Effects of a highly selective synthetic inhibitor of plasma kallikrein on disseminated intravascular coagulation in rats.
We found a new, highly selective plasma kallikrein inhibitor, trans-4-aminomethyl-cyclohexanecarbonylphenylalanine 4-carboxymethylanilide hydrochloride, called PKSI-527 in our laboratories. This study was conducted to evaluate PKSI-527, on thromboplastin (TP)- and endotoxin (LPS)-induced disseminated intravascular coagulation (DIC) in rats. PKSI-527 was infused intravenously at 0.1 mg/kg/min for 250 min. Three of the parameters of the coagulation and fibrinolysis system, fibrinogen level, platelet counts and fibrin(ogen) degradation products (FDP) level were assayed. PKSI-527 prevented the change in the coagulation and fibrinolysis system in LPS-induced DIC, however it was not clearly effective in TP-induced DIC. The parameters of organ failure, such as serum glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), creatine phosphokinase (CPK), lactate, blood urea nitrogen and beta-glucuronidase, were assayed. Although the changes in the fibrinogen level, platelet counts and FDP level were almost the same in both models, the parameters of organ failure apparently increased in LPS-induced DIC more so than in TP-induced DIC. PKSI-527 significantly suppressed the increases in GOT and GPT in LPS-induced DIC. These results indicate that plasma kallikrein may play a significant role in LPS-induced DIC. Therefore, PKSI-527, as a synthetic plasma kallikrein inhibitor may be a valuable tool to explore the mechanism of DIC and the accompanying organ failure.
Katsuura
Y
Y
Life Science Research Laboratory, Showa Denko K.K., Tokyo, Japan.
Okamoto
S
S
Ohno
N
N
Wanaka
K
K
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005340:Fibrinogen / Q000032:analysis; D007262:Infusions, Intravenous; D007610:Kallikreins / Q000037:antagonists & inhibitors*; D008297:Male; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010976:Platelet Count / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage*; D014148:Tranexamic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*
D005338:Fibrin Fibrinogen Degradation Products; D015842:Serine Proteinase Inhibitors; C064866:PKSI 527; D010649:Phenylalanine; D014148:Tranexamic Acid; D005340:Fibrinogen; D007610:Kallikreins