The purpose of this study was to examine whether the blockade of
thromboxane A2 (TxA2)/
prostaglandin H2 (
PGH2) receptor by the selective TxA2/
PGH2 receptor antagonist
KW-3635 (
sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]-6,11- dihydrodibenz[b,e]oxepine-2-carboxylate monohydrate, CAS 127166-41-0) is effective in enhancing
tissue-type plasminogen activator (tPA)-induced thrombolysis and preventing reocclusion in a model of femoral artery
thrombosis in anesthetized dogs. The
thrombus was formed by inserting a
copper coil into the femoral artery.
Sodium heparin (100 U/kg i.v.) was administered shortly after the formation of
thrombus. All dogs received i.v. tPA at a dose of 20 micrograms/kg/min starting 60 min after the formation of the occlusive
thrombus for up to 60 min if necessary, to achieve reperfusion. After 30 min of thrombotic occlusion, the animals received vehicle (Group I, controls, n = 9) or
KW-3635 (Group II, 0.3 mg/kg bolus i.v. + 0.3 mg/kg/h infusion, n = 9; Group III, 1 mg/kg bolus i.v. + 1 mg/kg/h infusion, n = 9) and the infusion of either vehicle or
KW-3635 was continued thereafter throughout the experiment. The time to reperfusion in Group I was 37.3 +/- 5.2 min, while those in Group II and Group III were 25.3 +/- 6.2 min (p greater than 0.05) and 17.3 +/- 3.1 min (p less than 0.05), respectively. Reocclusion occurred within 4 h in 100% of Group I, whereas the incidence of reocclusion was reduced to 67% in Group II and to 0% in Group III. These data suggest that endogenous TxA2 generation is involved in lysis and rethrombosis during
thrombolytic therapy by tPA.(ABSTRACT TRUNCATED AT 250 WORDS)