Comparison of a thromboxane receptor antagonist and aspirin in experimental arterial thrombosis.
The antithrombotic activities of aspirin, the thromboxane (Tx) A2/prostaglandin endoperoxide-receptor (TP-receptor) antagonist, SQ 30,741, and heparin were determined in anesthetized rats. Heparin (3 doses of 50, 300 U/kg), aspirin (1 and 10 mg/kg), SQ 30,741 (1 mg/kg + 1 mg/kg/h), or the combination of SQ 30,741 and aspirin (10 mg/kg) was administered intravenously before inducing occlusive thrombosis with 0.1-mA stimulation of the intimal surface of the carotid artery. Light and electron microscopy revealed the thrombi to be composed predominantly of platelets enmeshed in a fibrin network. Heparin (300 U/kg), SQ 30,741 and SQ 30,741 + aspirin decreased average thrombus weight by 54, 57 and 39%, respectively. These treatments also reduced the incidence of occlusion and improved carotid blood flow during thrombosis. In contrast, aspirin alone (1 and 10 mg/kg) and the lower heparin dose (50 U/kg) did not significantly affect thrombus weight or carotid blood flow. To verify adequate drug dosage, pharmacological activities were characterized ex vivo in separate rats. Aspirin (10 mg/kg) inhibited maximum thromboxane (Tx) B2 production in whole blood by 99 +/- 1% and SQ 30,741 blocked 96% of platelet TP-receptors. Heparin increased the activated partial thromboplastin time (APTT) partially at 50 U/kg (approximately 3-fold) and maximally at 300 U/kg (> 10-fold). These experiments demonstrate the contribution of platelet and coagulation mechanisms to a thrombosis model which is sensitive to a TP-receptor antagonist, but not aspirin.
Schumacher
W A
WA
Department of Pharmacology, Bristol-Myers Squibb, Pharmaceutical Research Institute, Princeton, N.J. 08543-4000.
Heran
C L
CL
Youssef
S
S
Megill
J R
JR
Michel
I
I
Durham
S K
SK
D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects; D004359:Drug Therapy, Combination; D006493:Heparin / Q000494:pharmacology*; D008297:Male; D008854:Microscopy, Electron; D010314:Partial Thromboplastin Time; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000188:drug therapy*; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D013929:Thromboxane B2 / Q000096:biosynthesis
D017482:Receptors, Thromboxane; C054215:SQ 30741; D013929:Thromboxane B2; D013928:Thromboxane A2; D006493:Heparin; D001241:Aspirin