Experimental pulmonary embolus in the rat: a new in vivo model to test thrombolytic drugs.
Currently, the effects of the thrombolytic drugs are tested in vivo in dog or rabbit models that require a relatively large amount of the drug. The goal of the present study was to describe a new model that would allow one to test the in vivo thrombolytic effect of drugs with a limited amount of compound. For this purpose, we have induced a pulmonary embolus in anesthetized rats by injecting I125 radiolabeled clots into the venous circulation and we have measured the lysis of these clots occurring either spontaneously or induced by increasing doses of wild-type tissue plasminogen activator (tPA) (from 0.125 to 2 mg/kg i.v.) or by streptokinase (750,000 I.U./kg i.v.) or urokinase (750,000 I.U./kg i.v.). In the plasma of these rats, we have also measured the plasminogen activation activity of tPA as well as the concentrations of plasminogen, fibrinogen, and alpha 2-antiplasmin. Spontaneously, there was a time dependent thrombolysis (33%/h) that could be partially inhibited by aprotinin. Wild-type tPA induced a dose-related thrombolysis with a limited decrease of plasma fibrinogen concentration with doses over 0.25 mg/kg. Streptokinase and to a smaller extent urokinase induced a larger hemostatic breakdown (as indicated by systemic fibrinogenolysis, plasminogen activation, and alpha 2-antiplasmin consumption). We conclude that the rat pulmonary embolus model is suitable for testing the thrombolytic efficacy, potency, and the fibrin specificity of thrombolytic drugs and requires a smaller amount of drug than the previously described in vivo models.
Clozel
J P
JP
Pharmaceutical Research Department, F. Hoffmann-La Roche & Co., Ltd. Basel, Switzerland.
Holvoet
P
P
Tschopp
T
T
D000818:Animals; D007611:Aprotinin / Q000494:pharmacology; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D008297:Male; D010960:Plasminogen Activators / Q000494:pharmacology; D011655:Pulmonary Embolism / Q000097:blood / Q000188:drug therapy*; D051381:Rats; D011919:Rats, Inbred Strains; D013300:Streptokinase / Q000627:therapeutic use; D013997:Time Factors; D014568:Urokinase-Type Plasminogen Activator / Q000627:therapeutic use
D005343:Fibrinolytic Agents; D007611:Aprotinin; D013300:Streptokinase; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator