Single bolus administration of recombinant tissue plasminogen activator: effects on infarct related vessel patency, microvascular perfusion, and microvascular reocclusion in a canine model of thrombotic occlusion/reperfusion.
OBJECTIVE
The aim was to evaluate the thrombolytic efficacy of recombinant double chain tissue plasminogen activator (Duteplase, t-PA) given as a single intravenous bolus versus an infusion in a canine model of coronary arterial occlusion/reperfusion.


METHODS
Coronary arterial thrombi were induced by a copper coil (placed under fluoroscopic control) in the left anterior descending coronary artery of anaesthetised dogs. Following 90 min thrombotic occlusion, animals were randomly assigned to one of two treatment groups: group 1 = t-PA infused intravenously at 0.6 x 10(6) IU.kg-1.h-1, or group 2 = t-PA (0.6 x 10(6) IU.kg-1) by intravenous bolus over 6 min. Both groups received concurrent heparin (six 1000 IU boluses, + 100 IU.kg-1.h-1) throughout t-PA administration and the 2 h reperfusion period.


METHODS
16 beagle dogs of either sex were used, weight 9.2-20.3 kg.


RESULTS
Radiolabelled microspheres were injected to assess microvascular coronary flow at various time points throughout the experimental period. Infarct related vessel patency (IRVP) was assessed arteriographically every 5 min. Infarct size was assessed histochemically at the end of the reperfusion period. IRVP was achieved within 42.9 (SEM 7.4) min and 43.1(7.0) min for infusion and bolus groups respectively; 60 min patency rates were 88% for both groups. t-PA restored full microvascular flow to ischaemic subendocardial and subepicardial regions in both groups compared to initial preocclusion regional blood flow. Extent of reactive hyperaemia was greater in infusion than bolus treatment animals: infusion group 1.18(0.15) v bolus group 0.72(0.14) ml.min-1.g-1 (subepicardial). Degree of microvascular reocclusion at 120 min reperfusion was similar for both groups despite aggressive anticoagulation throughout: infusion group 0.33(0.08) v bolus group 0.42(0.11) ml.min-1.g-1 (subendocardial). Areas of the myocardium at risk (R), absolute infarct size (I), and infarct risk ratio (I/R) were similar for both groups: R = 33.9(1.5) v 30.9(1.9)%; I = 15.9(3.1) v 13.3(3.1)%; I/R = 46.3(8.4) 42.1(9.2)%. Degree of systemic fibrinogenolysis was similar for both groups: infusion 1.65(0.40) to 0.67(0.07) g.litre-1 v bolus 1.68(0.15) to 0.96(0.12) g.litre-1.


CONCLUSIONS
Single bolus administration of t-PA showed equivalent efficacy to infusion dosing in respect of IRVP, microvascular reperfusion, and microvascular reocclusion. As a result the degree of tissue necrosis (I/R ratio) was no different when comparing the two dosing regimens. Similar degrees of systemic fibrinogenolysis were observed for both treatment groups.
Longridge
D J
DJ
Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent, United Kingdom.
Follenfant
M J
MJ
Ford
A J
AJ
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000188:drug therapy*; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D015425:Myocardial Reperfusion; D011994:Recombinant Proteins; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D014654:Vascular Patency / Q000187:drug effects*
D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator