title: Cardioprotective effects of the serine protease inhibitor aprotinin after regional ischemia and reperfusion on the beating heart.
abstract: OBJECTIVE
  Early coronary reperfusion of the ischemic myocardium is a desired therapeutic goal to preserve myocardium. However, reperfusion itself contributes to an additional myocardial injury (ie, reperfusion injury), which has been attributed to neutrophil infiltration with subsequent release of proteases and oxygen-derived radicals. We studied the effects of the serine protease inhibitor aprotinin (Trasylol) on myocardial ischemia and reperfusion in a rat model.
  
  
  METHODS
  The effects of aprotinin (5000 and 20,000 U/kg) were examined in vivo in a rat model of regional myocardial ischemia (20 minutes) and long-term reperfusion (24 hours). Cardioprotecive effects were determined by means of measurement of creatine kinase and myeloperoxidase activity within the myocardium, as well as histochemical analysis.
  
  
  RESULTS
  Aprotinin (20,000 U/kg) administrated 2 minutes before reperfusion significantly attenuated myocardial injury expressed as creatine kinase washout compared with that seen in vehicle-treated rats (65 +/- 25 vs 585 +/- 98 creatine kinase difference in units per 100 mg, P <.01). Administration of 5000 U/kg of the protease inhibitor resulted in partial inhibition of myocardial reperfusion injury. Moreover, cardiac myeloperoxidase activity in the ischemic myocardium, a marker of neutrophil accumulation, was significantly reduced after aprotinin treatment. Histologic analysis of the reperfused myocardium demonstrated reduced polymorphonuclear leukocyte infiltration and reduced tissue injury. Furthermore, aprotinin treatment resulted in decreased induction of cardiac myocyte apoptosis compared with that seen in vehicle-treated rats.
  
  
  CONCLUSIONS
  Inhibition of serine proteases with aprotinin appears to be an effective means of preserving ischemic myocardium from reperfusion injury, even after 24 hours of reperfusion. Aprotinin might exert cardioprotection through inhibition of polymorphonuclear leukocyte-induced myocardial injury and inhibition of reperfusion-induced apoptosis of cardiac myocytes.
authors.affiliation: Department of Cardiothoracic and Vascular Surgery and II Department of Medicine-Cardiology, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Diethard
authors.initials: D
authors.lastname: Pruefer
authors.forename: Ute
authors.initials: U
authors.lastname: Buerke
authors.forename: Markus
authors.initials: M
authors.lastname: Khalil
authors.forename: Manfred
authors.initials: M
authors.lastname: Dahm
authors.forename: Harald
authors.initials: H
authors.lastname: Darius
authors.forename: Hellmut
authors.initials: H
authors.lastname: Oelert
authors.forename: Michael
authors.initials: M
authors.lastname: Buerke
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D007611:Aprotinin / Q000008:administration & dosage*; D015415:Biomarkers / Q000097:blood; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D003131:Combined Modality Therapy; D003402:Creatine Kinase / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles / Q000378:metabolism; D007958:Leukocyte Count; D008297:Male; D008955:Models, Cardiovascular; D017202:Myocardial Ischemia / Q000097:blood / Q000188:drug therapy* / Q000601:surgery*; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000097:blood / Q000188:drug therapy / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D002316:Cardiotonic Agents; D015842:Serine Proteinase Inhibitors; D007611:Aprotinin; D009195:Peroxidase; D003402:Creatine Kinase