Nafamostat attenuated the impairment of fibrinolysis in animal sepsis model by suppressing the increase of plasminogen activator inhibitor type 1.
BACKGROUND
In endotoxemia, plasminogen activator inhibitor-1 (PAI-1) increases and develops clinical symptoms by suppressing fibrinolysis. We analyzed therapeutic advantage of nafamostat, a broad-range protease inhibitor, on fibrinolysis in an animal sepsis model.


METHODS
Male Wister rats infused with lipopolysaccharide (LPS) (50 mg/kg) alone or together with nafamostat (0.1 mg/kg/hr) for 4 hours were analyzed.


RESULTS
Plasma PAI-1 (4.2: 4.0-5.0 ng/mL, median and interquartile range) increased after LPS infusion (3700: 3400-4000), which was attenuated by nafamostat (2300: 2100-2600, p < 0.05). Fibrin(ogen) degradation products after LPS injection (173: 152-182 microg/mL) were further elevated by nafamostat (205: 205-228, p < 0.05), Nafamostat attenuated polymorphonuclear neutrophils infiltration in the liver, and tended to suppress plasma tumor necrosis factor-alpha levels. Nafamostat did not affect thrombin generation, platelet count, markers of liver and kidney function, and overall mortality.


CONCLUSIONS
Nafamostat appeared to improve impaired fibrinolysis by suppressing the increase of PAI-1 in plasma, though it did not largely improve clinical parameters.
Hryszko
Tomasz
T
Department of Physiology, Hamamatsu University School of Medicine, Handa-yama, Japan.
Inaba
Keisuke
K
Ihara
Hayato
H
Suzuki
Yuko
Y
Mogami
Hideo
H
Urano
Tetsumei
T
D000818:Animals; D001550:Benzamidines; D004347:Drug Interactions; D005340:Fibrinogen / Q000378:metabolism*; D005342:Fibrinolysis / Q000187:drug effects*; D006146:Guanidines / Q000494:pharmacology*; D016753:Interleukin-10 / Q000097:blood; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001550:Benzamidines; D006146:Guanidines; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D011480:Protease Inhibitors; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D005340:Fibrinogen; C032855:nafamostat