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J Thorac Cardiovasc Surg 2002;124:942-949
© 2002 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology (CSP)

Cardioprotective effects of the serine protease inhibitor aprotinin after regional ischemia and reperfusion on the beating heart

From the Department of Cardiothoracic and Vascular Surgery^a and II Department of Medicine-Cardiology,^b Johannes Gutenberg-University, Mainz, Germany.

Supported in part by grant Bu 819/3-1 of Deutsche Forschungsgemeinschaft and Robert Mueller-Foundation, Germany (U.B., M.K., H.D., and M.B.).

Received for publication Oct 18, 2001. Revisions requested Dec 10, 2001; revisions received Jan 15, 2002. Accepted for publication Feb 10, 2002. Address for reprints: Michael Buerke, MD, II Department of Medicine-Cardiology, Johannes Gutenberg-University, Langenbeck-Str 1, D-55101 Mainz, Germany (E-mail: buerke{at}mail.uni-mainz.de).

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.

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