Acceleration of recombinant tissue-type plasminogen activator-induced thrombolysis and prevention of reocclusion by the combination of heparin and the Arg-Gly-Asp-containing peptide bitistatin in a canine model of coronary thrombosis.
The effect of tissue-type plasminogen activator (t-PA) alone or in combination with heparin, the Arg-Gly-Asp-containing peptide bitistatin, or both heparin and bitistatin was evaluated on thrombolysis time and acute reocclusion in a canine model of coronary thrombosis. Thrombus formation was elicited by electrolytic injury with a needle electrode to the endothelial surface of the circumflex coronary artery in the open-chest, anesthetized dog in the presence of a flow-limiting critical stenosis. Thirty minutes after spontaneous coronary artery occlusion, t-PA (1 mg/kg i.v. over 90 minutes) was administered. Group 1 was given t-PA alone; reperfusion occurred at 78.2 +/- 5.6 minutes with a reperfusion incidence of 60% (6/10). Group 2 received t-PA plus heparin (100 units/kg plus 50 units/kg/hr); reperfusion occurred at 61.9 +/- 9.1 minutes with a reperfusion incidence of 90% (9/10). Group 3 received t-PA plus heparin plus bitistatin (30 micrograms/kg plus 3 micrograms/kg/min); reperfusion occurred at 47.3 +/- 7.6 minutes (p less than 0.05 versus group 1) with a reperfusion incidence of 90% (9/10). Group 4 received t-PA plus bitistatin, and reperfusion occurred at 51.8 +/- 8.5 minutes; however, the reperfusion incidence was only 60% (6/10). In groups 1, 2, and 4, acute reocclusion occurred in more than 80% of the reperfused dogs, whereas in group 3 reocclusion occurred in 22% (2/9) of the reperfused dogs (p less than 0.05 versus group 1). The dose of heparin used in this study increased activated partial thromboplastin times 1.5-2.0-fold over control.(ABSTRACT TRUNCATED AT 250 WORDS)
Shebuski
R J
RJ
Department of Pharmacology, Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486.
Stabilito
I J
IJ
Sitko
G R
GR
Polokoff
M H
MH
D000818:Animals; D003326:Coronary Circulation; D003327:Coronary Disease / Q000503:physiopathology*; D003328:Coronary Thrombosis / Q000503:physiopathology* / Q000517:prevention & control; D004285:Dogs; D004338:Drug Combinations; D004558:Electric Stimulation; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006439:Hemodynamics; D006493:Heparin / Q000494:pharmacology*; D008297:Male; D015425:Myocardial Reperfusion / Q000379:methods; D010314:Partial Thromboplastin Time; D010455:Peptides / Q000494:pharmacology*; D010974:Platelet Aggregation; D011994:Recombinant Proteins; D012008:Recurrence; D012910:Snake Venoms; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
D004338:Drug Combinations; D005343:Fibrinolytic Agents; D010455:Peptides; D011994:Recombinant Proteins; D012910:Snake Venoms; C062186:bitistatin; D006493:Heparin; D010959:Tissue Plasminogen Activator