Serine protease inhibitor nafamostat given before reperfusion reduces inflammatory myocardial injury by complement and neutrophil inhibition.
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-dependent cardioprotection. Reduced leukocyte accumulation and complement activity seem involved in the mechanism of this cardioprotective effect.
Schwertz
Hansjörg
H
Department of Medicine III, Martin-Luther-University, Halle, Germany.
Carter
Justin M
JM
Russ
Martin
M
Schubert
Sebastian
S
Schlitt
Axel
A
Buerke
Ute
U
Schmidt
Martin
M
Hillen
Heinz
H
Werdan
Karl
K
Buerke
Michael
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D001550:Benzamidines; D003167:Complement Activation / Q000187:drug effects*; D050718:Complement C1 Inhibitor Protein / Q000494:pharmacology / Q000627:therapeutic use; D051056:Complement Inactivating Agents / Q000494:pharmacology / Q000627:therapeutic use; D003170:Complement Pathway, Alternative / Q000187:drug effects; D003171:Complement Pathway, Classical / Q000187:drug effects; D003402:Creatine Kinase / Q000378:metabolism; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006439:Hemodynamics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D009336:Necrosis; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology; D011817:Rabbits; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001550:Benzamidines; D050718:Complement C1 Inhibitor Protein; D051056:Complement Inactivating Agents; D006146:Guanidines; D015842:Serine Proteinase Inhibitors; D003402:Creatine Kinase; C032855:nafamostat