Effect of selective endoperoxide/thromboxane A2 receptor antagonism with sulotroban on tPA-induced thrombolysis in a rabbit model of femoral arterial thrombosis.
The thrombolytic efficacy of recombinant tissue-type plasminogen activator (tPA) in the presence and absence of the selective endoperoxide/thromboxane A2 (TXA2) receptor antagonist, sulotroban (BM 13.177, SK&F 95587) was studied in a model of femoral artery thrombosis in the anesthetized rabbit. The thrombus was formed by injection of thrombin, CaCl2 and whole blood into an isolated segment of the femoral artery. After 30 min of stable thrombotic occlusion of the femoral artery, tPA was infused IV for 90 min at doses of 5.0, 7.5 and 10.0 micrograms/kg/min. In other experiments, sulotroban was administered as a bolus dose of 1 mg/kg/IV, followed by a constant infusion of 1 mg/kg/hr concurrent with tPA infusion. Sulotroban had no effect on the incidence of tPA-induced reperfusion at any dose studied or on residual clot weight. However, at a tPA dose of 10 micrograms/kg/min, IV lysis time was reduced in sulotroban treated animals from 65 min to 29 min (P less than 0.05), and the magnitude of femoral artery blood flow achieved as a result of tPA-induced reperfusion was greater in sulotroban-treated animals. These data suggest that adjunctive therapy with a selective endoperoxide/TXA2 antagonist improves the response to tPA when tPA is administered at a maximal or near maximally effective pharmacological dose.
Fujita
T
T
Department of Pharmacology, Smith Kline and French Laboratories, King of Prussia, PA 19406-0939.
Hasan
S
S
Storer
B L
BL
Shebuski
R J
RJ
D000818:Animals; D005263:Femoral Artery / Q000503:physiopathology; D005343:Fibrinolytic Agents; D066298:In Vitro Techniques; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D011449:Prostaglandin Endoperoxides; D011817:Rabbits; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000378:metabolism*; D017482:Receptors, Thromboxane; D011994:Recombinant Proteins / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D013927:Thrombosis / Q000188:drug therapy*; D013928:Thromboxane A2 / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
D005343:Fibrinolytic Agents; D011449:Prostaglandin Endoperoxides; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D011994:Recombinant Proteins; D013449:Sulfonamides; D013928:Thromboxane A2; C040624:sulotroban; D010959:Tissue Plasminogen Activator