Superior activity of a thromboxane receptor antagonist as compared with aspirin in rat models of arterial and venous thrombosis.
We determined the effects of aspirin and a novel thromboxane A2/prostaglandin endoperoxide (TP)-receptor antagonist, BMS-180291, on thrombosis and bleeding times in skin and mesenteric arteries. In anesthetized rats, occlusive thrombosis was induced in the carotid artery by topical application of ferrous chloride and in the vena cava by blood flow stasis combined with either infusion of thromboplastin or hypotonic saline. Aspirin (1, 10, and 50 mg/kg) did not reduce arterial or venous thrombus weight significantly. BMS 180,291 (150 micrograms/kg/min) decreased arterial thrombus weight and hypotonic saline-induced caval thrombus weight by 58 and 57%, respectively. BMS-180291 lacked antithrombotic activity at a lower dose (50 micrograms/kg/min) and failed to inhibit thromboplastin-induced caval thrombosis. BMS-180291 (150 micrograms/kg/min) significantly reduced arterial thrombus weight by 40% when plasma epinephrine concentration was increased to 5 ng/ml. BMS-180291 and aspirin produced increases of only < or = 30% in bleeding times. These results demonstrate that BMS-180291 has antithrombotic activity in experimental aspirin-resistant arterial and venous thrombosis. Both aspirin and BMS-180291 have only modest effects on small artery hemostasis in rats.
Schumacher
W A
WA
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
Heran
C L
CL
Steinbacher
T E
TE
Youssef
S
S
Ogletree
M L
ML
D000818:Animals; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use*; D001760:Bleeding Time; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002341:Carotid Artery Thrombosis / Q000188:drug therapy*; D004195:Disease Models, Animal; D004837:Epinephrine / Q000097:blood; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D010080:Oxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011422:Propionates / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000188:drug therapy*; D014684:Venae Cavae
D019086:Bridged Bicyclo Compounds, Heterocyclic; D010080:Oxazoles; D010975:Platelet Aggregation Inhibitors; D011422:Propionates; D017482:Receptors, Thromboxane; C078904:ifetroban; D001241:Aspirin; D004837:Epinephrine