Gastroenterology

Gastroenterology

Volume 122, Issue 5, May 2002, Pages 1248-1257
Gastroenterology

Clinical Research
Dietary nitrate generates potentially mutagenic concentrations of nitric oxide at the gastroesophageal junction,☆☆

https://doi.org/10.1053/gast.2002.32963Get rights and content

Abstract

Background & Aims: Twenty-five percent of absorbed dietary nitrate is re-secreted in saliva, and 30% of this is reduced to nitrite by buccal bacteria. When saliva is swallowed, the acidic gastric juice reduces the nitrite to nitric oxide. The aim of this study was to examine the anatomic distribution of nitric oxide generation within the lumen of the upper gastrointestinal tract under basal conditions and after ingesting nitrate equivalent to that in salad portion. Methods: Using custom-made sensors, the dissolved luminal nitric oxide concentration and pH were measured at 1-cm increments for 2 minutes throughout the length of the stomach and distal esophagus in 15 Helicobacter pylori–negative healthy volunteers with and without ingestion of 2 mmol potassium nitrate. Serum nitrate and saliva nitrite concentrations were also monitored. Results: The nitrate ingestion increased mean (range) serum nitrate from 30 μmol/L (18–49) to 95 μmol/L (32–152), mean salivary nitrite from 36 μmol/L (19–153) to 252 μmol/L (32–600), and mean peak luminal nitric oxide concentration from 4.7 μmol/L (1.4–7.8) to 23.2 μmol/L (2.1–50) (P < 0.05 for each). After nitrate, the peak nitric oxide concentration occurred in 11 of the 15 (73%) subjects within 1 cm distal to the gastroesophageal pH step-up point. The mean nitric oxide concentration over the 1-cm segment immediately distal to the gastroesophageal pH step-up after nitrate was 7.5 μmol/L (range, 0.5–30.7) and was significantly higher than at all other sites. Nitric oxide concentrations greater than 50 μmol/L were observed at the precise location where neutral esophageal pH fell to acidic gastric pH. Conclusions: Luminal generation of nitric oxide from dietary nitrate via salivary nitrite is maximal at the gastroesophageal junction and cardia. The high concentrations of nitric oxide generated may contribute to the high incidence of mutagenesis and neoplasia at this site.

GASTROENTEROLOGY 2002;122:1248-1257

Section snippets

Nitric oxide sensor

It was necessary to construct a sensor that would allow real-time in situ measurement of local concentrations of nitric oxide within the upper gastrointestinal tract. This was performed in collaboration with World Precision Instruments and was a modification of their standard laboratory nitric oxide sensor (ISO-NOP; World Precision Instruments, INC., Sarasota, FL). The sensor consists of a stainless steel canula containing an electrode that produces a current when exposed to nitric oxide. The

In vitro assessment of nitric oxide sensor

The custom-made nitric oxide sensor gave a linear response up to a nitric oxide concentration of 100 μmol/L. The sensor also showed a rapid response to changes in concentration of nitric oxide. On placing the sensor in a solution at 37°C containing 40 μmol/L nitric oxide, 80% maximal response was recorded within 10 seconds. On transferring it to a nitric oxide–free solution, 80% maximal resolution was recorded within 10 seconds.

The simultaneous measurement of nitric oxide in the solution in

Discussion

This study confirms previous reports that the nitrite present in saliva is converted to nitric oxide on entering the acid stomach.13, 14, 15, 16 By using a novel nitric oxide probe, we have extended previous work by showing that the highest nitric oxide concentrations generated in the gastric lumen occur at the gastroesophageal junction and cardia where saliva first meets acidic gastric juice.

The original report of luminal intragastric production of nitric oxide from salivary nitrite was by

Acknowledgements

The authors are grateful to Dr. Aled Evans and colleagues in the Department of Clinical Physics and Bio-Engineering, Southern General Hospital, Glasgow for their technical support.

References (68)

  • CJ Schorah et al.

