EFFECT OF A NEW CCK-A RECEPTOR ANTAGONIST, DEXLOXIGLUMIDE, ON THE EXOCRINE PANCREAS IN THE RAT

The effect of dexloxiglumide, a new potent cholecystokinin (CCK) antag onist, on pancreatic enzyme secretion and growth was studied in the ra t. Pancreatic exocrine secretion was studied both in vitro (isolated a nd perfused pancreatic segments) and in vivo (anaesthetized animals wi th cannulation of the common bile duct) whereas the trophic effect was investigated after short-term (7 days) administration of the CCK-agon ist, caerulein, or camostate (a potent trypsin inhibitor), with or wit hout dexloxiglumide. CCK-8 stimulated amylase release from in vitro pa ncreatic segments in a concentration-dependent manner. Dexloxiglumide displaced the concentration response curves to CCK-8 to the right with out affecting the maximum response, suggesting a competitive antagonis m. 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 confi rmed results from irt vitro studies since intravenous dexloxiglumide r educed pancreatic exocrine secretion induced by submaximal CCK-8 stimu lation (0.5 nmol/kg/h) in a dose-dependent manner, the ID50 being 0.64 mg/kg. Both exogenous and endogenous (released by camostate) CCK incr eased the weight of the pancreas, the total pancreatic protein and DNA , trypsin and amylase content. Dexloxiglumide (25 mg/kg), administered together with caerulein (1 mu g/kg), reduced the peptide-induced incr ease 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 ant agonist. These results demonstrate the ability of dexloxiglumide to an tagonize the effects of CCK on pancreatic secretion and growth, sugges ting that this compound is a potent and selective antagonist of CCK-A- receptors in the pancreas.