title: Oxygen radical scavenging agents as adjuvant therapy with tissue plasminogen activator in a canine model of coronary thrombolysis.
abstract: OBJECTIVE
  Early thrombolysis can reduce infarct size and enhance the long term recovery of contractile function after acute myocardial infarction. These benefits of early reperfusion may be confounded, however, by platelet mediated reocclusion after initial lysis, and "reperfusion injury" mediated by oxygen derived free radicals. Superoxide dismutase (SOD)--as well as its action as a potent free radical scavenging agent--inhibits platelet aggregation in vitro. Thus our primary objectives were to determine whether SOD+catalase, given as adjuvant therapy with recombinant human tissue plasminogen activator, could inhibit platelet aggregation and thereby reduce the time to lysis and maintain arterial patency. Whether SOD+catalase enhanced myocardial salvage or improved acute recovery of contractile function in the setting of thrombosis/thrombolysis was also assessed.
  
  
  METHODS
  Two anaesthetised open chest canine models were used: a model of thrombosis/thrombolysis and an in vivo model of platelet aggregation. In protocol I coronary thrombosis was induced by endothelial injury and injection of blood+thrombin+CaCl2. At three hours after occlusion, control animals received saline and tissue plasminogen activator and treated dogs received SOD+catalase and tissue plasminogen activator. Variables measured included coronary blood flow (for assessment of the time to lysis and incidence and duration of spontaneous reocclusion); regional myocardial blood flow; segment shortening; and infarct size. In protocol II dogs underwent endothelial injury and coronary stenosis, resulting in cyclic variations in coronary blood flow caused by formation and dislodgement of platelet thrombi. At 30 minutes after placement of the stenosis, dogs received either saline and tissue plasminogen activator or SOD+catalase and tissue plasminogen activator. Variables measured included the frequency of cyclic flow variations and the duration of occlusion per 30 minute time interval.
  
  
  RESULTS
  SOD+catalase slightly reduced the time required to achieve reflow: time to lysis was 35(SEM 5) v 22(4) minutes for control v treated groups (p < 0.05). Protocol II showed that this accelerated time to lysis was due to acute inhibition of platelet aggregation by the scavenging agents. Despite continuous infusion however, SOD+catalase failed to maintain vessel patency in either limb of the study. In protocol I, reocclusion occurred in 90% of control dogs (with 49(8)% of the time after initial lysis spent reoccluded), v 83% in the treated group (36(12)% of the time reoccluded; NS v controls). Also, both groups remained dyskinetic after reflow: at one hour after initial lysis, segment shortening was -6(9)% v -6(20)% of baseline preocclusion values in the subset of control v treated dogs in which the left anterior descending coronary artery was patent at the time of measurement (NS). Finally, infarct size was similar in both groups, averaging 32(9)% v 38(9)% of the myocardium at risk in control v treated animals (NS).
  
  
  CONCLUSIONS
  Although SOD+catalase acutely attenuated platelet aggregation and slightly accelerated lysis, these agents failed to limit platelet mediated rethrombosis. Furthermore, SOD+catalase did not enhance myocardial salvage and did not improve acute recovery of contractile function after thrombosis/thrombolysis. Thus SOD+catalase given as adjuvant therapy with tissue plasminogen activator did not have a substantial beneficial effect on either the efficacy of thrombolysis or on "reperfusion injury" in this canine model.
authors.affiliation: Heart Institute, Hospital of the Good Samaritan, Los Angeles, CA 90017.
authors.forename: K
authors.initials: K
authors.lastname: Przyklenk
authors.forename: R A
authors.initials: RA
authors.lastname: Kloner
mesh_terms: D000818:Animals; D002374:Catalase / Q000627:therapeutic use*; D003326:Coronary Circulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000188:drug therapy*; D004285:Dogs; D004359:Drug Therapy, Combination; D005260:Female; D006439:Hemodynamics / Q000502:physiology; D007700:Kinetics; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D010974:Platelet Aggregation / Q000502:physiology; D012008:Recurrence; D013482:Superoxide Dismutase / Q000627:therapeutic use*; D015912:Thrombolytic Therapy / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
chemical_list: D002374:Catalase; D013482:Superoxide Dismutase; D010959:Tissue Plasminogen Activator