Thrombostatin Inhibits Cyclic Flow Variations in Stenosed Canine Coronary Arteries

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Abstract
Thrombostatins are a group of compounds based upon a breakdown product of bradykinin, RPPGF. They inhibit -thrombin-induced platelet activation by binding to protease activated receptor 1 and, at a lower affinity, by interacting with thrombin’s active site. After a single intravenous infusion of MAP4-RPPGF (11.58 mg/kg), its t½α was 4.5 min with a clearance of 2.0 ml/min. MAP4-RPPGF administration had a sustained antiplatelet effect, preventing γ-thrombin-induced (12.5 nM) platelet activation for 4 h. Its antiplatelet effect summated with that of aspirin and/or clopidogrel. MAP4-RPPGF was compared with aspirin and clopidogrel in the Folts model of coronary artery thrombosis. Dogs were randomized to 3 treatment groups: aspirin 1.14 mg/kg i. v., clopidogrel 0.5 mg/kg i. v., or MAP4-RPPGF 0.77 mg/kg i. v. Cyclic flow variations (CFV) were recorded in 5 untreated dogs hourly for 3 successive hours and for 1 h before (all groups >11 CFV/h), and for 2 h after drug infusion in each of the 3 treatment groups. After 1 h drug treatment, all groups of animals had <6 CFV/h; after 2 h treatment, all had <1 CFV/h. All agents significantly reduced CFV from control at each hour, but none was significantly better than any other. Thrombostatin was as effective as aspirin or clopidogrel in inhibiting coronary artery thrombosis in this canine model.
Funding Information
  • NIH (HL56415, HL61081 and HL61981)