Animal data strongly support a role for inflammation in myocardial ischemia reperfusion injury. Attempts at cardioprotection by immunomodulation (such as with the specific C5 antibody pexelizumab) in humans have been disappointing. We hypothesized that a broader spectrum antiinflammatory agent might yield successful cardioprotection. The serine protease inhibitor nafamostat (FUT-175), which is already in clinical use, is a potent antiinflammatory synthetic serine protease inhibitor with anticomplement activity that we tested in a well-established rabbit model of 1 hour of myocardial ischemia followed by 3 hours of reperfusion. Compared to vehicle-treated animals, nafamostat (1 mg/kg of body weight) administered 5 minutes before reperfusion significantly reduced myocardial injury assessed by plasma creatine kinase activity (38.1 ± 6.0 versus 57.9 ± 3.7I U/g protein; P < 0.05) and myocardial necrosis (23.6 ± 3.1% versus 35.7 ± 1.0%; P < 0.05) as well as myocardial leukocyte accumulation (P < 0.05). In parallel in vitro studies, Nafamostat was a significantly more potent broad spectrum complement suppressor than C1 inhibitor. Nafamostat appears to have capability as an inhibitor of both complement pathways and as a broad-spectrum antiinflammatory agent by virtue of its serine protease inhibition. Administration of nafamostat before myocardial reperfusion after ischemia produced significant, dose-dependant cardioprotection. Reduced leukocyte accumulation and complement activity seem involved in the mechanism of this cardioprotective effect.
From the *Department of Medicine III, Martin-Luther-University, Halle, Germany; and †Abbott Pharmaceuticals, Ludwigshafen, Germany.
Received for publication August 31, 2007; accepted April 4, 2008
Hansjörg Schwertz and Justin M. Carter contributed equally to the completed work.
This study was supported by Grant Bu 819/3-1 of the Deutsche Forschungsgemeinschaft. Ute Buerke is supported by a state grant of Saxony-Anhalt. Justin M. Carter is supported by the South Cleveland Heart Fund.
Reprints: Michael Buerke, MD, Department of Medicine III, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Str. 40,06120 Halle, Germany (e-mail: firstname.lastname@example.org).