METHODS AND RESULTS: Blood flow velocity in the left anterior descending coronary artery (LAD) of 32 anesthetized mongrel dogs was monitored by a pulsed Doppler flow probe.
Coronary thrombosis was induced by applying electrical stimulation to the LAD at the site where an external constrictor was used to narrow the artery. Three hours after the formation of occlusive
thrombus, animals were randomly assigned to receive one of the following: 1) t-PA (80 micrograms/kg + 8 micrograms.kg-1.min-1 i.v.) and saline; 2) t-PA and
hirulog, a
hirudin-based synthetic
peptide and specific
thrombin inhibitor (2 mg/kg + 2 mg.kg-1.hr-1 i.v.); 3) t-PA and
ridogrel, a combined
thromboxane A2 synthetase inhibitor and receptor antagonist (5 mg/kg + 2.5 mg.kg-1.hr-1 i.v.); or 4) t-PA,
hirulog, and
ridogrel. Reperfusion developed in 14% (one of seven) of dogs treated with t-PA alone at an average of 86 +/- 4 minutes
after treatment, in 78% (seven of nine) of dogs treated with t-PA plus
hirulog at 53 +/- 11 minutes, in 13% (one of eight) of dogs treated with t-PA plus
ridogrel at 85 +/- 5 minutes, and in 88% (seven of eight) of dogs treated with t-PA,
hirulog, and
ridogrel at 37 +/- 10 minutes (comparison of the frequency of and the time to reperfusion, both p < 0.01). Among the dogs with reestablished coronary blood flow, reocclusion developed in the one treated with t-PA alone at 36 minutes after reperfusion, in seven of the seven treated with t-PA plus
hirulog at 66 +/- 15 minutes, and in two of the seven treated with t-PA,
hirulog, and
ridogrel at 151 +/- 21 minutes (comparison of the frequency of and time to reocclusion, both p < 0.05). Reocclusion was not detected in the one dog treated with t-PA and
ridogrel or in the other five dogs treated with t-PA,
hirulog, and
ridogrel within 180 minutes after reperfusion.
Hirulog prolonged and maintained activated clotting times at a level twice that of baseline values.
Hirulog inhibited ex vivo platelet aggregation induced by
thrombin, and
ridogrel inhibited platelet aggregation induced by
U46619, a
thromboxane mimetic.
CONCLUSIONS: