Journal of Gastroenterology

, 44:1118 | Cite as

Ecabet sodium induces neuronal nitric oxide synthase-derived nitric oxide synthesis and gastric adaptive relaxation in the human stomach

  • Yoshiaki Matsumoto
  • Masanori Ito
  • Masataka Tsuge
  • Taiji Matsuo
  • Shinji Tanaka
  • Ken Haruma
  • Kazuaki Chayama
Original Article—Alimentary Tract
First Online:
Received:
Accepted:

Abstract

Background

Gastric adaptive relaxation (GAR) is a major factor of functional dyspepsia (FD). Nitric oxide (NO) could be the key molecule responsible for GAR. We previously reported that the physiological gastric reservoir ability can be evaluated by measuring the cross-sectional area of the proximal stomach by abdominal ultrasonography (US). Ecabet sodium (ES), a gastro-protective antiulcer agent, has been shown to improve symptoms in FD patients. We examined the effects of ES on GAR in humans and on NO synthesis in vitro.

Methods

GAR was measured by US in 14 subjects, 8 of whom had a pressure sensor inserted into their stomach, after treatment with ES, placebo, or no drugs. NO was measured in SH-SY 5Y cells using a fluorescent indicator. Neuronal, endothelial and inducible NO synthase (nNOS, eNOS and iNOS, respectively) expressions were examined in SH-SY 5Y cells by Western blotting.

Results

Compared to placebo, ES induced significantly greater dilatation of the proximal stomach after the subjects drank 300–400 ml water (P < 0.05). After ES intake, the intragastric pressure did not change significantly, but it tended to be lower (n = 8; P = 0.15). ES increased NO production and nNOS expression, but not iNOS or eNOS expression, in SH-SY 5Y cells in vitro. Pretreatment with non-selective NO synthase (NOS) inhibitor, but not with iNOS-selective inhibitor, reduced NO production by ES.

Conclusion

ES may promote GAR in humans through nNOS-related NO; therefore, it may be useful for patients with FD.

Keywords

Ecabet sodium Functional dyspepsia Gastric adaptive relaxation Nitric oxide Ultrasonography 

Abbreviations

ANOVA

Analysis of variance

CGRP

Calcitonin gene-related peptide

CPSN

Capsaicin-sensitive afferent nerves

DAF-2

Diaminofluorescein-2

ES

Ecabet sodium

FD

Functional dyspepsia

GAR

Gastric adaptive relaxation

NO

Nitric oxide

NOS

Nitric oxide synthase

nNOS

Neuronal nitric oxide synthase

eNOS

Endothelial nitric oxide synthase

iNOS

Inducible nitric oxide synthase

US

Ultrasonography

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Notes

Acknowledgments

We thank Professor Masaharu Yoshihara (Health Service Center of Hiroshima University) and Professor Yukihito Higashi (Department of Cardiovascular Physiology and Medicine, Hiroshima University) for their valuable suggestions. This study was carried out at the Analysis Center of Life Science, Hiroshima University.

