Magnitude of thromboxane receptor antagonism necessary for antithrombotic activity in monkeys.
SQ 30741 was characterized as a competitive antagonist of thromboxane receptor-mediated platelet activation in vitro that does not inhibit the activity of enzymes involved in prostaglandin, prostacyclin, and thromboxane biosynthesis. The threshold intravenous dose for antithrombotic activity was measured in anesthetized monkeys as the minimum amount of SQ 30741 required to inhibit thrombotic cyclic blood flow reductions in stenotic renal arteries. Platelet responsiveness was measured ex vivo before and during inhibition of thrombosis by the shape-change response to a thromboxane mimetic, U 46619. The threshold antithrombotic SQ 30741 dose (0.32 +/- 0.04 mg/kg; n = 5) was accompanied by an 8.5 +/- 1.1-fold shift to the right of the U 46619 concentration-effect curve, implying antagonism of 87 +/- 3% of platelet thromboxane receptors. The antithrombotic activity of SQ 30741 persisted for 109 +/- 10 min and was not reversed by indomethacin. However, in two out of seven monkeys SQ 30741 (7 mg/kg iv) did not interrupt the cyclical flow reductions. Vehicle treatment did not impede thrombosis and caused a 1.4 +/- 0.3-fold shift of the U 46619 concentration-effect curve (n = 4). In separate monkeys, SQ 30741 (0.33 mg/kg iv) produced identical dose ratios (8.6 +/- 0.7, n = 8) for inhibition of U 46619-induced mesenteric vasoconstriction. Thus the threshold antithrombotic dose of SQ 30741 caused the same magnitude of antagonism of platelet (ex vivo) and vascular (in vivo) thromboxane receptors.
Schumacher
W A
WA
Department of Pharmacology, Squibb Institute for Medical Research, Princeton, New Jersey 08543-4000.
Heran
C L
CL
Goldenberg
H J
HJ
Harris
D N
DN
Ogletree
M L
ML
D000818:Animals; D001667:Binding, Competitive; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects*; D005260:Female; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D008251:Macaca / Q000502:physiology*; D008252:Macaca fascicularis / Q000502:physiology*; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000502:physiology*; D017482:Receptors, Thromboxane; D012016:Reference Values; D013152:Splanchnic Circulation / Q000187:drug effects*; D013928:Thromboxane A2 / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; C054215:SQ 30741; D013928:Thromboxane A2; D007213:Indomethacin