The current study was done to evaluate the effects of short term (60 minutes) pancreatic biliary duct obstruction (PBDO) with intraductal
hypertension (IDH) stimulated by
secretin (0.2 clinical unit per kilogram per hour) and
caerulein (0.2 microgram per kilogram per hour) plus 30 minutes of temporary pancreatic
ischemia (ISCH) produced by
ligation of celiac and superior mesenteric artery on the exocrine pancreas and protective effects of a new potent
protease inhibitor, ONO3307 in combination with
xanthine oxidase inhibitor,
allopurinol, in this multifactor related model of
acute pancreatitis in rats. Twelve hours after PBDO with IDH plus ISCH, we observed
hyperamylasemia (23 +/- 3 units per milliliter) (p < 0.01); moderate pancreatic histologic changes; pancreatic
edema (water content--81 +/- 2 percent) (p < 0.02), as well as the impaired
amylase (2,889 +/- 328 units per kilogram per hour) (p < 0.01) and
cathepsin B output (7 +/- 3 units per kilogram per hour) (p < 0.01) into the pancreatic juice of rats stimulated by
caerulein (control group--serum
amylase levels, 6 +/- 1 units per milliliter; pancreatic water content, 74 +/- 1 percent. Furthermore, PBDO with IDH plus ISCH caused the redistribution of lysosomal
enzyme from lysosomal fraction (12 kilo times gravity pellet; 40 +/- 3 percent; p < 0.01) to
zymogen fraction (1.3 kilo times gravity pellet; 38 +/- 3 percent; p < 0.01) (control group--12 kilo times gravity pellet, 59 +/- 2 percent; 1.3 kilo times gravity pellet, 24 +/- 2 percent) and the impaired pancreatic adenylate energy metabolism (0.79 +/- 0.02, p < 0.02) (control group--energy charge equals 0.88 +/- 0.01). Only PBDO with IDH caused no significant changes. Although only ONO3307 or
allopurinol therapy showed the partial significant protective effects against pancreatic
injuries, improving serum
amylase levels, the administration of ONO3307 in combination
therapy with
allopurinol showed almost complete protective effects against the pancreatic
injuries induced by PBDO with IDH plus ISCH (serum
amylase levels, 9 +/- 2 units per milliliter; pancreatic water content, 76 +/- 2 percent;
amylase and
cathepsin B output, 7,127 +/- 946 and 18 +/- 3 units per kilogram per hour; 1.3 kilo times gravity pellet, 28 +/- 2 percent; 12 kilo times gravity pellet, 54 +/- 2 percent, and energy charge equals 0.85 +/- 0.02).(ABSTRACT TRUNCATED AT 400 WORDS)