Anti‐inflammatory actions of aprotinin provide dose‐dependent cardioprotection from reperfusion injury

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 mm 2 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. British Journal of Pharmacology (2008) 155 , 93–102; doi: 10.1038/bjp.2008.223 ; published online 9 June 2008