Dietary nitrate generates potentially mutagenic concentrations of nitric oxide at the gastroesophageal junction

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 micromol/L (18-49) to 95 micromol/L (32-152), mean salivary nitrite from 36 micromol/L (19-153) to 252 micromol/L (32-600), and mean peak luminal nitric oxide concentration from 4.7 micromol/L (1.4-7.8) to 23.2 micromol/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 micromol/L (range, 0.5-30.7) and was significantly higher than at all other sites. Nitric oxide concentrations greater than 50 micromol/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.