Chemical synthesis of nitric oxide in the stomach from dietary nitrate in humans
Open accessAbstract
BACKGROUND/AIMS: It has been suggested that dietary nitrate, after concentration in the saliva and reduction to nitrite by tongue surface bacteria, is chemically reduced to nitric oxide (NO) in the acidic conditions of the stomach. This study aimed to quantify this in humans. METHODS: Ten healthy fasting volunteers were studied twice, after oral administration of 2 mmol of potassium nitrate or potassium chloride. Plasma, salivary and gastric nitrate, salivary and gastric nitrite, and gastric headspace NO concentrations were measured over six hours. RESULTS: On the control day the parameters measured varied little from basal values. Gastric nitrate concentration was 105.3 (13) mumol/l (mean (SEM), plasma nitrate concentration was 17.9 (2.4) mumol/l, salivary nitrate concentration 92.6 (31.6) mumol/l, and nitrite concentration 53.9 (22.8) mumol/l. Gastric nitrite concentrations were minimal (< 1 mumol/l). Gastric headspace gas NO concentration was 16.4 (5.8) parts per million (ppm). After nitrate ingestion, gastric nitrate peaked at 20 minutes at 3430 (832) mumol/l, plasma nitrate at 134 (7.2) mumol/l, salivary nitrate at 1516.7 (280.5) mumol/l, and salivary nitrite at 761.5 (187.7) mumol/l after 20-40 minutes. Gastric nitrite concentrations tended to be low, variable, and any rise was non-sustained. Gastric NO concentrations rose considerably from 14.8 (3.1) ppm to 89.4 (28.6) ppm (p < 0.0001) after 60 minutes. All parameters remained increased significantly for the duration of the study. CONCLUSIONS: A very large and sustained increase in chemically derived gastric NO concentrations after an oral nitrate load was shown, which may be important both in host defence against swallowed pathogens and in gastric physiology.
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The half-life of nitrate is 5-8 h, much longer than that of nitrite, which has been reported as 1-5 min ex vivo and ~20-45 min in vivo.
“The half-life of nitrate is 5-8 h [77,79,111,141,142], which is much longer than that of nitrite, which has been reported as being 1-5 min ex vivo [77,142] and ~20-45 min in vivo [86,112].”
From Vascular effects of dietary nitrate (as found in green leafy vegetables and beetroot) via the nitrate-nitrite-nitric oxide pathway (2013) · cites this paper as [141]
The Results report that nitrate concentrations remained elevated over the six-hour study, while the rise in gastric nitrite was not sustained. Neither the Results nor the Discussion gives a nitrate half-life of 5–8 hours or the claimed ex vivo or in vivo nitrite half-lives; searches for those values found no supporting passage. (LLM, conf=0.76)
Experimental — accuracy not yet measuredNitrite is swallowed and can undergo downstream reactions, including formation of NO and NO-donating species following protonation to HNO2 and secondary nitrosating and nitrating species in the low pH of the stomach, or further reduction by enteric bacterial nitrite reductases.
“Nitrite is then swallowed where it can undergo a diversity of downstream reactions, including formation of NO and NO-donating species following a) protonation to HNO2 and an array of secondary nitrosating and nitrating species in reactions facilitated by the low pH of the stomach[80,83,89–91], or b) further reduction by enteric bacterial nitrite reductases (NiRs)[74].”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [83]
Approximately 25% of total circulating nitrate is actively sequestered into salivary glands and concentrated in saliva up to 20 times that in plasma, in proportion to the dietary load of nitrate.
“In proportion to the dietary load of nitrate, approximately 25% of total circulating nitrate is actively sequestered into salivary glands and concentrated in saliva up to 20 times that in plasma[73,75,82–88].”
From Enterosalivary nitrate metabolism and the microbiome: Intersection of microbial metabolism, nitric oxide and diet in cardiac and pulmonary vascular health (2017) · cites this paper as [83]
In the acidic environment of the stomach, part of swallowed nitrite is protonated to nitrous acid and decomposed to form nitrogen oxides such as NO, NO2, and N2O3.
“In the acidic environment of the stomach, part of the swallowed nitrite is immediately protonated to nitrous acid (NO2− + H+ → HNO2), then decomposed to form a variety of nitrogen oxides such as NO, nitrogen dioxides (NO2), and dinitrogen trioxide (N2O3)”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [23]
Nitrite reduction to NO involves mechanisms including pH-dependent reduction in the stomach, reduction by xanthine oxidase, deoxyhemoglobin, myoglobin, cytochrome P450, and enzymes of the mitochondrial respiratory chain.
“The mechanisms involved in nitrite reduction to NO include pH-dependent reduction in the stomach [9,10] or reduction by xanthine oxidase [11,12], deoxyhemoglobin [13], myoglobin [14,15], cytochrome P450 [16], and enzymes of the mitochondrial respiratory chain [17].”
From Sodium nitrite downregulates vascular NADPH oxidase and exerts antihypertensive effects in hypertension (2011) · cites this paper as [10]
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- Authors
- McKnight, G. M., Smith, L. M., Drummond, R. S., Duncan, C. W., Golden, M., & Benjamin, N.
- Affiliations
- University of Aberdeen (GB)
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 1997-02
- Volume
- 40
- Issue
- 2
- Pages
- 211-214
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC1027050
- OpenAlex
- W2002338268
- Cited by
- 375
- References
- 18
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 5 · 2023: 6 · 2022: 4 · 2021: 8 · 2020: 7 · 2019: 13 · 2018: 15 · 2017: 12 · 2016: 17 · 2015: 17 · 2014: 15 · 2013: 15 · 2012: 14
- FWCI
- 7.32
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gut (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Biochemistry › Phytochemicals and Antioxidant Activities
- Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
- Keywords
- nitric oxide, dietary nitrate, salivary nitrate, plasma nitrate, gastric acid, gastric physiology
- MeSH terms
- Administration, Oral, Adult, Female, Gastric Mucosa, Gastrointestinal Contents, Humans, Hydrogen-Ion Concentration, Male, Nitrates, Nitric Oxide, Nitrites, Potassium Chloride, Saliva, Potassium Compounds
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