Effect of deramciclane, a new 5-HT receptor antagonist, on cholecystokinin-induced changes in rat gastrointestinal function

Recent studies suggested that serotonin receptors may be involved in modula ting the actions of cholecystokinin (CCK) in the gastrointestinal tract. Th e present work was designed to compare the effects of deramciclane, a recen tly developed serotonin-2 (5-HT2A/2C) receptor antagonist, and lorglumide, a CCKA receptor antagonist, on exogenous and endogenous CCK-induced pancrea tic enzyme secretion and pancreatic growth, as well as on the emptying of t he stomach and the gallbladder. Pancreatic secretory function was tested wh ile CCK release was evoked by diversion of bile-pancreatic juice in rats. A daptive growth of the pancreas was induced by chronic intragastric administ ration of camostate, a potent synthetic trypsin inhibitor in rats. Gastric emptying of a noncaloric test meal was investigated in response to intraduo denal intralipid infusion, also in rats. In fasted mice, gallbladder emptyi ng was examined in response to intragastric egg yolk administration. In rat s, diversion of bile-pancreatic juice from the duodenum stimulated pancreat ic amylase secretion. This action was blocked by deramciclane and by lorglu mide. Pancreatic hypertrophy and hyperplasia induced by chronic camostate a dministration was also suppressed by both the serotonin- and the CCK-recept or antagonists. Intraduodenal administration of intralipid induced a signif icant delay in gastric emptying. This effect was inhibited by both deramcic lane and lorglumide in rats. In mice? intragastric administration of egg yo lk elicited an accelerated release of bile from the gallbladder. Prior trea tment with either deramciclane or lorglumide abolished this response. Lorgl umide was able to inhibit the functional responses elicited by exogenous CC K administration in both pancreas, stomach and gallbladder, while deramcicl ane was not effective under such circumstances. Our data show that deramcic lane inhibited the effects of CCK on pancreatic, gastric and gallbladder fu nction when its endogenous release was stimulated, but did not alter the ef fects of exogenously administered peptide. These results suggest that serot onin, primarily via 5-HT2A, receptors, may modulate CCK-mediated gastrointe stinal functions in rats. (C) 1999 Elsevier Science B.V. All rights reserve d.