Protection by a new synthetic protease inhibitor, ONO3307, of the rat exocrine pancreas during acute edematous pancreatitis induced by a supramaximal dose of caerulein in comparison with FOY007.
The present study investigated the protective effects of the new potent synthetic protease inhibitors, ONO3307 (4-sulfamoyl phenyl-4-guanidinobenzoate methanesulfonate) and FOY007 (gabexate misilate), on the exocrine pancreas in rat caerulein-induced acute pancreatitis in both in vitro and in vivo experiments. These protease inhibitors prevented hyperamylasemia, pancreatic edema, congestion of amylase, redistribution of lysosomal enzyme in acinar cells, and lactic dehydrogenase (LDH) discharge from dispersed acini. They also inhibited the cathepsin B leakage from the lysosomes in a dose-dependent manner in doses of 2-10 mg/kg.h of ONO3307 and 20-50 mg/kg.h of FOY007. These results indicate that both ONO3307 and FOY007 exert protective effects against pancreatitis at subcellular levels in lysosomes and cellular or organelle membranes. Proteases appear to be important in the pathogenesis and development of acute pancreatitis, and low-molecular-weight protease inhibitors may be of clinical use in the treatment of acute pancreatitis.
Hirano
T
T
First Department of Surgery, Faculty of Medicine, Kyoto University, Japan.
Manabe
T
T
Tobe
T
T
D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D001834:Body Water; D002401:Cathepsin B / Q000378:metabolism; D002108:Ceruletide; D004487:Edema / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D016670:Gabexate / Q000627:therapeutic use*; D006146:Guanidines / Q000627:therapeutic use*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects; D008297:Male; D010179:Pancreas / Q000187:drug effects* / Q000201:enzymology; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D051381:Rats; D011919:Rats, Inbred Strains; D015842:Serine Proteinase Inhibitors / Q000627:therapeutic use*
D006146:Guanidines; D015842:Serine Proteinase Inhibitors; D016670:Gabexate; C062836:ONO 3307; D002108:Ceruletide; D007770:L-Lactate Dehydrogenase; D000681:Amylases; D002401:Cathepsin B