Action of the cholecystokinin antagonist L364,718 on gastric emptying in the rat

Green, T.; Dimaline, R.; Peikin, Steven R.; Dockray, Graham J.

doi:10.1152/ajpgi.1988.255.5.g685

Cited by 32 publications

(34 citation statements)

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“…The two receptors display about 50% sequence homology (Silvente-Poirot et al 1993;Kopin et al 1992). The cholecystokinin-A receptor mediates the cholecystokinin-8~-induced exocrine pancreatic secretion and the cholecystokinin-8s induced inhibition of gastric emptying (Green et al 1988). Monitoring gastric emptying in mice is a useful and simple way to screen the effect of cholecystokinin receptor ligands on cholecystokinin-A receptors (Lotti e f al.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Three Novel Cholecystokinin‐B/Gastrin Receptor Antagonists: A Study of their Effects on Rat Stomach Enterochromaffin‐Like Cell Activity

Ding

Lindström

Håkanson

1997

Pharmacology & Toxicology

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Gastrin stimulates rat stomach enterochromaffin-like (ECL) cells via activation of cholecystokinin-Blgastrin receptors. The stimulation is manifested in the activation of the histamine-forming enzyme histidine decarboxylase and in the secretion of histamine and pancreastatin, a chromogranin A-derived peptide. We have examined the short-term effects of three novel cholecystokinin-B/gastrin receptor antagonists (YF476, JB93182 and AG041R) on the ECL cells in intact fasted rats. The drugs and/or gastrin were infused intravenously for 3 hr and the oxyntic mucosal histidine decarboxylase activity and the serum pancreastatin concentration were measured. We also studied the effects of the three drugs on gastric emptying in mice, a cholecystokinin-A receptor-nediated response. YF476, JB93182 and AG041R antagonized the gastrin-evoked histidine decarboxylase activation in a dose-dependent manner. YF476, JB93182 and AGO41 R induced maximal inhibition at 0.03, 0.1 and 0.1 pmol kg-' hr-I, respectively; the corresponding IDso values were 0.002, 0.008, and 0.01 pmol kg-' hr-'. YF476 was selected for further analysis. It produced a rightward shift of the gastrin doseresponse curve, consistent with competitive inhibition. Moreover, it antagonized the omeprazole-evoked histidine decarboxylase activation and the gastrin-and omeprazole-induced rise in the circulating pancreastatin concentration. None of the three drugs tested inhibited gastric emptying or prevented the cholecystokinin-8s-induced inhibition of gastric emptying at the doses tested. The results show that YF476, JB93182 and AG041R are potent and selective cholecystokinin-B/ gastrin receptor antagonists, and that YF476 is 4-5 times more potent than JB93182 and AG041R.

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Section: Discussionmentioning

confidence: 99%

Evaluation of Three Novel Cholecystokinin‐B/Gastrin Receptor Antagonists: A Study of their Effects on Rat Stomach Enterochromaffin‐Like Cell Activity

Ding

Lindström

Håkanson

1997

Pharmacology & Toxicology

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“…Therefore, it seemed worthwhile to establish an appropriate animal model to test compounds known to release endogenous CCK for their ability to slow gastric emptying and improve postprandial hyperglycaemia in NIDDM. Camostat inhibited gastric emptying in conventional, non-diabetic rats via a CCK-dependent mechanism [10], but this has not been studied in rat models of IDDM or NIDDM. Furthermore, camostat stimulates secretin release in the rat [9], and secretin inhibits gastric emptying in conventional, nondiabetic rats [15,16].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the effect of treatment with a synthetic trypsin inhibitor (camostat), on gastric emptying of glucose and postprandial hyperglycaemia was determined. Camostat is a strong stimulant of CCK and secretin release [8,9] and an inhibitor of gastric emptying [10] in rats.…”

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confidence: 99%

Accelerated gastric emptying of glucose in Zucker type 2 diabetic rats: role in postprandial hyperglycaemia

