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.