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

Abstract

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.

Inhibition of gastrin-stimulated gastric acid secretion by medium-chain triglycerides and long-chain triglycerides in healthy young men

“…Although our data are in contrast with a role of CCK as an enterogastrone, it can not be excluded that CCK acts locally as a neurotransmitter or neuromodulator to inhibit gastric acid secretion, since specific cholecystokinin recep tor antagonists augment gastric acid secretion in previous experiments [36][37][38][39][40][41].…”

“…Several possibil ities have been suggested [7,[9][10][11][12]34]. Of old, one of the most important enterogastrone candidates is CCK [7], In previous studies, infusion of high, probably supraphysiological, doses of CCK inhibited gastric acid secretion [35], Recent studies with CCK receptor antagonists also support an inhibitory effect of endogenous CCK on gastric acid secretion, since specific type A CCK-receptor antagonists augmented basal as well as stimulated gastric acid output [36][37][38][39][40][41]. However, in the present study infusion of CCK did not inhibit gastric acid secretion, and medium chain triglycerides were able to inhibit gastric acid secretion without concomitant release of CCK.…”

Gastrointestinal motor and secretory responses to cholinergic stimulation in humans. Differential modulation by muscarinic and cholecystokinin receptor blockade

“…In the present study, this phenomenon was also seen in the basal interdigestive state and with bethanechol infusion. A feedback mechanism between duodenal bile secretion and CCK release could be operative, and inhibition of biliary secretion by loxiglumide would enhance CCK release [30].…”

Sucrose polyester does not inhibit gastric acid secretion or stimulate cholecystokinin release in men

“…It has been suggested that the inhibition of gastric acid secretion is also mediated at least in part by CCK (8)(9)(10)(18)(19)(20)(21)(22). uonsulfated gastrin-17 was Cambridge Research Biochemicals (Cheshire, United King dom).…”

“…This might be the reason for the absence of plasma CCK secretion and suppression of gastric acid secretion in response to sucrose polyester. CCK may be involved in the suppression of gastric acid secretion by intraduodenal fat (18)(19)(20)(21)(22), although we showed that suppres sion of acid secretion can be reached by medium-chain triacylglycerols without concomitant CCK release (39). The in crease of plasma CCK in response to digestible fat was TABLE 1 Gastric acid output in (he stomach before gastrin infusion (basal), during gastrin infusion, and during intraduodenal perfusion of sucrose polyester (SPE), digestible fat, or saline in eight volunteers; intravenous gastrin infusion was continued during the intraduodenal perfusion of fat7 …”