et al. 1997

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Phillips et al. [1] demonstrated abnormally rapid gastric emptying of glucose solutions in patients with recently diagnosed non-insulin-dependent diabetes mellitus (NIDDM), which contrasts with delayed gastric emptying (gastroparesis), a well-documented late manifestation of diabetes attributed to autonomic neuropathy [2]. Intravenous administration of cholecystokinin (CCK), a physiological inhibitor of gastric emptying in healthy humans [3], normalized gastric emptying of a glucose test meal in NIDDM diabetic patients and reduced the postprandial hyperglycaemia [4]. This outcome was predicted from studies in healthy human subjects which showed that CCK regulated postprandial blood glucose levels by slowing gastric emptying [5]. These studies support the hypothesis [1] that accelerated gastric emptying in early NIDDM in humans may contribute to poor glucose control by increasing the rate of glucose entry into the small intestine, thereby increasing absorption rate and exacerbating postprandial hyperglycaemia.To further examine this phenomenon, the gastric emptying of glucose was investigated in a newly Diabetologia (1997) Summary Patients with early non-insulin-dependent diabetes mellitus (NIDDM) empty glucose solutions from their stomachs more rapidly than non-diabetic control subjects, and this exacerbates postprandial hyperglycaemia.To determine if accelerated gastric emptying occurred in a rat model of NIDDM and influenced postprandial hyperglycaemia, gastric emptying of glucose was measured, and the effect of slowing the gastric emptying rate on postprandial hyperglycaemia was observed. We tested eight male obese Zucker diabetic rats and eight age-matched lean Zucker controls at 10-13 weeks of age to measure gastric emptying of glucose (by gamma scintigraphy). Rats fasted overnight were gavaged with 30 % glucose at 1 ml/100 g body weight. Separately, six Zucker diabetic rats and six lean controls were tested for sensitivity to the inhibitory effects of cholecystokinin and secretin on gastric emptying. The diabetic rats emptied glucose significantly faster than controls (t 1/2 = 37.3 ± 1.5 vs 58.8 ± 2.3 min in controls), and aging exaggerated this differential. Camostat, a stimulant of cholecystokinin and secretin release, added to the glucose meal significantly slowed gastric emptying (t 1/2 = 123 ± 23 and 166 ± 19 min, diabetic vs lean, respectively), and significantly reduced postprandial hyperglycaemia in diabetic rats. Compared to Zucker lean controls, Zucker diabetic rats were as sensitive (cholecystokinin) or more sensitive (secretin) to gastrointestinal hormones that inhibit gastric emptying. The results demonstrate accelerated gastric emptying in a rat model of NIDDM, consistant with similar observations in humans with early NIDDM. These results also support the proposal that interventions to slow gastric emptying may improve glucose control in this disease. [Diabetologia (1997) 40: 136-142]

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“…Alternatively, it is possible that higher doses ofMK-329 might demonstrate an acceleration ofgastric emptying if the CCK receptors involved were different in some way from those mediating gallbladder contraction. This is unlikely, however, as animal studies have revealed MK-329 to be a potent antagonist of CCK-induced inhibition of gastric emptying (8,25,26). Since gastric emptying and CCK release are regulated by various properties of a meal, including nutrient composition, it is also possible that an alteration of gastric emptying with MK-329 may be demonstrable with other diets.…”

Section: Discussionmentioning

confidence: 99%

Effects of a novel cholecystokinin (CCK) receptor antagonist, MK-329, on gallbladder contraction and gastric emptying in humans. Implications for the physiology of CCK.

Liddle¹,

Gertz²,

Kanayama³

et al. 1989

J. Clin. Invest.

155

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To explore the physiology of cholecystokinin (CCK) in humans, we investigated the effect on gallbladder contraction and gastric emptying of a recently developed CCK receptor antagonist, . In a double-blind, four-period crossover study eight subjects received single doses of 0.5, 2, or 10 mg MK-329, or placebo, followed by an intravenous infusion of CCK-8 (30 pmol/kg. h). In placebo-treated subjects gallbladder volumes decreased on average to 43% of initial volumes after 2 h of CCK infusion. MK-329 caused a dose-dependent inhibition of CCK-stimulated gallbladder contraction with 10 mg producing complete blockade (P < 0.01, cf. placebo).Gallbladder contraction and gastric emptying rates after a mixed meal were then measured in a two-period crossover study. Subjects received placebo or 10 mg of MK-329 2 h before eating. Gastric emptying of both solids and liquids was measured simultaneously by gamma scintigraphy. In placebotreated subjects plasma CCK levels increased postprandially to 2.3 pM, gallbladder volumes decreased 68.4±3.8% (SE), and the times for 50% emptying of liquids and solids from the stomach were 58±10 and 128±8 min, respectively. In MK-329-treated subjects there was a marked elevation in peak CCK levels to 13.8 pM (P < 0.01, cf. placebo), and gallbladder contraction was completely inhibited. Solid and liquid emptying rates were unaffected.These findings demonstrate that (a) MK-329 is a potent, orally active antagonist of CCK in humans, and (b) CCK is the major regulator of postprandial gallbladder contraction. These data also support the concept of negative feedback regulation of CCK secretion and suggest that mechanisms other than CCK play a dominant role in the regulation of postprandial gastric emptying rates.

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Action of the cholecystokinin antagonist L364,718 on gastric emptying in the rat

Cited by 32 publications

References 0 publications

Evaluation of Three Novel Cholecystokinin‐B/Gastrin Receptor Antagonists: A Study of their Effects on Rat Stomach Enterochromaffin‐Like Cell Activity

Evaluation of Three Novel Cholecystokinin‐B/Gastrin Receptor Antagonists: A Study of their Effects on Rat Stomach Enterochromaffin‐Like Cell Activity

Accelerated gastric emptying of glucose in Zucker type 2 diabetic rats: role in postprandial hyperglycaemia

Effects of a novel cholecystokinin (CCK) receptor antagonist, MK-329, on gallbladder contraction and gastric emptying in humans. Implications for the physiology of CCK.

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