Cholecystokinin Receptor Antagonist Loxiglumide: Influence on Bilio-Pancreatic Secretion and Gastrointestinal Hormones in Man

Schmidt, Wolfgang E.; Creutzfeldt, W.; Höcker, Michael; Choudhury, Anjona Roy; Nustede, R.; Schleser, Andreas; Nitsche, R.; Rovati, Lucio C.; Schafmayer, A.; Fölsch, Ulrich R.

doi:10.1159/000200391

Cited by 12 publications

(4 citation statements)

References 26 publications

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“…It was also observed during infusion of the CCK analogue cerulein [22]. When CCK-8 was infused, antagonist treat ment slightly increased plasma CCK concen trations in one study [3], but had no efect in further studies [23,24].…”

Section: Discussionmentioning

confidence: 91%

CCK Receptor Antagonist Loxiglumide Alters Uptake of CCK in Perfused Liver and Pancreatic Acini of the Rat

Beckh

Göke²,

Ruff³

et al. 1991

Digestion

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The aim of the present study was to analyze the effect of the specific cholecystokinin (CCK) receptor antagonist loxiglumide on hepatic and pancreatic processing of CCK-8 and the CCK analogue cerulein. Rat liver perfusion was performed in a non-recirculating system. CCK concentrations were measured by radioimmunoassay in perfusates from the inflow cannula (portal vein) and the outflow cannula (hepatic vein). In rat pancreatic acini, the effect of loxiglumide on internalization and surface-binding of radiolabelled CCK-8 was determined. Cerulein (20 nM, 2 nM) was extracted in a single pass through the liver by 29.7 and 25.4%, respectively. The hepatic uptake of CCK-8 (50 pM, 2 nM) was more than 90 and 89.9%, respectively. Loxiglumide drastically inhibited hepatic extraction of both peptides and reduced internalization of ¹²⁵I-CCK-8 in pancreatic acini dose dependently by 39–93%. These results demonstrate that the potent CCK receptor antagonist loxiglumide significantly decreased CCK uptake by the liver and pancreas.

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Section: Discussionmentioning

confidence: 91%

CCK Receptor Antagonist Loxiglumide Alters Uptake of CCK in Perfused Liver and Pancreatic Acini of the Rat

Beckh

Göke²,

Ruff³

et al. 1991

Digestion

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“…This finding provides support for the hypothesis that CCK release in response to a meal ; feedback-controlled by bile acids, as has been sho-7-In dogs and humans [50,5 11. Since CCK-receptor antago-nists almost completely inhibit postprandial gallbladder emptying and bile secretion into the duodenum [16][17][18][23][24][25][26], it is suggested that CCK release in humans is regulated via negative feedback control by bile acids: decreasing intraduodenal concentrations of bile acids stimulate postprandial CCK secretion. Feedback regulation of CCK release by intraluminal protease activity is probably of minor importance.…”

Section: Discussionmentioning

confidence: 99%

“…Ten healthy male volunteers (aged [22][23][24][25][26][27][28][29], all within + 10% of ideal body weight, participated in the studies. The protocol of this investigation was approved on 5 January 1988 by the Ethical Committee of the Medical Faculty, University of Gottingen.…”

Section: Subjectsmentioning

confidence: 99%

“…We acknowledge support with the statistical analysis by Dr M. Nauck and help with GIP determinations by Dr R. Ebert. Some data are part of MD theses (MH, AS), some results have been published in abstract form [24,25]. This investigation was supported by a grant from the Deutsche Forschungsgemeinschaft (FO 73/7-9) and by Rotta Research Laboratory.…”

Section: Acknowledgmentsmentioning

confidence: 99%

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Cholecystokinin receptor antagonist loxiglumide modulates plasma levels of gastro‐entero‐pancreatic hormones in man Feedback control of cholecystokinin and gastrin secretion

