Digestive Diseases and Sciences

, Volume 55, Issue 6, pp 1627–1636

Relationship Between Low-Dose Aspirin-Induced Gastric Mucosal Injury and Intragastric pH in Healthy Volunteers

  • Masafumi Nishino
  • Mitsushige Sugimoto
  • Chise Kodaira
  • Mihoko Yamade
  • Naohito Shirai
  • Mutsuhiro Ikuma
  • Tatsuo Tanaka
  • Haruhiko Sugimura
  • Akira Hishida
  • Takahisa Furuta
Original Article


Background and Aims

Gastric acid plays an important role in the pathogenesis of gastric mucosal lesions. We investigated whether aspirin-induced gastric mucosal injury might have any association with the intragastric pH.

Materials and Methods

Fifteen healthy, Helicobacter pylori-negative volunteers randomly underwent the four different 7-day regimens: (1) aspirin 100 mg, (2) rabeprazole 10 mg, (3) aspirin 100 mg + rabeprazole 10 mg, and (4) aspirin 100 mg + rabeprazole 40 mg. Gastric mucosal injury based on the modified Lanza score (MLS), 24-h intragastric pH, and histopathology of gastric mucosa were evaluated prior to the start and on day 7 of each regimen.


The median MLSs were 0 in the baseline and the rabeprazole 10 mg regimen. The median MLS in the aspirin regimen was 3, while those in both aspirin + rabeprazole 10 mg and aspirin + rabeprazole 40 mg regimens were 0. Rabeprazole significantly prevented the gastric mucosal injury by aspirin (P = 0.001 for rabeprazole 10 mg and P = 0.005 for rabeprazole 40 mg). The MLSs were negatively correlated with the 24-h intragastric pH (P = −0.711, < 0.001), whereas aspirin had no effect on the intragastric pH. Aspirin expanded the mean diameter of the microvessels of the gastric mucosa, which, in turn, was negatively correlated with the intragastric pH.


Aspirin might induce gastric mucosal injury by affecting the mucosal microvessels in an acid-dependent manner. Sustained maintenance of the intragastric pH at an elevated value is necessary to prevent gastric mucosal damage induced by aspirin.


