ENDOGENOUS PROSTAGLANDIN ENDOPEROXIDES AND PROSTACYCLIN MODULATE THE THROMBOLYTIC ACTIVITY OF TISSUE PLASMINOGEN-ACTIVATOR - EFFECTS OF SIMULTANEOUS INHIBITION OF THROMBOXANE A2 SYNTHASE AND BLOCKADE OF THROMBOXANE A2/PROSTAGLANDIN H2 RECEPTORS IN A CANINE MODEL OF CORONARY-THROMBOSIS

We tested the hypothesis that simultaneous inhibition of TxA2 synthase and blockade of TxA2/PHG2 receptors is more effective in enhancing thrombolysis and preventing reocclusion after discontinuation of tissue plasminogen activator (t-PA) than either intervention alone. Coronary thrombosis was induced in 35 dogs by placing a copper coil into the left anterior descending coronary artery. Coronary flow was measured with a Doppler flow probe. 30 min after thrombus formation, the animals received saline (controls, n = 10); SQ 29548 (0.4 mg/kg bolus + 0.4 mg/kg per h infusion), a TxA2/PGH2 receptor antagonist (n = 8); dazoxiben (5 mg/kg bolus + 5 mg/kg per h infusion), a TxA2 synthase inhibitor (n = 9); or R 68070 (5 mg/kg bolus + 5 mg/kg per h infusion), a drug that blocks TxA2/PGH2 receptors and inhibits TxA2 synthase (n = 8). Then, all dogs received heparin (200 U/kg) and a bolus of t-PA (80 fig/kg) followed by a continuous infusion (8 Mg/kg per min) for up to 90 min or until reperfusion was achieved. The time to thrombolysis did not change significantly in SQ 29548-treated dogs as compared with controls (42 ± 5 vs. 56 ± 7 min, respectively, P = NS), but it was significantly shortened by R 68070 and dazoxiben (11 ± 2 and 25 ± 6 min, respectively, P < 0.001 vs. controls and SQ 29548-treated dogs). R 68070 administration resulted in a lysis time significantly shorter than that observed in the dazoxiben-treated group (P < 0.01). Reocclusion was observed in eight of eight control dogs, five of seven SQ 29548-treated dogs, seven of nine dazoxiben-treated dogs, and zero of eight R 68070-treated animals (P < 0.001). TxB2 and 6-keto-PGF1α, measured in blood samples obtained from the coronary artery distal to the thrombus, were significantly increased at reperfusion and at reocclusion in control animals and in dogs receiving SQ 29548. R 68070 and dazoxiben prevented the increase in plasma TxB2 levels, whereas 6-keto-PGF1α levels were significantly increased with respect to control and SQ 29548-treated dogs. Thus, simultaneous inhibition of TxA2 synthase and blockade of TxA2/PGH2 receptors is more effective than either inter-vention alone in this experimental model in enhancing thrombolysis and preventing reocclusion after t-PA administration.