Effect of a new potent CCK antagonist, lorglumide, on caerulein‐ and bombesin‐induced pancreatic secretion and growth in the rat

Abstract

1 The effect of lorglumide, a new potent cholecystokinin (CCK) antagonist, on pancreatic secretion and growth induced by caerulein and bombesin was studied in the rat. 2 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 investiged after short-term (5 days) administration of the peptides and/or lorglumide. 3 Both caerulein and bombesin stimulated amylase release from in vitro pancreatic segments in a concentration-dependent manner. Although the efficacy of both peptides was virtually identical, the potency of caerulein was higher than that of bombesin. Lorglumide displaced the concentrationresponse curves to caerulein 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 not significantly different from unity. The calculated pA2 for lorglumide was 7.31 + 0.45. The antagonist, however, was completely ineffective when tested against bombesin-induced amylase release. 4 In vivo experiments confirmed results from in vitro studies since lorglumide (5 and I0mgkg 1) significantly reduced pancreatic exocrine secretion induced by caerulein without affecting the response to bombesin. 5 Administration of either peptide increased the weight of the pancreas, the total pancreatic protein and DNA, trypsin and amylase content. Lorglumide (10mgkg-1), administered together with caerulein, reduced the peptide-induced increase in pancreatic weight, protein and enzyme content. On the contrary, when lorglumide was given together with bombesin, all the parameters that were examined were not altered by concomitant administration of the antagonist. 6 These results have demonstrated the ability of lorglumide to antagonize the effects on the pancreas of a CCK-analogue, caerulein, and its inability to affect bombesin-induced pancreatic secretion and growth, suggesting that lorglumide is a potent and selective antagonist of CCK-receptors in the pancreas.

Role of Cholecystokinin, Gastrin and Gastrin-Releasing Peptide in the Regulation of Pancreatic Secretion in Cats

“…The mediation of CCK in the ca nine pancreatic secretion induced by bombe sin is also supported by the previous finding that bombesin, unlike CCK, is unable to stimulate amylase release from the dispersed canine pancreatic acini [26], It is of interest that in rats, but not in other species, bombe sin stimulates exocrine pancreas mainly by direct action on acinar cells and not through the release of CCK and gastrin or via cholin ergic pathways. This is supported by obser vations showing that the stimulation of pan creatic protein or enzyme secretion induced by bombesin cannot be suppressed by pep tidergic or nonpeptidergic antagonists of CCK receptors either in vivo or in vitro [ 19,27,28], More detailed studies confirmed the presence of specific and separate receptors for CCK and bombesin-like peptides in the rat pancreas [2].…”

Effect of Bombesin and Its Mammalian Counterpart, GRP, on Exocrine Pancreas in the Rat

“…Both peptides are potent and polyvalent releasers of several gastroin testinal peptides [2,18], some of which may affect exocrine pancreas, CCK being the most important one. However, the lack of effect of lorlumide, a new potent CCKreceptor antagonist [26] and the in vitro effects of bombesin-like peptides on amylase release [11,12,21,29] strongly suggest a direct stimulatory effect of these peptides on exocrine pancreas.…”

A major quantitative trait locus co-localizing with cholecystokinin type A receptor gene influences poor pancreatic proliferation in a spontaneously diabetogenic rat

“…The CCKAR has been reported to be implicated as a mediator of pancreatic growth in response to cholecystokinin and tumorigenesis in the pancreas (Povoski et al 1994;Scarpignato et al 1989). Recently, Takiguchi et al (1997) reported that the OLETF CCKAR gene possesses a homozygous DNA deletion that includes the promoter region and the first and second exons, and therefore can not be expressed in the pancreas.…”