined.


RESULTS
The intravenous administration of SK&F 106760 caused a dose-related inhibition of ex vivo platelet aggregation. In the carotid artery thrombosis model, an occlusive thrombus formed at stenotic sites in the region of the carotid bifurcation. The thrombogenic process caused a progressive reduction in carotid blood flow and reduced the cortical microvascular perfusion and electroencephalographic power. Based on nuclear magnetic resonance spectroscopy, the occlusive events depleted the stores of high-energy phosphates (adenosine triphosphate and phosphocreatine) and increased the lactate concentration in the forelimb somatosensory area of the parietal cortex. In this model, the administration of 1 mg/kg i.v. SK&F 106760 prevented thrombosis of the stenotic carotid artery. Consequently, neurophysiological, cerebral hemodynamic, and metabolic parameters were all improved significantly in the SK&F 106760-treated group. No dog receiving SK&F 106760 reoccluded during the 1-hour posttreatment observation period. In contrast, thrombosis of the carotid artery was associated with neurophysiological deterioration in six of the nine dogs treated with 5 mg/kg i.v. aspirin. Both spontaneous and evoked (increased carotid stenosis) aspirin-resistant thrombosis were abolished by SK&F 106760 treatment.


CONCLUSIONS
These results suggest that antagonism of fibrinogen binding to platelet glycoprotein IIb/IIIa (the final common pathway for aggregation) may represent a new and more effective antithrombotic approach to the treatment of cerebral transient ischemic attacks and infarction associated with extracranial carotid artery disease.
Willette
R N
RN
Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa. 19406-0939.
Sauermelch
C F
CF
Rycyna
R
R
Sarkar
S
S
Feuerstein
G Z
GZ
Nichols
A J
AJ
Ohlstein
E H
EH
D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism*; D002341:Carotid Artery Thrombosis / Q000503:physiopathology*; D016893:Carotid Stenosis / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004285:Dogs; D004338:Drug Combinations; D004569:Electroencephalography; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*
D004338:Drug Combinations; D005343:Fibrinolytic Agents; D010456:Peptides, Cyclic; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; C071275:SK&F 106760; D001241:Aspirin