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Gastroparesis Worsens Indomethacin-Induced Gastric Antral Ulcers by Bile Reflux via Activation of 5-HT3 and Dopamine D2 Receptors in Mice

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Abstract

Background/Aims

We examined the contributions of gastric emptying and duodenogastric bile reflux in the formation of gastric antral ulcers induced by NSAIDs in mice.

Methods

We used the murine re-fed indomethacin (IND) experimental ulcer model. Outcome measures included the appearance of gastric lesions 24 h after IND treatment and the assessment of gastric contents and the concentration of bile acids 1.5 h after re-feeding. The effects of atropine, dopamine, SR57227 (5-HT3 receptor agonist), apomorphine, ondansetron, haloperidol, and dietary taurocholate and cholestyramine were also examined.

Results

IND (10 mg/kg, s.c.) induced severe lesions only in the gastric antrum in the re-fed model. The antral lesion index and the amount of food intake during the 2-h refeeding period were positively correlated. Atropine and dopamine delayed gastric emptying, increased bile reflux, and worsened IND-induced antral lesions. SR57227 and apomorphine worsened antral lesions with increased bile reflux. These effects were prevented by the anti-emetic drugs ondansetron and haloperidol, respectively. The anti-emetic drugs markedly decreased the severity of antral lesions and the increase of bile reflux induced by atropine or dopamine without affecting delayed gastric emptying. Antral lesions induced by IND were increased by dietary taurocholate but decreased by the addition of the bile acid sequestrant cholestyramine.

Conclusions

These results suggest that gastroparesis induced by atropine or dopamine worsens NSAID-induced gastric antral ulcers by increasing duodenogastric bile reflux via activation of 5-HT3 and dopamine D2 receptors.

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Acknowledgments

The authors are greatly indebted to Ms. Ai Sato, Ms. Chihiro Takagi, Ms. Miki Horikawa and Ms. Fumika Kotera, students in our Department, Doshisha Women’s College of Liberal Arts, for their technical assistance, and Drs. Y. Amagase and Y. Mizukawa for valuable discussions and suggestions.

Funding

Doshisha Women’s College of Liberal Arts (TU), VA Merit Review I01BX001245 (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, University of California Los Angeles, Los Angeles, CA, 90025, USA

    Yasutada Akiba & Jonathan D. Kaunitz

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  1. Hiroshi Satoh
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Correspondence to Hiroshi Satoh.

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Ethical approval

Experimental protocols were approved by the Animal Research Committees at Doshisha Women’s College of Liberal Arts, Kodo, Kyotanabe, Kyoto, Japan (Approval Number Y16-031).

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Satoh, H., Akiba, Y., Urushidani, T. et al. Gastroparesis Worsens Indomethacin-Induced Gastric Antral Ulcers by Bile Reflux via Activation of 5-HT3 and Dopamine D2 Receptors in Mice. Dig Dis Sci 68, 3886–3901 (2023). https://doi.org/10.1007/s10620-023-08086-x

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