References

  1. 1.
    Geeraerts B, Tack J. Functional dyspepsia: past, present, and future. J Gastroenterol. 2008;43:251–5.CrossRefPubMedGoogle Scholar
  2. 2.
    Miwa H, Osada T, Nagahara A, Ohkusa T, Hojo M, Tomita T, et al. Effect of a gastro-protective agent, rebamipide, on symptom improvement in patients with functional dyspepsia: a double-blind placebo-controlled study in Japan. J Gastroenterol Hepatol. 2006;21:1826–31.CrossRefPubMedGoogle Scholar
  3. 3.
    Peura DA, Gudmundson J, Siepman N, Pilmer BL, Freston J. Proton pump inhibitors: effective first-line treatment for management of dyspepsia. Dig Dis Sci. 2007;52:983–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Suzuki H, Nishizawa T, Hibi T. Therapeutic strategies for functional dyspepsia and the introduction of Rome III classification. J Gastroenterol. 2006;41:513–23.CrossRefPubMedGoogle Scholar
  5. 5.
    Haruma K, Kusunoki H, Manabe N, Kamada T, Sato M, Ishii M, et al. Real-time assessment of gastroduodenal motility by ultrasonography. Digestion. 2008;77:48–51.CrossRefPubMedGoogle Scholar
  6. 6.
    Troncon LE, Thompson DG, Ahluwalia NK, Barlow J, Heggie L. Relations between upper abdominal symptoms and gastric distension abnormalities in dysmotility like functional dyspepsia and after vagotomy. Gut. 1995;37:17–22.CrossRefPubMedGoogle Scholar
  7. 7.
    Hayakawa T, Arakawa T, Kase Y, Akiyama S, Ishige A, Takeda S, et al. Liu-Jun-Zi-Tang, a kampo medicine, promotes adaptive relaxation in isolated guinea pig stomachs. Drugs Exp Clin Res. 1999;25:211–8.PubMedGoogle Scholar
  8. 8.
    Matsumoto M, Yoshimura R, Akiho H, Higuchi N, Kobayashi K, Matsui N, et al. Gastric emptying in diabetic patients by the (13)C-octanoic acid breath test: role of insulin in gastric motility. J Gastroenterol. 2007;42:469–74.CrossRefPubMedGoogle Scholar
  9. 9.
    Kusunoki H, Haruma K, Hata J, Tani H, Okamoto E, Sumii K, et al. Real-time ultrasonographic assessment of antroduodenal motility after ingestion of solid and liquid meals by patients with functional dyspepsia. J Gastroenterol Hepatol. 2000;15:1022–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Aoki S, Haruma K, Kusunoki H, Hata J, Hara M, Yoshida S, et al. Evaluation of gastric emptying measured with the 13C-octanoic acid breath test in patients with functional dyspepsia: comparison with ultrasonography. Scand J Gastroenterol. 2002;37:662–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Matsumoto Y, Ito M, Kamino D, Tanaka S, Haruma K, Chayama K. Relation between histologic gastritis and gastric motility in Japanese patients with functional dyspepsia: evaluation by transabdominal ultrasonography. J Gastroenterol. 2008;43:332–7.CrossRefPubMedGoogle Scholar
  12. 12.
    Kamino D, Manabe N, Hata J, Haruma K, Tanaka S, Chayama K. Long-term ultrasonographic follow-up study of gastric motility in patients with functional dyspepsia. J Clin Biochem Nutr. 2008;42:1–6.CrossRefGoogle Scholar
  13. 13.
    Murata H, Kawano S, Tsuji S, Kamada T, Matsuzawa Y, Katsu K, et al. Combination therapy of ecabet sodium and cimetidine compared with cimetidine alone for gastric ulcer: prospective randomized multicenter study. J Gastroenterol Hepatol. 2003;18:1029–33.CrossRefPubMedGoogle Scholar
  14. 14.
    Iizuka M, Itou H, Konno S, Shirasaka T, Horie Y, Shindo K, et al. Efficacy of ecabet sodium enema on steroid resistant or steroid dependent ulcerative colitis. Gut. 2006;55:1523.CrossRefPubMedGoogle Scholar
  15. 15.
    Ohkusa T, Takashimizu I, Fujiki K, Araki A, Ariake K, Shimoi K, et al. Prospective evaluation of a new anti-ulcer agent, ecabet sodium, for the treatment of Helicobacter pylori infection. Aliment Pharmacol Ther. 1998;12:457–61.CrossRefPubMedGoogle Scholar
  16. 16.
