Cholecystokinin receptor antagonist loxiglumide modulates plasma levels of gastro-entero-pancreatic hormones in man. Feedback control of cholecystokinin and gastrin secretion.
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.
Schmidt
W E
WE
Department of Medicine, University Hospital, Georg August University, Göttingen, Germany.
Creutzfeldt
W
W
Höcker
M
M
Nustede
R
R
Choudhury
A R
AR
Schleser
A
A
Rovati
L C
LC
Fölsch
U R
UR
D000328:Adult; D002766:Cholecystokinin / Q000097:blood* / Q000378:metabolism; D004435:Eating; D005246:Feedback; D005755:Gastrins / Q000097:blood* / Q000378:metabolism; D006728:Hormones / Q000097:blood*; D006801:Humans; D008297:Male; D011377:Proglumide / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors
D005755:Gastrins; D006728:Hormones; D011949:Receptors, Cholecystokinin; C053737:loxiglumide; D002766:Cholecystokinin; D011377:Proglumide