Prevention of reocclusion following tissue type plasminogen activator-induced thrombolysis by the RGD-containing peptide, echistatin, in a canine model of coronary thrombosis.
We evaluated the effect of the RGD-containing peptide, echistatin, on thrombolysis time and acute reocclusion in a canine model of coronary thrombosis/thrombolysis. Occlusive thrombus formation was induced by electrical injury, via a stimulating electrode, to the endothelial surface of the circumflex coronary artery in the open-chest, anesthetized dog in the presence of a critical stenosis. Fifteen minutes after occlusive thrombus formation, dogs received either an intravenous infusion of vehicle (saline at 0.1 ml/min) or echistatin (15 micrograms/kg/min i.v.). Heparin was given as an initial bolus (100 U/kg i.v.) 15 min after thrombus formation and repeated at hourly intervals (50 U/kg). This dose of heparin increased activated partial thromboplastin time to 1.5- to 2.5- fold over control. Thrombolysis was induced with recombinant tissue-type plasminogen activator (tPA) at a total dose of 1 mg/kg, intravenously administered over 90 min with 10% given as an initial bolus. The vehicle-treated animals reperfused at 48 +/- 9 min with a reperfusion incidence of 60% (3/5). The echistatin-treated animals reperfused at 46 +/- 5 min with a reperfusion incidence of 100% (5/5). After stopping the tPA infusion, acute reocclusion occurred in 100% (3/3) of the vehicle-treated dogs and in only 20% (1/5) of the echistatin-treated dogs. Echistatin caused a greater than 5-fold increase in buccal mucosa bleeding time and almost completely inhibited ex vivo platelet aggregation to ADP, collagen, and U-46619. Residual thrombus wet weight, determined at the end of the experiment, was significantly lower for the echistatin group (2.1 +/- 0.2 mg) compared to the vehicle group (5.8 +/- 0.7 mg).(ABSTRACT TRUNCATED AT 250 WORDS)
Holahan
M A
MA
Department of Pharmacology, Upjohn Laboratories, Kalamazoo, Mich.
Mellott
M J
MJ
Garsky
V M
VM
Shebuski
R J
RJ
D000818:Animals; D003328:Coronary Thrombosis / Q000188:drug therapy / Q000517:prevention & control*; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects; D006439:Hemodynamics; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D010455:Peptides; D010477:Perfusion; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D012008:Recurrence; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D014757:Viper Venoms / Q000627:therapeutic use*
D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D014757:Viper Venoms; C057986:echistatin; D010959:Tissue Plasminogen Activator