Protection by gabexate mesilate (FOY) of the exocrine pancreas in rats with acute pancreatitis induced by a supramaximal dose of caerulein.
Earlier studies have reported that interstitial oedematous pancreatitis characterized by hyperamylasaemia can be seen during the early stage of stimulation of supramaximal dose of caerulein. The present study investigated the changes in both cellular and lysosomal fragility and the protective effects of a synthetic protease inhibitor gabexate mesilate (FOY) on this non-invasive model of experimental pancreatitis. The infusion of FOY (50 mg/kg/h) prevented the caerulein-induced increase in serum amylase and pancreatic oedema formation and reduced the elevated amylase content significantly. The administration of FOY with caerulein also reduced the increased lactic dehydrogenase (LDH) discharge significantly and inhibited the cathepsin B leakage from lysosomes in an in vitro incubation system. These results indicate that FOY plays its protective role at the subcellular level--that is, in lysosomes by inhibiting some proteases such as phospholipase A2. The importance of esterases in the pathogenesis of acute pancreatitis is demonstrated. This type of esterase inhibitor may be valuable clinically in the treatment of acute pancreatitis and these results also suggest the role of lysosomal fragility in the pathogenesis of progression 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 / Q000032:analysis / Q000097:blood; D000818:Animals; D002401:Cathepsin B / Q000378:metabolism / Q000493:pharmacokinetics; D002108:Ceruletide / Q000009:adverse effects* / Q000037:antagonists & inhibitors; D016670:Gabexate / Q000627:therapeutic use*; D007770:L-Lactate Dehydrogenase / Q000493:pharmacokinetics; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009929:Organ Size; D010179:Pancreas / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D016670:Gabexate; D002108:Ceruletide; D007770:L-Lactate Dehydrogenase; D000681:Amylases; D002401:Cathepsin B