    Gastric juice ascorbic acid: effects of disease and implications for gastric carcinogenesis

    Am J Clin Nutr

    (1991)
  • GM Sobala et al.

    Ascorbic acid in the human stomach

    Gastroenterology

    (1989)
  • JP Byrne et al.

    Comparative study of intestinal metaplasia and mucin staining at the cardia and esophagogastric junction in 225 symptomatic patients presenting for diagnostic open-access gastroscopy

    Am J Gastroenterol

    (1999)
  • SJ Spechler et al.

    Prevalence of metaplasia at the gastroesophageal junction

    Lancet

    (1994)
  • PC Ford et al.

    Autoxidation kinetics of aqueous nitric oxide

    FEBS Lett

    (1993)
  • T O'Connor et al.

    Fpg protein of E. coli is a zinc finger protein whose cysteine residues have a structural and/or functional role

    J Biol Chem

    (1993)
  • H-J Altmann et al.

    Effects of BHA and related phenols on the forestomach of rats

    Food Chem Toxicol

    (1986)
  • S Tamano et al.

    Variation in susceptibility to the induction of forestomach tumours by butylated hydroxyanisole among rats of different strains

    Food Chem Toxicol

    (1998)
  • R Kroes et al.

    Forestomach carcinogens: possible mechanisms of action

    Food Chem Toxicol

    (1986)
  • SS Mirvish et al.

    Effect of sodium ascorbate on tumor induction in rats treated with morpholine and sodium nitrite, and with nitrosomorpholine

    Cancer Lett

    (1976)
  • SS Mirvish

    Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC

    Cancer Lett

    (1995)
  • AT Prach et al.

    Increasing incidence of Barrett's oesophagus: education, enthusiasm, or epidemiology?

    Lancet

    (1997)
  • E Felley-Bosco

    Role of nitric oxide in genotoxicity: implication for carcinogenesis

    Cancer Metastasis Rev

    (1998)
  • GM McKnight et al.

    Chemical synthesis of nitric oxide in the stomach from dietary nitrate in humans

    Gut

    (1997)
  • R Walker

    Nitrates, nitrites and N-nitrosocompounds: a review of the occurrence in food and diet and the toxicological implications

    Food Addit Contam

    (1990)
  • DA Wagner et al.

    Metabolic fate of an oral dose of 15N-labeled nitrate in humans: effect of diet supplementation with ascorbic acid

    Cancer Res

    (1983)
  • A Moriya et al.

    In vitro studies indicate that acid catalysed generation of N-nitrosocompounds from dietary nitrate will be maximal at the gastro-oesophageal junction

    Scand J Gastroenterol

    (2002)
  • A Aneman et al.

    Continuous measurement of gastric nitric oxide production

    Am J Physiol

    (1996)
  • N Benjamin et al.

    Stomach NO synthesis [letter]

    Nature

    (1994)
  • C Duncan et al.

    Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate

    Nat Med

    (1995)
  • JON Lundberg et al.

    Intragastric nitric oxide production in humans: measurements in expelled air

    Gut

    (1994)
  • A Moriya et al.

    Oxygen facilitates nitrosoamine synthesis by depleting ascorbic acid in acid stomach: relevance to proximal gastric cancer (abstr)

    Gastroenterology

    (1999)
  • Y-K Kim et al.

    Effects of ascorbic acid on the nitrosation of dialkyl amines

    Adv Chem Series

    (1982)
  • CA Bunton

    Oxidation of ascorbic acid and similar reductones by nitrous acid

    Nature

    (1959)
  • Cited by (0)

    Address requests for reprints to: Kenneth E. L. McColl, M.D., University Department of Medicine & Therapeutics, Western Infirmary, Glasgow, G11 6NT Scotland. e-mail: [email protected]; fax: 0141 211 2895.

    ☆☆

    This study was supported by a grant from the Biomedical and Clinical Research Committee of the Chief Scientist Office, Scottish Home and Health Department.

    View full text