1. This study compares a
cyclo-oxygenase inhibitor (
aspirin), a
5-HT2 antagonist (
ZM170809) and a combined
thromboxane synthase inhibitor/receptor antagonist (
ZD1542) as adjuncts to
tissue plasminogen activator (rt-PA). 2. Application of an anodal current (332 +/- 4.1 microA) to the stenosed left circumflex coronary artery of 20 anaesthetized dogs produced a stable platelet-rich occlusive
thrombus. 3. After initial i.v. administration of recombinant human
tissue type plasminogen activator (rt-PA, 3 mg bolus +2 mg kg-1 h-1 for 30 min) thrombolysis occurred in 15 out of 20 dogs. All 15 dogs reoccluded. 4. The second i.v. administration of rt-PA in the presence of either
aspirin,
ZM170809,
ZD1542 or saline resulted in thrombolysis in all 20 dogs. 5. Both the combined
thromboxane synthase inhibitor/receptor antagonist (
ZD1542) and
5-HT2 antagonist (
ZM170809) significantly (P < 0.05) reduced the time taken to lyse the
thrombus compared with the saline group. The times were 14.4 +/- 2.7 min, 18.0 +/- 3.9 min and 36.8 +/- 6.2 min for
ZD1542,
ZM170809 and saline respectively. 6.
Aspirin did not offer any additional benefit to using rt-PA alone. The times to thrombolysis were 36.8 +/- 8.4 min for
aspirin and 36.8 +/- 6.2 min for the saline group. 7. The number of dogs in which the circumflex coronary artery reoccluded within 60 min of terminating the second infusion of rt-PA were five for saline, four for
aspirin, two for
ZD1542 and two for
ZM170809. 8. These results indicate that both
ZD1542 and
ZM170809 are more effective adjuncts than
aspirin in thrombolysis and may provide an improvement in current clinical practice.