Protective effects of prophylaxis with a protease inhibitor and a free radical scavenger against a temporary ischemia model of pancreatitis.

Objective: To evaluate the protective effects of combined prophylaxis with 4-sulfamoylphenyl, 4-guanidinobenzoate methanesulfonate (E3123), potent new protease inhibitor, and superoxide dismutase (SOD), a free radical scavenger, against the multifactor-related pancreatic injuries that occur in acute pancreatitis.

Design: Controlled experimental study in rats with pancreatitis induced by a temporary ischemic model of pancreaticobiliary-duct (PBD) obstruction.

Setting: A university-affiliated hospital.

Experimental Subjects: Seventy-eight male Wistar rats, weighing approximately 300 g each.

Interventions: In 18 rats the PBD was occluded with a metal clip, and cerulein was infused for 30 minutes at an hourly rate of 0.2 microgram/kg. After 1 hour the metal clip was removed and the abdomen closed (PBD obstruction group). In 21 rats the same protocol was followed, but ischemia was induced by occlusion of celiac and caudate mesenteric arteries for 30 minutes (ischemia group). In 24 rats the same protocol was followed as for the ischemia group, but 1 hour before and throughout the experiment, E3123 was infused at an hourly rate of 5 mg/kg, and before occlusion of the PBD and immediately after release of the occlusions of the PBD and arteries, SOD, 1 mg/kg, was injected intravenously (treatment group). Fifteen rats underwent laparotomy and gentle manipulation of the pancreatobiliary duct and celiac and caudate mesenteric arteries only (control group).

Main Outcome Measures: Serum amylase levels and pancreatic water and amylase levels, histologic changes in pancreas, subcellular amylase and cathepsin-B activities and in-vivo amylase and cathepsin-B outputs.

Results: Serum amylase levels and pancreatic water and amylase content were significantly (p < 0.05) reduced in the treatment group (mean [+/- standard error] 13 [2] U/mL, 77 [2] % of wet weight and 503 [56] U/mg of DNA respectively) compared with the ischemia group (25 [3] U/mL, 83 [2] % of wet weight and 731 [52] U/mg of DNA respectively). PBD obstruction and ischemia also caused a significant (p < 0.05) subcellular redistribution of cathepsin B from the lysosomal to the zymogen fraction and impaired output of amylase and cathepsin B into pancreatic juice, which was compensated for in the treatment group.

Conclusions: Temporary pancreatic ischemia and oxygen-derived free radicals appear to play an important role in the pathogenesis of acute pancreatitis. E3123 and SOD may be useful in the prophylaxis of clinical pancreatitis.