Proton pump inhibitor Rabeprazole CYP2C19 Microvessel 





Cytochrome P450 2C19

H. pylori

Helicobacter pylori


Intermediate metabolizer


Modified Lanza score


Non-steroidal anti-inflammatory drug




Poor metabolizer


Rapid metabolizer


  1. 1.
    Nishikawa K, Sugiyama T, Kato M, et al. Non-Helicobacter pylori and non-NSAID peptic ulcer disease in the Japanese population. Eur J Gastroenterol Hepatol. 2000;12(6):635–640.CrossRefPubMedGoogle Scholar
  2. 2.
    Awtry EH, Loscalzo J. Aspirin. Circulation. 2000;101(10):1206–1218.PubMedGoogle Scholar
  3. 3.
    Taha AS, Angerson WJ, Knill-Jones RP, Blatchford O. Upper gastrointestinal haemorrhage associated with low-dose aspirin and anti-thrombotic drugs - a 6-year analysis and comparison with non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther. 2005;22(4):285–289.CrossRefPubMedGoogle Scholar
  4. 4.
    Collaborative overview of randomised trials of antiplatelet therapy–I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists’ Collaboration. Bmj. 1994;308(6921):81-106.Google Scholar
  5. 5.
    Schoen RT, Vender RJ. Mechanisms of nonsteroidal anti-inflammatory drug-induced gastric damage. Am J Med. 1989;86(4):449–458.CrossRefPubMedGoogle Scholar
  6. 6.
    Halter F. Mechanism of gastrointestinal toxicity of NSAIDs. Scand J Rheumatol Suppl. 1988;73:16–21.CrossRefPubMedGoogle Scholar
  7. 7.
    Yeomans ND, Lanas AI, Talley NJ, et al. Prevalence and incidence of gastroduodenal ulcers during treatment with vascular protective doses of aspirin. Aliment Pharmacol Ther. 2005;22(9):795–801.CrossRefPubMedGoogle Scholar
  8. 8.
    Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ. 2000;321(7270):1183–1187.CrossRefPubMedGoogle Scholar
  9. 9.
    Pilotto A, Franceschi M, Leandro G, et al. Proton-pump inhibitors reduce the risk of uncomplicated peptic ulcer in elderly either acute or chronic users of aspirin/non-steroidal anti-inflammatory drugs. Aliment Pharmacol Ther. 2004;20(10):1091–1097.CrossRefPubMedGoogle Scholar
  10. 10.
    Serrano P, Lanas A, Arroyo MT, Ferreira IJ. Risk of upper gastrointestinal bleeding in patients taking low-dose aspirin for the prevention of cardiovascular diseases. Aliment Pharmacol Ther. 2002;16(11):1945–1953.CrossRefPubMedGoogle Scholar
  11. 11.
    Furuta T, Shirai N, Sugimoto M, Ohashi K, Ishizaki T. Pharmacogenomics of proton pump inhibitors. Pharmacogenomics. 2004;5(2):181–202.CrossRefPubMedGoogle Scholar
  12. 12.
    Furuta T, Shirai N, Takashima M, et al. Effect of genotypic differences in CYP2C19 on cure rates for Helicobacter pylori infection by triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin. Clin Pharmacol Ther. 2001;69(3):158–168.CrossRefPubMedGoogle Scholar
  13. 13.
    Ishizaki T, Horai Y. Review article: cytochrome P450 and the metabolism of proton pump inhibitors—emphasis on rabeprazole. Aliment Pharmacol Ther. 1999;13(Suppl 3):27–36.CrossRefPubMedGoogle Scholar
  14. 14.
    Yasuda S, Horai Y, Tomono Y, et al. Comparison of the kinetic disposition and metabolism of E3810, a new proton pump inhibitor, and omeprazole in relation to S-mephenytoin 4′-hydroxylation status. Clin Pharmacol Ther. 1995;58(2):143–154.CrossRefPubMedGoogle Scholar
  15. 15.
    Adachi K, Katsube T, Kawamura A, et al. CYP2C19 genotype status and intragastric pH during dosing with lansoprazole or rabeprazole. Aliment Pharmacol Ther. 2000;14(10):1259–1266.CrossRefPubMedGoogle Scholar
  16. 16.
    Shirai N, Furuta T, Moriyama Y, et al. Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH. Aliment Pharmacol Ther. 2001;15(12):1929–1937.CrossRefPubMedGoogle Scholar
  17. 17.
    Ieiri I, Kishimoto Y, Okochi H, et al. Comparison of the kinetic disposition of and serum gastrin change by lansoprazole versus rabeprazole during an 8-day dosing scheme in relation to CYP2C19 polymorphism. Eur J Clin Pharmacol. 2001;57(6–7):485–492.PubMedGoogle Scholar
  18. 18.
    Horai Y, Kimura M, Furuie H, et al. Pharmacodynamic effects and kinetic disposition of rabeprazole in relation to CYP2C19 genotypes. Aliment Pharmacol Ther. 2001;15(6):793–803.CrossRefPubMedGoogle Scholar
  19. 19.