    Kagaya H, Kato M, Komatsu Y, Mizushima T, Sukegawa M, Nishikawa K, et al. High-dose ecabet sodium improves the eradication rate of Helicobacter pylori in dual therapy with lansoprazole and amoxicillin. Aliment Pharmacol Ther. 2000;14:1523–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Ito M, Tanaka S, Yoshihara M, Chayama K, Haruma K. Single administration of ecabet sodium diminishes the level of delta-13CO2 in urea breath test. J Gastroenterol. 2002;37:674–5.CrossRefPubMedGoogle Scholar
  18. 18.
    Lee JH, Kim JJ, Hahm KB, Lee DH, Kim N, Kim SK, et al. Efficacy and safety of ecabet sodium on functional dyspepsia: a prospective, double-blinded, randomized, multi-center controlled trial. World J Gastroenterol. 2006;12:2756–61.PubMedGoogle Scholar
  19. 19.
    Suzuki T, Hirano M. Clinical effect of ecabet sodium on functional dyspepsia. J New Rem Clin. 2004;53:67–72. written in Japanese.Google Scholar
  20. 20.
    Grant MK, Cuadra AE, El-Fakahany EE. Endogenous expression of nNOS protein in several neuronal cell lines. Life Sci. 2002;71:813–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Finney JS, Kinnersley N, Hughes M, O’Bryan-Tear CG, Lothian J. Meta-analysis of antisecretory and gastrokinetic compounds in functional dyspepsia. J Clin Gastroenterol. 1998;26:312–20.CrossRefPubMedGoogle Scholar
  22. 22.
    Nagao Y, Kodama H, Yonezawa T, Taguchi A, Fujino S, Nakahara K, et al. Correlation between the drinkability of beer and gastric emptying. Biosci Biotechnol Biochem. 1998;62:846–51.CrossRefPubMedGoogle Scholar
  23. 23.
    Higuchi K, Tominaga K, Uno H, Yasuda M, Hashiume M, Matsumoto M, et al. Effects of ecabet sodium, an antiulcer drug, on gastric adaptive relaxation in isolated guinea-pig stomachs. Drugs Exp Clin. 2002;28:105–11.Google Scholar
  24. 24.
    Kobayashi D, Mashimo H, Watanabe N. nNOS-derived NO plays an important role in gastric adaptive relaxation. Rinsho Byori. 2004;52:117. written in Japanese.Google Scholar
  25. 25.
    Desai KM, Zembowicz A, Sessa WC, Vane JR. Nitroxergic nerves mediate vagally induced relaxation in the isolated stomach of the guinea pig. Proc Natl Acad Sci USA. 1991;88:11490–4.CrossRefPubMedGoogle Scholar
  26. 26.
    Inui T, Saito N, Okuyama K, Kinoshita M. The effect of ecabet sodium on NO production by constitutive NO synthase in cultured gastric mucosal cells of guinea pigs. Jpn J Pharmacol. 2000;82:252.Google Scholar
  27. 27.
    Yang Kim H, Hahm KB, Choi MG, Rew JS, Seol SY, Chun HJ, et al. Prospective multi-center trial for the efficacy of ecabet sodium on the relief of dyspepsia in Korean patients with chronic gastritis. J Clin Biochem Nutr. 2007;41:160–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Katagiri F, Inoue S, Saito Y, Itoh H, Takeyama M. Ecabet sodium raises plasma levels of calcitonin gene-related peptide and substance P in healthy humans. J Pharm Pharmacol. 2005;57:799–805.CrossRefPubMedGoogle Scholar
  29. 29.
    Arakawa T, Uno H, Fukuda T, Higuchi K, Kobayashi K, Kuroki T. New aspects of gastric adaptive relaxation, reflex after food intake for more food: involvement of capsaicin-sensitive sensory nerves and nitric oxide. J Smooth Muscle Res. 1997;33:81–8.PubMedGoogle Scholar
  30. 30.
    Kinoshita M, Kume E, Tamaki H. Roles of prostaglandins, nitric oxide and the capsaicin-sensitive sensory nerves in gastroprotection produced by ecabet sodium. J Pharmacol Exp Ther. 1995;275:494–501.PubMedGoogle Scholar

Copyright information

© Springer 2009

Authors and Affiliations

  • Yoshiaki Matsumoto
    • 1
  • Masanori Ito
    • 1
  • Masataka Tsuge
    • 1
  • Taiji Matsuo
    • 1
  • Shinji Tanaka
    • 2
  • Ken Haruma
    • 3
  • Kazuaki Chayama
    • 1
  1. 1.Department of Medicine and Molecular Science, Graduate School of Biomedical SciencesHiroshima UniversityHiroshimaJapan
  2. 2.Department of EndoscopyHiroshima University HospitalHiroshimaJapan
  3. 3.Department of GastroenterologyKawasaki Medical SchoolKurashikiJapan

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