1. Anti-inflammatory actions of aprotinin provide dose-dependent cardioprotection from reperfusion injury.
- Author
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Carter J, Buerke U, Rössner E, Russ M, Schubert S, Schmidt H, Ebelt H, Pruefer D, Schlitt A, Werdan K, and Buerke M
- Subjects
- Animals, Apoptosis drug effects, Cell Adhesion drug effects, Disease Models, Animal, Dose-Response Relationship, Drug, Endothelial Cells drug effects, Endothelial Cells immunology, Hemodynamics drug effects, Leukocyte Count, Male, Myocardial Reperfusion Injury immunology, Myocardial Reperfusion Injury physiopathology, Myocardium pathology, Necrosis, Neutrophils immunology, Rabbits, Time Factors, Anti-Inflammatory Agents pharmacology, Aprotinin pharmacology, Myocardial Reperfusion Injury prevention & control, Myocardium immunology, Neutrophil Infiltration drug effects, Neutrophils drug effects, Serine Proteinase Inhibitors pharmacology
- Abstract
Background and Purpose: Myocardial injury following ischaemia and reperfusion has been attributed to activation and transmigration of polymorphonuclear leukocytes (PMNs) with release of mediators including oxygen-derived radicals and proteases causing damage., Experimental Approach: We studied the serine protease inhibitor aprotinin in an in vivo rabbit model of 1 h of myocardial ischaemia followed by 3 h of reperfusion (MI+R). Aprotinin (10,000 Ukg(-1)) or its vehicle were injected 5 min prior to the start of reperfusion., Key Results: Myocardial injury was significantly reduced with aprotinin treatment as indicated by a reduced necrotic area (11+/-2.7% necrosis as percentage of area at risk after aprotinin; 24+/-3.1% after vehicle; P<0.05) and plasma creatine kinase activity (12.2+/-1.5 and 17.3+/-2.3 IU g(-1) protein in aprotinin and vehicle groups, respectively, P<0.05). PMN infiltration (assessed by myeloperoxidase activity) was significantly decreased in aprotinin-treated animals compared to vehicle (P<0.01). Histological analysis also revealed a substantial increase in PMN infiltration following MI+R and this was significantly reduced by aprotinin therapy (44+/-15 vs 102+/-2 PMN mm2 in aprotinin vs vehicle-treated animals, P<0.05). In parallel in vitro experiments, aprotinin inhibited neutrophil-endothelium interaction by reducing PMN adhesion on isolated, activated aortic endothelium. Finally, immunohistochemical analysis illustrated aprotinin significantly reduced myocardial apoptosis following MI+R., Conclusions and Implications: Inhibition of serine proteases by aprotinin inhibits an inflammatory cascade initiated by MI+R. The cardioprotective effect appears to be at least partly due to reduced PMN adhesion and infiltration with subsequently reduced myocardial necrosis and apoptosis.
- Published
- 2008
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