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Proton Pump Inhibitors Prevent Gastric Antral Ulcers Induced by NSAIDs via Activation of Capsaicin-Sensitive Afferent Nerves in Mice

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Abstract

Background/Aims

We examined the effects of proton pump inhibitors (PPIs) on gastric antral ulcers induced by non-steroidal anti-inflammatory drugs in re-fed mice and the role of capsaicin-sensitive afferent nerves (CSANs) in the protective effects of PPIs on the antral mucosa.

Methods

Male mice were administered indomethacin after 2 h of re-feeding of diet after a 24-h fast, and gastric lesions were examined 24 h after indomethacin dosing. The effects of PPIs (lansoprazole and omeprazole), histamine H2-receptor antagonists (H2-RAs, famotidine, ranitidine), capsaicin and misoprostol on the formation of antral ulcers induced by indomethacin were examined. Functional ablation of CSANs was caused by pretreatment of mice with a high dose of capsaicin.

Results

Indomethacin produced lesions selectively in the gastric antrum in re-fed conditions. Formation of antral ulcers was not affected by H2-RAs, but inhibited by PPIs, capsaicin and misoprostol. The anti-ulcer effect of lansoprazole was 30 times stronger than that of omeprazole. Antral ulcers induced by indomethacin were markedly aggravated in mice with ablated CSANs. The effects of PPIs and capsaicin on ulcer formation were inhibited by ablation of CSANs, pretreatment with a capsaicin receptor antagonist (capsazepine/ruthenium red) and an inhibitor of nitric oxide synthesis (L-NAME). However, the inhibitory effect of misoprostol was not prevented by the ablation of CSANs or drugs.

Conclusions

The results suggested that CSANs play an important role in protection of the antral mucosa and that both lansoprazole and omeprazole are capable of preventing NSAID-induced antral ulcers by activating CSANs.

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Acknowledgments

The authors are greatly indebted to Ms. Kyoko Hayashi, Ms. Ai Sato, Ms. Chika Takagi and Ms. Miki Horikawa, students in our Department, for their technical assistance, and Drs. Y. Amagase and Y. Mizukawa for valuable discussions and suggestions.

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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. Departments of Medicine, School of Medicine, University of California Los Angeles, B114, R217, West LA VAMC, 11301 Wilshire Blvd., Los Angeles, CA, 90025, USA

    Yasutada Akiba

  3. Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, 90073, USA

    Yasutada Akiba

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  1. Hiroshi Satoh
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Satoh, H., Akiba, Y. & Urushidani, T. Proton Pump Inhibitors Prevent Gastric Antral Ulcers Induced by NSAIDs via Activation of Capsaicin-Sensitive Afferent Nerves in Mice. Dig Dis Sci 65, 2580–2594 (2020). https://doi.org/10.1007/s10620-020-06157-x

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