Cardioprotection and thrombolysis by anistreplase in anesthetized dogs.
Anistreplase is a thrombolytic agent comprising a complex of streptokinase, lys-plasminogen, and a p-anisoyl group, which temporarily protects the catalytic center of the enzyme complex. Streptokinase was previously shown to reduce infarct size (IS) in dogs with a fibrin-rich clot in the left anterior descending coronary artery (LAD) without necessarily producing reperfusion. Therefore, we hypothesized that IS in this model would be reduced by anistreplase. In addition, we studied the effect of tissue-type plasminogen activator (t-PA) on IS, testing our hypothesis in anesthetized dogs in which thrombin (100 U) and calcium (50 microliters, 0.05 M) were sequentially injected into the LAD to form a thrombus, anistreplase [0.01, 0.05, or 0.10 U/kg intravenous (i.v.) bolus], t-PA (0.1, 0.5, 2, or 8 micrograms/kg/min infusion for 60 min) or vehicle (VEH) was administered 55 min later. Anistreplase (0.05 or 0.10 U/kg) significantly (p < 0.05) reduced clot weight (VEH 22 +/- 3 mg; anistreplase 0.05 U/kg, 13 +/- 4 mg; anistreplase 0.10 U/kg, 0.7 +/- 0.6 mg), increased incidence of reperfusion (VEH 0%; anistreplase 0.05 U/kg, 42%; anistreplase 0.10 U/kg, 100%) and reduced IS (VEH 23 +/- 3%; anistreplase, 0.05 U/kg, 14 +/- 2%; anistreplase 0.10 U/kg, 15 +/- 2%). t-PA reduced thrombin weight (VEH 26 +/- 3 mg; 2 micrograms/kg/min t-PA 12 +/- 4; 8 micrograms/kg/min t-PA 2 +/- 2 mg) and increased incidence of reperfusion (VEH 0%; 2 micrograms/kg/min 75%; 8 micrograms/kg/min 100%), but IS was not altered (VEH 19 +/- 3%; 0.1 microgram/kg/min 18 +/- 3%; 0.5 microgram/kg/min 23 +/- 2%; 2 micrograms/kg/min 16 +/- 5%; 8 micrograms/kg/min: 19 +/- 3%).(ABSTRACT TRUNCATED AT 250 WORDS)
Feuerstein
G Z
GZ
SmithKline Beecham Pharmaceuticals Division of Pharmacology, King of Prussia, PA 19406-0939, USA.
Nichols
A J
AJ
Valocik
R E
RE
Gagnon
R
R
Sellars
T S
TS
Fears
R C
RC
Ferres
H
H
Ruffolo
R R
RR
D000758:Anesthesia; D000818:Animals; D016255:Anistreplase / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D006339:Heart Rate / Q000187:drug effects; D006490:Hemostatics / Q000494:pharmacology; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D009206:Myocardium / Q000201:enzymology; D009195:Peroxidase / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
D005343:Fibrinolytic Agents; D006490:Hemostatics; D016255:Anistreplase; D009195:Peroxidase; D010959:Tissue Plasminogen Activator