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Cholecystokinin-Induced Duodenogastric Bile Reflux Increases the Severity of Indomethacin-Induced Gastric Antral Ulcers in Re-fed Mice

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Abstract

Background/Aims

We examined the involvement of cholecystokinin (CCK) in the exacerbation of indomethacin (IND)-induced gastric antral ulcers by gastroparesis caused by atropine or dopamine in mice.

Methods

Male mice were fed for 2 h (re-feeding) following a 22-h fast. Indomethacin (IND; 10 mg/kg, s.c.) was administered after re-feeding; gastric lesions were examined 24 h after IND treatment. In another experiment, mice were fed for 2 h after a 22-h fast, after which the stomachs were removed 1.5 h after the end of the feeding period. Antral lesions, the amount of gastric contents, and the gastric luminal bile acids concentration were measured with or without the administration of the pro- and antimotility drugs CCK-octapeptide (CCK-8), atropine, dopamine, SR57227 (5-HT3 receptor agonist), apomorphine, lorglumide (CCK1 receptor antagonist), ondansetron, and haloperidol alone and in combination.

Results

IND produced severe lesions only in the gastric antrum in re-fed mice. CCK-8, atropine, dopamine, SR57227 and apomorphine administered just after re-feeding increased bile reflux and worsened IND-induced antral lesions. These effects were significantly prevented by pretreatment with lorglumide. Although atropine and dopamine also increased the amount of gastric content, lorglumide had no effect on the delayed gastric emptying provoked by atropine and dopamine. Both ondansetron and haloperidol significantly inhibited the increase of bile reflux and the exacerbation of antral lesions induced by atropine and dopamine, respectively, but did not affect the effects of CCK-8.

Conclusions

These results suggest that CCK-CCK1 receptor signal increases bile reflux during gastroparesis induced by atropine and dopamine, exacerbating IND-induced antral ulcers.

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Acknowledgments

The authors are greatly indebted to Ms. Fumika Kotera, Ms. Yuri Matsunaga and Ms. Nodoka Moriyama, students in our department, for their technical assistance, and Drs. Y. Amagase and Y. Mizukawa for valuable discussions and suggestions.

Disclaimer

The contents do not represent the views of the Department of Veterans Affairs or the United States Government.

Funding

Doshisha Women’s College of Liberal Arts (TU) and the resources and the use of facilities at the West Los Angeles VAMC, Los Angeles, CA, USA (YA; JDK).

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Authors and Affiliations

  1. Department of Pathophysiology, Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kodo, Kyotanabe, Kyoto, 610-0395, Japan

    Hiroshi Satoh & Tetsuro Urushidani

  2. Greater Los Angeles Veterans Affairs Healthcare System, B114, R217, West LA VAMC, 11301 Wilshire Blvd., Los Angeles, CA, 90073, USA

    Yasutada Akiba & Jonathan D. Kaunitz

  3. Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90025, USA

    Yasutada Akiba & Jonathan D. Kaunitz

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  1. Hiroshi Satoh
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  2. Yasutada Akiba
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Correspondence to Hiroshi Satoh.

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Experimental protocols were approved by the Animal Research Committees at Doshisha Women’s College of Liberal Arts, Kodo, Kyotanabe, Kyoto, Japan (Approval number Y20-009).

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Satoh, H., Akiba, Y., Urushidani, T. et al. Cholecystokinin-Induced Duodenogastric Bile Reflux Increases the Severity of Indomethacin-Induced Gastric Antral Ulcers in Re-fed Mice. Dig Dis Sci 69, 1156–1168 (2024). https://doi.org/10.1007/s10620-024-08352-6

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