Carboxypeptidase B inhibitors reduce tissue factor-induced renal microthrombi in rats.
Procarboxypeptidase B (also known as thrombin-activatable fibrinolysis inhibitor) is a recently described plasma zymogen known to be activated by thrombin in plasma. Carboxy-terminal lysine residues from partially degraded fibrin are important for the binding and activation of plasminogen, and carboxypeptidase B, an active form of procarboxypeptidase B, has been shown to inhibit fibrinolysis by eliminating these residues. The present paper investigates the effects of carboxypeptidase B inhibitors, DL-mercaptomethyl-3-guanidinoethylthiopropanoic acid (MGPA) and potato-derived carboxypeptidase inhibitor (CPI), on tissue factor (TF)-induced microthrombosis in rats. Intravenous injection of MGPA (3 mg/kg and higher) or CPI (0.3 mg/kg and higher) after microthrombi formation dramatically attenuated TF-induced glomerular fibrin deposition with an increase in plasma levels of D-dimer. These results indicate that carboxypeptidase B inhibitors can enhance endogenous fibrinolysis and reduce thrombi in the TF-induced microthrombosis model after systemic administration even after thrombi formation.
Muto
Yuko
Y
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd, 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan. yuko_muto@meiji.co.jp
Suzuki
Kokichi
K
Sato
Eriko
E
Ishii
Hidemi
H
D015097:3-Mercaptopropionic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D043424:Carboxypeptidase B; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors* / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005337:Fibrin / Q000187:drug effects / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D007678:Kidney Glomerulus / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013925:Thromboplastin / Q000494:pharmacology*; D013927:Thrombosis / Q000097:blood / Q000517:prevention & control*
D011480:Protease Inhibitors; C029729:2-mercaptomethyl-3-guanidinoethylthiopropionic acid; D005337:Fibrin; D013925:Thromboplastin; D015097:3-Mercaptopropionic Acid; D002268:Carboxypeptidases; D043424:Carboxypeptidase B