A ferret model of electrical-induction of arterial thrombosis that is sensitive to aspirin.
An experimental model of acute thrombosis was developed in pentobarbital- anesthetized ferrets. A 10-min anodal electrical stimulation of 1 mA was delivered to the external surface of the carotid artery while measuring carotid blood flow (CBF). This produced an occlusive thrombus in all vehicle-treated ferrets within 41 +/- 3 min with an average weight of 8 +/- 1 mg (n = 7). These thrombi were enriched in both platelets and fibrin and were adherent at the site of transmural vascular injury as determined by light and electron microscopy. To determine the model's sensitivity to antiplatelet drugs, aspirin or a thromboxane (TxA2) receptor antagonist (ifetroban) were administered 15 min before electrical stimulation. Thrombus weight was reduced 58% by aspirin (10 mg/kg, i.v.) and 74% by ifetroban (1 mg/kg + 1 mg/kg per hr, i.v.). Both drugs also improved CBF and decreased vascular occlusion. Ferrets were more sensitive than rats to aspirin's inhibition of collagen-induced platelet aggregation as determined ex vivo in whole blood. Separate in vitro platelet aggregation studies revealed species differences in reactivity to U-46619 (TxA2 receptor agonist) and collagen in the order of human > ferret > rat, with relatively lesser variations in ADP responses. These studies identify the ferret as a useful species for evaluating antithrombotic drugs in a model in which aspirin is efficacious.
Schumacher
W A
WA
Department of Pharmacology, Bristol-Myers Squibb Research Institute, Princeton, New Jersey, USA.
Steinbacher
T E
TE
Megill
J R
JR
Durham
S K
SK
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001792:Blood Platelets / Q000166:cytology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D002339:Carotid Arteries / Q000187:drug effects / Q000648:ultrastructure; D020212:Carotid Artery Injuries; D003094:Collagen / Q000633:toxicity; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000009:adverse effects; D005289:Ferrets; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008854:Microscopy, Electron; D008855:Microscopy, Electron, Scanning; D010080:Oxazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011517:Prothrombin Time; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D013045:Species Specificity; D013927:Thrombosis / Q000188:drug therapy* / Q000503:physiopathology; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D019086:Bridged Bicyclo Compounds, Heterocyclic; D010080:Oxazoles; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D014662:Vasoconstrictor Agents; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D005337:Fibrin; D003094:Collagen; C078904:ifetroban; D001241:Aspirin