Schmidt

Creutzfeldt

Höcker

et al. 1991

Eur J Clin Investigation

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The effect of the potent specific cholecystokinin (CCK) receptor antagonist loxiglumide on meal-stimulated plasma concentrations of CCK, gastrin, pancreatic polypeptide (PP), neurotensin, glucose-dependent insulinotropic polypeptide (GIP), insulin and C peptide was investigated in a placebo-controlled study in 10 healthy male volunteers. Intravenous infusion of loxiglumide (10 mg kg-1 h-1) significantly augmented integrated incremental IR-CCK levels 7.3-fold after stimulation by a standard breakfast (504 +/- 54 vs 3.665 +/- 365 pmol-1 135 min-1, P less than 0.001), as measured by a specific CCK radioimmunoassay. Basal IR-CCK concentrations were not affected by administration of loxiglumide. Oral treatment with bile acids (2 g ursodeoxycholic acid plus 2 g chenodeoxycholic acid) together with the meal abolished this augmentation, whereas high-dose substitution with pancreatic enzymes (4.2 g pancreatin) reduced elevated IR-CCK levels by only 38%. CCK-like bioactivity, determined by a bioassay using rat pancreatic acini, was not detectable in all samples that contained loxiglumide at plasma concentrations of 100-250 micrograms ml-1. Plasma gastrin concentrations in response to the breakfast were elevated 3.2-fold during loxiglumide infusion and not influenced by substitution with bile acids or pancreatic enzymes. Meal-stimulated integrated incremental plasma PP concentrations were significantly suppressed (55-65% inhibition, P less than 0.01) by loxiglumide. Infusion of the CCK receptor antagonist only slightly increased postprandial peak plasma glucose, insulin and C-peptide levels, whereas GIP and neurotensin levels were not significantly influenced. These findings suggest: (i) CCK secretion is under feedback control by intraduodenal bile acids and to a lesser extent by pancreatic enzymes; (ii) simultaneous extraction of CCK and loxiglumide results in circulating plasma CCK-like bioactivity of zero; (iii) gastrin secretion is feedback controlled via an indirect mechanism probably involving CCK-induced somatostatin secretion; (iv) release of PP is under inhibitory control of CCK; (v) CCK does not play a major role as insulinotropic hormone in the entero-insular axis in humans.

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A novel neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), in human intestine: evidence for reduced content in Hirschsprung's disease

et al. 1992

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A novel neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), exhibits sequence homology with vasoactive intestinal polypeptide (VIP) and occurs in the mammalian brain, lung and gut. The distribution of PACAP in ganglionic and aganglionic portions of the large intestine of patients with Hirschsprung's disease was examined by immunohistochemistry and radioimmunoassay. PACAP-immunoreactive nerve fibers were distributed in all layers of the ganglionic and aganglionic segments of the intestine, although they were less numerous in the latter, and PACAP-immunoreactive nerve cell bodies were seen in the ganglionic portion of the intestine. The concentration of immunoreactive PACAP was lower in the aganglionic than in the ganglionic segment of the intestinal wall. PACAP and VIP were found to coexist in both ganglionic and aganglionic segments of the intestine. Apparently, PACAP participates in the regulation of gut motility. The scarcer PACAP innervation of the aganglionic segment may contribute to the defect in intestinal relaxation seen in patients with Hirschsprung's disease.

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Cholecystokinin Receptor Antagonist Loxiglumide: Influence on Bilio-Pancreatic Secretion and Gastrointestinal Hormones in Man

Cited by 12 publications

References 26 publications

CCK Receptor Antagonist Loxiglumide Alters Uptake of CCK in Perfused Liver and Pancreatic Acini of the Rat

CCK Receptor Antagonist Loxiglumide Alters Uptake of CCK in Perfused Liver and Pancreatic Acini of the Rat

Cholecystokinin receptor antagonist loxiglumide modulates plasma levels of gastro‐entero‐pancreatic hormones in man Feedback control of cholecystokinin and gastrin secretion

A novel neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), in human intestine: evidence for reduced content in Hirschsprung's disease

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