Anti-inflammatory actions of aprotinin provide dose-dependent cardioprotection from reperfusion injury.
OBJECTIVE
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.


METHODS
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.


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
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.
Carter
Jm
J
Department of Medicine III, Martin-Luther-University, Halle, Germany.
Buerke
U
U
Rössner
E
E
Russ
M
M
Schubert
S
S
Schmidt
H
H
Ebelt
H
H
Pruefer
D
D
Schlitt
A
A
Werdan
K
K
Buerke
M
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D007611:Aprotinin / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology; D006439:Hemodynamics / Q000187:drug effects; D007958:Leukocyte Count; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D009336:Necrosis; D020556:Neutrophil Infiltration / Q000187:drug effects*; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D011817:Rabbits; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013997:Time Factors
D000893:Anti-Inflammatory Agents; D015842:Serine Proteinase Inhibitors; D007611:Aprotinin