Effect of thromboxane synthase inhibition on the thrombolytic action of tissue-type plasminogen activator in a rabbit model of peripheral arterial thrombosis.
The thrombolytic efficacy of recombinant tissue-type plasminogen activator (tPA) in the presence and absence of a thromboxane synthase inhibitor was studied in a model of femoral artery thrombosis in the anesthetized rabbit. The thrombus was formed by injection of thrombin and whole blood into an isolated segment of the femoral artery. After 30 min of stable thrombotic occlusion of the femoral artery, sodium heparin (300 U/kg, i.v.) was administered and tPA was infused locally to the site of the thrombus for 30 min at 0.01, 0.10 or 1.0 microgram/kg/min. In other experiments, CGS 13080, a selective thromboxane synthase inhibitor, was administered at a dose of 2 mg/kg i.v., 5 min before tPA was infused and at the end of the 30 min tPA infusion. Pretreatment with CGS 13080 resulted in a shorter time to tPA-induced reperfusion, greater incidence of reperfusion and increased the magnitude of femoral artery blood flow achieved after effective thrombolysis. Furthermore, pretreatment with CGS 13080 resulted in a greater than 10-fold enhancement in the effective dose of tPA. These data indicate that thromboxane synthase inhibition may be beneficial as an adjunct to thrombolytic therapy with tPA.
Shebuski
R J
RJ
Dept. of Pharmacology, Smith Kline & French Laboratories, King of Prussia, PA 19406.
Storer
B L
BL
Fujita
T
T
D000818:Animals; D001783:Blood Flow Velocity / Q000187:drug effects; D004357:Drug Synergism; D005263:Femoral Artery / Q000187:drug effects / Q000503:physiopathology; D005342:Fibrinolysis / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000008:administration & dosage; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D011817:Rabbits; D013927:Thrombosis / Q000188:drug therapy* / Q000503:physiopathology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000494:pharmacology*
D005343:Fibrinolytic Agents; D007093:Imidazoles; D011725:Pyridines; C037787:pirmagrel; D010959:Tissue Plasminogen Activator; D013930:Thromboxane-A Synthase