    Lanza FL, Royer GL Jr, Nelson RS, Chen TT, Seckman CE, Rack MF. A comparative endoscopic evaluation of the damaging effects of nonsteroidal anti-inflammatory agents on the gastric and duodenal mucosa. Am J Gastroenterol. 1981;75(1):17–21.PubMedGoogle Scholar
  20. 20.
    Naito Y, Yoshikawa T, Iinuma S, et al. Rebamipide protects against indomethacin-induced gastric mucosal injury in healthy volunteers in a double-blind, placebo-controlled study. Dig Dis Sci. 1998;43(9 Suppl):83S–89S.PubMedGoogle Scholar
  21. 21.
    Dixon MF, Genta RM, Yardley JH, Correa P. Classification, grading of gastritis. The updated Sydney System. International workshop on the histopathology of gastritis Houston, 1994. Am J Surg Pathol. 1996;20(10):1161–1181.CrossRefPubMedGoogle Scholar
  22. 22.
    Svedlund J, Sjodin I, Dotevall G. GSRS—a clinical rating scale for gastrointestinal symptoms in patients with irritable bowel syndrome and peptic ulcer disease. Dig Dis Sci. 1988;33(2):129–134.CrossRefPubMedGoogle Scholar
  23. 23.
    Funatsu T, Chono K, Hirata T, Keto Y, Kimoto A, Sasamata M. Mucosal acid causes gastric mucosal microcirculatory disturbance in nonsteroidal anti-inflammatory drug-treated rats. Eur J Pharmacol. 2007;554(1):53–59.CrossRefPubMedGoogle Scholar
  24. 24.
    Elliott SL, Ferris RJ, Giraud AS, Cook GA, Skeljo MV, Yeomans ND. Indomethacin damage to rat gastric mucosa is markedly dependent on luminal pH. Clin Exp Pharmacol Physiol. 1996;23(5):432–434.CrossRefPubMedGoogle Scholar
  25. 25.
    Kitchingman GK, Prichard PJ, Daneshmend TK, Walt RP, Hawkey CJ. Enhanced gastric mucosal bleeding with doses of aspirin used for prophylaxis and its reduction by ranitidine. Br J Clin Pharmacol. 1989;28(5):581–585.PubMedGoogle Scholar
  26. 26.
    Savarino V, Mela GS, Zentilin P, et al. Effect of one-month treatment with nonsteroidal antiinflammatory drugs (NSAIDs) on gastric pH of rheumatoid arthritis patients. Dig Dis Sci. 1998;43(3):459–463.CrossRefPubMedGoogle Scholar
  27. 27.
    Janssen M, Baak LC, Jansen JB, Dijkmans BA, Vandenbroucke JP, Lamers CB. Effects of indomethacin on intragastric pH and meal-stimulated serum gastrin secretion in rheumatoid arthritis patients. Aliment Pharmacol Ther. 1993;7(4):393–400.PubMedCrossRefGoogle Scholar
  28. 28.
    Odashima M, Otaka M, Jin M, et al. Attenuation of gastric mucosal inflammation induced by aspirin through activation of A2A adenosine receptor in rats. World J Gastroenterol. 2006;12(4):568–573.PubMedGoogle Scholar
  29. 29.
    Wallace JL, Zamuner SR, McKnight W, et al. Aspirin, but not NO-releasing aspirin (NCX-4016), interacts with selective COX-2 inhibitors to aggravate gastric damage and inflammation. Am J Physiol Gastrointest Liver Physiol. 2004;286(1):G76–G81.CrossRefPubMedGoogle Scholar
  30. 30.
    Yao T, Kato M, Asaka M. Pathology of gastric mucosal injury induced by low-dose aspirin. Gi Forefr. 2007;3(1):32–36. Japanese.Google Scholar
  31. 31.
    Kitahora T, Guth PH. Effect of aspirin plus hydrochloric acid on the gastric mucosal microcirculation. Gastroenterology. 1987;93(4):810–817.PubMedGoogle Scholar
  32. 32.
    Shimatani T, Inoue M, Kuroiwa T, et al. Acid-suppressive efficacy of a reduced dosage of rabeprazole: comparison of 10 mg twice daily rabeprazole with 20 mg twice daily rabeprazole, 30 mg twice daily lansoprazole, and 20 mg twice daily omeprazole by 24-hr intragastric pH-metry. Dig Dis Sci. 2005;50(7):1202–1206.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Masafumi Nishino
    • 1
  • Mitsushige Sugimoto
    • 1
  • Chise Kodaira
    • 1
  • Mihoko Yamade
    • 1
  • Naohito Shirai
    • 2
  • Mutsuhiro Ikuma
    • 1
  • Tatsuo Tanaka
    • 3
  • Haruhiko Sugimura
    • 4
  • Akira Hishida
    • 1
  • Takahisa Furuta
    • 5
  1. 1.First Department of MedicineHamamatsu University School of MedicineHamamatsuJapan
  2. 2.Department of GastroenterologyEnshu General HospitalHamamatsuJapan
  3. 3.Department of Endoscopic & Photodynamic MedicineHamamatsu University School of MedicineHamamatsuJapan
  4. 4.First Department of PathologyHamamatsu University School of MedicineHamamatsuJapan
  5. 5.Center for Clinical ResearchHamamatsu University School of Medicine HamamatsuJapan

Personalised recommendations