Effect of CCK and its antagonists on gastric emptying

doi:10.1016/0928-4257(93)90035-R

Journal of Physiology-Paris

Volume 87, Issue 5, 1993, Pages 291-300

https://doi.org/10.1016/0928-4257(93)90035-R Get rights and content

Abstract

Cholecystokinin (CCK) belongs to the group of substances known as brain-gut peptides: it functions both as a neuropeptide and a gut hormone. The peptide and its synthetic derivatives (like for instance CCK-8 and the amphibian counterpart caerulein) significantly delay emptying of gastric contents in both animals and humans. The fact that CCK, in doses mimicking postprandial plasma levels, strongly affects emptying rate suggests the peptide to be a physiologic regulator of gastric emptying. Unfortunately, clear definition of the role of CCK in the physiology of gastric motor activity has long been hampered by the lack of specific and potent non-peptide antagonists of CCK-receptors. The availability of such compounds has stimulated a broad array of investigations into the physiological actions of this hormone and examination of its putative role in certain diseases. This paper summarizes the available data concerning the effect of CCK and its antagonists on gastric emptying. The use of selective CCK-antagonists has allowed to establish that the gastric motor effect of the peptide is direct and mediated through the stimulation of CCK-A receptors. As a consequence, CCK-A antagonism results in acceleration of emptying rate under certain experimental and clinical conditions. This peculiar pharmacologic effect of CCK-A antagonists, which could be useful in the treatment of functional dyspepsia (idiopathic or diabetic), gastroparesis and gastro-esophageal reflux disease (where patients often display a delayed emptying rate of solid food) needs to be further investigated, in order to fully explore their potential as gastrokinetic drugs.

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We investigated the role of oxytocin, cholecystokinin, and vagal afferent pathway via TRPV1 receptors on the slower gastric emptying induced by acute exercise. For this purpose, a separate group of sedentary or acute exercise rats were pretreated with 40 μg/kg of atosiban (oxytocin antagonist), 1 mg/kg of devazepide, or 5 mg.kg of lorglumide (CCK antagonist) and 1 mg/kg of capsazepine (TRPV1 antagonist) intraperitoneally according to Scarpignato et al. [31] and Wu et al. [32]. This treatment was realized 30 min before acute exercise or sedentary activity.
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Cholecystokinin (CCK) is known to have a short biological half-life. In order to prolong the half-life and create a new investigative tool, we previously PEGylated the peptide, yielding PEG-CCK₉, and demonstrated that it had a dose-dependent prolonged anorectic effect. The aim of this study was to investigate whether PEG-CCK₉ reduces food intake by inducing satiation or by abnormal physiological effects, such as pain, malaise, or nausea.
An observational study was performed to examine the effects of different doses of PEG-CCK₉ (1, 2, 4, 8, or 16 μg kg^− 1) on feeding and other behaviors. The behavioral sequence associated with satiety (BSS), i.e. the orderly progression from eating, through grooming and activity, to resting, was analyzed.
From the lowest dose tested (1 μg kg^− 1), PEG-CCK₉ caused a dose-dependent reduction in food intake due to a dose-related reduction in both the duration and frequency of eating and a dose-dependent increase in duration of rest. A dose-dependent acceleration in the temporal profile of the BSS was observed, while the normal structure of feeding behaviors was well preserved, except at the dose of 16 μg kg^− 1 of PEG-CCK₉, at which a decrease in eating rate and grooming behavior was observed, together with the occurrence of a significant number of abdominal cramps.
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Chronic nutritional disorders such as protein malnutrition are associated with delayed gastric emptying and increased postprandial cholecystokinin (CCK) levels. This study investigated the mechanisms involved in gastric emptying adaptation to low-protein diet. Two groups of 12 rats were adapted to a low-protein (LPD) or standard diet (SD) for 3 weeks. As compared to rats fed a SD, in rats adapted to a LPD gastric emptying was delayed, whereas postprandial CCK levels were increased. LPD enhanced antral muscle contractile response to CCK and cerulein without altering response to acetylcholine. This increased contractility was associated with up-regulation of CCK-A receptor mRNA levels in antral muscle. Our data suggest that modulation of gastric emptying after adaptation to a low-protein diet involves up-regulation of both CCK-A receptors and CCK-induced contraction of antral smooth muscle.
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Effect of CCK and its antagonists on gastric emptying

Abstract

Eur J Pharmacol

Gastroenterology

Gastroenterology

Eur J Pharmacol

Eur J Pharmacol

Trends Pharmacol Sci

J Biol Chem

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Brain Res

Life Sci

Eur J Pharmacol

Lancet

Brain Res

Regul Pept

Physiol Behav

Eur J Pharmacol

Gastroenterology

Pharmacol Res

Gastroenterology

Antinociceptive and gastrointestinal transit effects of cholecystokinin (CCK-8) and related analogs of CCK-8 in the mouse

Peptides: Gastrointestinal hormones

Receptor on smooth muscle cells: characterization by contraction and specific antagonists

Am J Physiol

Gastric emptying of caloric meals cutaneous electrogastrogram and cholecystokinin

J Gastrointest Motil

Role of cholecystokinin in the regulation of gastric emptying and motility

Gastroenterology

Drug effects on gastric emptying in animal models depend on the nature of test meals used

Am J Physiol

Gastrointestinal drug receptors

J Gastroenterol

L-364, 718: a review of the biochemical and pharmacological characterization as a highly potent peripherally selective CCK antagonist

A potent nonpeptide cholecystokinin antagonist selective for peripheral tissues isolated from Aspergillus alliaceus

Science

Functionally distinct receptors for cholecystokinin and gastrin on dispersed chief cells from guinea-pig stomach

Am J Physiol

Clinical efficacy and prokinetic effect of the CCK-A antagonist Loxiglumide in non-ulcer dyspepsia

Gastroenterology

Oral administration of loxiglumide (CCK antagonist) inhibits postprandial gallbladder contraction without affecting gastric emptying

Dig Dis Sci

The effects of cholecystokinin octapeptide on human isolated alimentary muscle

Br J Pharmacol

Comparative neuroendocrinology of gut peptides

Role of cholecystokinin in the regulation of gastric function after caloric meals

Gastroenterology

Detection of cholecystokinin-58 in human blood by inhibition of degradation

Am J Physiol

The effect of cholecystokinin on human taenia coli

Digestion

Recent developments in cholecystokinin antagonist research

Drugs Future

Intraventricular CCK inhibits food intake and gastric emptying in babbons

Am J Physiol

Potential methodologic problems with in vivo immunoneutralization of pancreatic polypeptide

Pancreas

Involvement of endogenous opiates in regulation of gastric emptying of fat test meals in mice

Am J Physiol

Cholecystokinin and gastrin antagonists

Med Res Rev

The role of local cholinergic pathways in the motor response to cholecystokinin and gastrin in isolated guinea pig fundus and antrum

Scand J gastroenterol