Effect of a new CCK-A receptor antagonist, dexloxiglumide, on the exocrine pancreas in the rat

Abstract

The effect of dexloxiglumide, a new potent cholecystokinin (CCK) antagonist, on pancreatic enzyme secretion and growth was studied in the rat. Pancreatic exocrine secretion was studied both in vitro (isolated and perfused pancreatic segments) and in vivo (anaesthetized animals with cannulation of the common bile duct) whereas the trophic effect was investigated after short-term (7 days) administration of the CCK-agonist, caerulein, or camostate (a potent trypsin inhibitor), with or without dexloxiglumide. CCK-8 stimulated amylase release from in vitro pancreatic segments in a concentration-dependent manner. Dexloxiglumide displaced the concentration response curves to CCK-8 to the right without affecting the maximum response, suggesting a competitive antagonism. The Schild plot analysis of data gave a straight line with a slope (0.90±0.36) not significantly different from unity. The calculated pA 2 for dexloxiglumide was 6.41 ± 0.38. In vivo experiments confirmed results from in vitro studies since intravenous dexloxiglumide reduced pancreatic exocrine secretion induced by submaximal CCK-8 stimulation (0.5 nmol/kg/h) in a dose-dependent manner, the ID 50 being 0.64 mg/kg. Both exogenous and endogenous (released by camostate) CCK increased the weight of the pancreas, the total pancreatic protein and DNA, trypsin and amylase content. Dexloxiglumide (25 mg/kg), administered together with caerulein (1 μg/kg), reduced the peptide-induced increase in pancreatic weight, protein and enzyme content. Similarly, when dexloxiglumide was given together with camostate (200 mg/kg), all the observed changes were reduced by concomitant administration of the antagonist. These results demonstrate the ability of dexloxiglumide to antagonize the effects of CCK on pancreatic secretion and growth, suggesting that this compound is a potent and selective antagonist of CCK-A-receptors in the pancreas.