Inhibitory effect of a cholecystokinin antagonist on the proliferative response of the pancreas to pancreatobiliary diversion

Abstract

Since pancreatobiliary diversion probably stimulates pancreatic growth by increasing cholecystokinin secretion, the effect of the cholecystokinin antagonist CR-1409 on this adaptive response was tested. Male Wistar rats (n=108) weighing 220-250g were randomized to receive either pancreatobiliary diversion (n=60) or sham diversion (n=48) and thereafter to receive either saline injections or CR-1409 (10 mg/kg/day, subcutaneously). Rats were killed at four, seven, and 14 days postoperatively, when blood was obtained for cholecystokinin assay and the pancreas was assessed for proliferative activity by three techniques: nucleic acid and protein assay, bromodeoxyuridine labelling, and metaphase arrest after vincristine administration (1 mg/ kg, intraperitoneally). Pancreatobiliary diversion increased plasma cholecystokinin concentrations by 91% at seven days and 137% at 14 days, irrespective of CR-1409 treatment. Total pancreatic RNA content was doubled by pancreatobiliary diversion at four days (2·15 v 1·07 mg/100 g body weight: p<0·001) and at seven days (3·43 v 1·76 mg/100 g: p<0·001), and trebled at 14 days (4-27 v 1-32 mg/100 g: p<0·00l). Pancreatobiliary diversion increased bromodeoxyuridine labelling index from 1·1 to 3·7% at seven days and the cell birth rate from 0·09 to 0·06%. CR-1409 completely abolished this proliferative response and partly prevented the rise in RNA. The results confirm pancreatic hypertrophy and increased acinar cell proliferation after pancreatobiliary diversion. CR-1409 prevents this adaptive growth, probably by blocking cholecystokinin receptors. Bromodeoxyuridine labelling and the metaphase arrest technique may be used to assess pancreatic cell kinetics.