Effect of thromboxane receptor antagonists on venous thrombosis in rats

WA Schumacher and CL Heran

Department of Pharmacology, Squibb Institute for Medical Research, Princeton, New Jersey.

The activities of two structurally unrelated thromboxane/prostaglandin endoperoxide receptor antagonists, SQ 30,741 and BM 13,505, were compared to heparin in a model of venous thrombosis. A combination of blood stasis with osmotic and pressure stress was used to induce thrombus formation in the vena cava of anesthetized rats. Intravenous infusions of SQ 30,741 (500 micrograms/kg/min) and BM 13,505 (50 micrograms/kg/min) produced significant (P less than .01) and equivalent reductions in thrombus mass of 58 and 56%, respectively. Thrombus reduction in response to heparin (50 U/kg) was greater (95%; P less than .001) than in response to the thromboxane antagonists. Either lower doses of SQ 30,741 (50 and 100 micrograms/kg/min) or aspirin (30 and 60 mg/kg) were ineffective in altering thrombus formation. However, a subthreshold dose of SQ 30,741 (100 micrograms/kg/min) increased (P less than .01) the antithrombotic activity obtained with both threshold (0.5 U/kg) and subthreshold (0.3 U/kg) doses of heparin. SQ 30,741 (500 micrograms/kg/min) did not change activated partial thromboplastin times or inhibit platelet loss induced by contact activation in response to kaolin in vivo. This suggests that SQ 30,741 does not interfere with components of the coagulation cascade that are not dependent on platelet factors. The extent of thromboxane antagonism achieved with SQ 30,741 (50 and 500 micrograms/kg/min) and BM 13,505 (50 micrograms/kg/min) was determined from parallel shifts in dose- dependent U-46,619-induced vasoconstriction in vivo (approximately 200- and 1300-fold, respectively, for SQ 30,741 and 200-fold for BM 13,505). These data demonstrate that thromboxane antagonists inhibit venous thrombosis partially, but only at doses producing near complete receptor inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 248, Issue 3, pp. 1109-1115, 03/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics