The DOI matches its Crossref record; 57 of the 58 references it cites were found in a registry or an index, and 1 are not checked yet.
Dietary nitrite restores NO homeostasis and is cardioprotective in endothelial nitric oxide synthase-deficient mice
Open accessAbstract
Endothelial production of nitric oxide (NO) is critical for vascular homeostasis. Nitrite and nitrate are formed endogenously by the stepwise oxidation of NO and have, for years, been regarded as inactive degradation products. As a result, both anions are routinely used as surrogate markers of NO production, with nitrite as a more sensitive marker. However, both nitrite and nitrate are derived from dietary sources. We sought to determine how exogenous nitrite affects steady-state concentrations of NO metabolites thought to originate from nitric oxide synthase (NOS)-derived NO as well as blood pressure and myocardial ischemia-reperfusion (I/R) injury. Mice deficient in endothelial nitric oxide synthase (eNOS-/-) demonstrated decreased blood and tissue nitrite, nitrate, and nitroso proteins, which were further reduced by low-nitrite (NOx) diet for 1 week. Nitrite supplementation (50 mg/L) in the drinking water for 1 week restored NO homeostasis in eNOS-/- mice and protected against I/R injury. Nitrite failed to alter heart rate or mean arterial blood pressure at the protective dose. These data demonstrate the significant influence of dietary nitrite intake on the maintenance of steady-state NO levels. Dietary nitrite and nitrate may serve as essential nutrients for optimal cardiovascular health and may provide a novel prevention/treatment modality for disease associated with NO insufficiency.
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“the nitrate/nitrite content of the fruits and vegetables could contribute to their cardiovascular health benefits in animals [29,33,78,79,80,81,82,83] and humans [31,84,85,86].”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [82]
In the citing paper
“pretreatment with this compound, delivered as a salt in the form of sodium nitrite, protects against ischemia/reperfusion (I/R) injury in the heart in preclinical models (7, 19, 20, 40, 46, 60, 79, 189).”
From Inorganic nitrite supplementation for healthy arterial aging (2014) · cites this paper as [20]
In the citing paper
“in vivo administration of nitrite either via direct infusion [25, 37, 83], dietary supplementation [84-86] or in the form of its two-electron oxidized precursor nitrate [87-89] leads to a decrease in blood pressure in normal and hypertensive patients with a concomitant increase in markers of NO formation”
From Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy (2011) · cites this paper as [85]
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Citations
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Cited by
Sorted by citations
Items 101–161 of 161
Periodontal treatment causes a longitudinal increase in nitrite‐producing bacteria
Simpson, A., Johnston, W., Carda‐Diéguez, M., Mira, A., Easton, C., Henriquez, F. L., Culshaw, S., Rosier, B. T., & Burleigh, M. C. (2024) · Molecular Oral Microbiology · doi:10.1111/omi.12479 · Cited by 15
“These include the maintenance of endothelial function and control of blood pressure (BP) (Bryan et al., 2008; Kapil et al., 2020), regulation of platelet function (Webb et al., 2008), enhancement of exercise performance (Senefeld et al., 2020), improved efficiency of muscle contraction (Bailey et…”
BackgroundPreserving vessel function during ischemic disease: new possibilities of inorganic nitrite therapy
Kevil, C. G., & Patel, R. P. (2008) · Expert Review of Cardiovascular Therapy · doi:10.1586/14779072.6.9.1175 · Cited by 14
“Recent studies have shown that dietary nitrite is an effective means by which to increase circulating nitrite levels which affords protection against acute myocardial I/R injury in mice [46,47].”
Ferreira, G. C., Pinheiro, L. C., Oliveira‐Paula, G. H., de Angelis, C. D., Portella, R. L., & Tanus-Santos, J. E. (2021) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2021.109658 · Cited by 14
Cell Survival Programs and Ischemia /Reperfusion: Hormesis, Preconditioning, and Cardioprotection
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Bailey, S. J., Blackwell, J. R., Wylie, L. J., Emery, A., Taylor, E., Winyard, P. G., & JONES, A. M. (2016) · Nitric Oxide · doi:10.1016/j.niox.2016.12.008 · Cited by 13
“It has been demonstrated that NO can be generated through the O2-independent reduction of nitrite (NO2 ) to complement O2-dependent NO generation through the NO synthases [3-5].”
BackgroundAnti-oxidant effect of nitrite in the pancreatic islets of type 2 diabetic male rats.
Ghasemi, A., Gheibi, S., Kashfi, K., & Jeddi, S. (2023) · PubMed Central · doi:10.22038/ijbms.2023.68245.14900 · Cited by 11
“This nitrite dose was chosen based on previous reports from our laboratory (7) and others (6, 25, 26), showing it to be safe, and producing favorable metabolic effects.”
Neuman, R. B., Hayek, S. S., Poole, J. C., Rahman, A. M., Menon, V., Kavtaradze, N., Polhemus, D. J., Veledar, E., Lefer, D. J., & Quyyumi, A. A. (2015) · Journal of Clinical Hypertension · doi:10.1111/jch.12649 · Cited by 11
“Extracted plasma was flash frozen and stored at 80°C and subsequently analyzed for nitrite and nitrate levels by ion chromatography (ENO20; Eicom USA, San Diego, CA) as previously described.(30)”
MethodGiv, V., Aminaei, M., & Nikoei, R. (2022) · Research in Sports Medicine · doi:10.1080/15438627.2022.2090250 · Cited by 10
“When the synthesis of nitric oxide is disrupted by the enzyme nitric oxide synthase, and in situations where access to oxygen is low, the reduction of nitrate to nitrite and the subsequent conversion of nitrite to nitric oxide increase nitric oxide production (Bryan et al., 2008).”
BackgroundEvidence-based sports supplements: A redox analysis
Margaritelis, N. V., Cobley, J. N., Nastos, G. G., Παπανικολάου, Κ., Bailey, S. J., Kritsiligkou, P., & Nikolaidis, M. G. (2024) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2024.08.012 · Cited by 10
Nebivolol Acts as a S-Nitrosoglutathione Reductase Inhibitor
Jiang, H., Polhemus, D. J., Islam, K. N., Torregrossa, A. C., Li, Z., Potts, A., Lefer, D. J., & Bryan, N. S. (2016) · Journal of Cardiovascular Pharmacology and Therapeutics · doi:10.1177/1074248415626300 · Cited by 10
Nitrate-Reducing Oral Bacteria: Linking Oral and Systemic Health
Bryan, N. S., & Petrosino, J. F. (2017) · Springer eBooks · doi:10.1007/978-3-319-46189-2_3 · Cited by 11
The potential use of salivary nitrite as a marker of NO status in humans
Bryan, N. S. (2014) · Nitric Oxide · doi:10.1016/j.niox.2014.12.011 · Cited by 11
Metagenomics: Implications in Oral Health and Disease
Nagarajan, M., Prabhu, V. R., & Kamalakkannan, R. (2017) · Elsevier eBooks · doi:10.1016/b978-0-08-102268-9.00009-4 · Cited by 10
Kautza, B. C., Gómez, H., Escobar, D. A., Corey, C. G., Ataya, B., Luciano, J. A., Botero, A. M., Gordon, L. M., Brumfield, J. M., Martinez, S., et al. (2015) · Nitric Oxide · doi:10.1016/j.niox.2015.09.006 · Cited by 9
“These data suggest that this pathway contributes to an endogenous adaptive response to limit tissue injury to an insult such as HS/R and are consistent with studies demonstrating that dietary nitrite mediates preconditioning in other models of inflammatory and/or hypoxic injury(14, 17, 33, 42, 46, 47).”
ResultBlood collection vials and clinically used intravenous fluids contain significant amounts of nitrite
Almeida, L. E. F., Kamimura, S., Nettleton, M. Y., Batista, C. M. D. S., Walek, E., Khaibullina, A., Wang, L., & Quezado, Z. (2017) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.04.014 · Cited by 8
Fernandes, J. D. O., Conde-Tella, S. O., Ferraz, I. S., Ciampo, L. A. D., & Tanus-Santos, J. E. (2020) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-020-03994-2 · Cited by 8
“The plasma concentrations of nitrite and nitrate are closely related to their dietary content [2, 21], and several previous studies have shown how important the dietary content of these metabolites are to determine their plasma concentrations and the associated health benefits [4, 30, 31].”
BackgroundYamasaki, H., Imai, H., Tanaka, A., & Otaki, J. M. (2023) · Microorganisms · doi:10.3390/microorganisms11020397 · Cited by 8
“Such distinct mechanisms have been called the “nitrate-nitrite-NO pathway” [86–88], “NOS-independent mechanism” [89], “nitrite-dependent NO production pathway” [65,90], “nitrite pathway” [91], or the “reductive pathway” [92].”
Yassaghi, Y., Jeddi, S., Yousefzadeh, N., Kashfi, K., & Ghasemi, A. (2023) · BMC Cardiovascular Disorders · doi:10.1186/s12872-023-03425-2 · Cited by 8
“In addition, as summarized in Table 2, in vivo studies indicated that nitrite [24, 25] and nitrate [25, 26] administration for 7 days in mice or nitrate administration for 60 days [9] in male rats increase the resistance to MIRI.”
BackgroundBringing Nitric Oxide to the Molybdenum World—A Personal Perspective
Maia, L. B. (2023) · Molecules · doi:10.3390/molecules28155819 · Cited by 7
Wang, L., Almeida, L. E. F., Kamimura, S., van der Meulen, J. H., Nagaraju, K., Quezado, M., Wakim, P., & Quezado, Z. (2018) · Nitric Oxide · doi:10.1016/j.niox.2018.08.005 · Cited by 7
“Others showed that nitrite supplementation increases nitrite levels in wild type and endothelial NOS knockout mice and that in models of ischemia/reperfusion injury in cardiac muscle it has salutary effects [28; 29].”
BackgroundImpact of mitochondria on nitrite metabolism in HL-1 cardiomyocytes
Dungel, P., Teuschl, A., Banerjee, A., Paier-Pourani, J., Redl, H., & Kozlov, A. V. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00101 · Cited by 7
Kina-Tanada, M., Sakanashi, M., Arasaki, A., & Tsutsui, M. (2018) · Folia Pharmacologica Japonica · doi:10.1254/fpj.151.148 · Cited by 7
Chiletti, R., Fincher, S. H., Horton, S., Peek, G. J., Checchia, P. A., & Butt, W. W. (2024) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2024.12.027 · Cited by 6
Trevisi, P., Casini, L., Nisi, I., Messori, S., & Bosi, P. (2010) · Journal of Animal Physiology and Animal Nutrition · doi:10.1111/j.1439-0396.2010.01042.x · Cited by 6
An Overview of Nitrite and Nitrate
Bryan, N. S. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-805413-0.00003-x · Cited by 6
Beetroot supplementation improves the physiological responses to incline walking
Waldron, M., Waldron, L., Lawlor, C., Gray, A. J., & Highton, J. M. (2018) · European Journal of Applied Physiology · doi:10.1007/s00421-018-3843-x · Cited by 6
“Thus, the availability of NO can be preserved when enzymatic 85 synthesis of NO via nitric oxide synthase (NOS) has been compromised (Bryan et al. 2008).”
InfluentialNitrate and Nitrite in Aging and Age-Related Disease
Johnson, L. C., DeVan, A. E., Justice, J. N., & Seals, D. R. (2017) · Springer eBooks · doi:10.1007/978-3-319-46189-2_18 · Cited by 5
Yassaghi, Y., Jeddi, S., Kashfi, K., & Ghasemi, A. (2023) · EXCLI journal · doi:10.17179/excli2023-6740 · Cited by 4
“The re-sults of the sensitivity analysis showed no considerable change after excluding studies with very high doses (overall ES=-17.3 %, 95 % CI=-22.1, -12 .4, P<0.001) (Johnson et al., 1990b, a19911991) or non-healthy conditions (overall ES=-17.2 %, 95 % CI=-21.6, - 12.8, P<0.001) (Bryan et al., 2008; Hendgen-Cotta e…”
BackgroundMethodResultInfluentialLi, F., Li, X., Fu, Y., Hu, X., Zhou, D., Dai, Y., & Jeon, Y. (2022) · Journal of Applied Phycology · doi:10.1007/s10811-022-02868-y · Cited by 4
“2010), whereas, the NO generated by eNOS may control cardiovascular homeostasis (Bryan et al. 2008).”
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Enhancement of nitrite on heme-induced oxidative reactions: A potential toxicological implication
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Kumar, S., Barthwal, M. K., & Dikshit, M. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.110.177444 · Cited by 3
“Moreover, the use of chronic dietary nitrite supplementation (50 mg/liter) in drinking water for 1 week restored NO homeostasis in eNOS( / ) mice and protected them against ischemia and reperfusion injury (Bryan et al., 2008).”
BackgroundResultInfluentialEffect of nitrite treatment on endothelial nitric oxide synthase in human left ventricle biopsy
Bailey, J., Arif, S., Mascaro, J. G., Bonser, R. S., Frenneaux, M. P., & Madhani, M. (2013) · BMC Pharmacology and Toxicology · doi:10.1186/2050-6511-14-s1-p3 · Cited by 3
Nitrite Therapy for Ischemic Syndromes
Kevil, C. G., & Lefer, D. J. (2010) · Elsevier eBooks · doi:10.1016/b978-0-12-373866-0.00018-6 · Cited by 4
The Mitochondrion: A Physiological Target of Nitrite
Guimarães, D. A., Reyes, C., & Shiva, S. (2017) · Springer eBooks · doi:10.1007/978-3-319-46189-2_5 · Cited by 2
Pan, A.-Q., Liu, X., Han, H., Gao, S., & Lin, Y. (2025) · Physical Chemistry Chemical Physics · doi:10.1039/d4cp04253k · Cited by 2
Lefer, D. J., & Bolli, R. (2012) · Elsevier eBooks · doi:10.1016/b978-0-12-381510-1.00028-4 · Cited by 2
Nitrate and Exercise Performance
Bailey, S. J., Vanhatalo, A., & JONES, A. M. (2017) · Springer eBooks · doi:10.1007/978-3-319-46189-2_20 · Cited by 3
Nitrite and Nitrate in Ischemia–Reperfusion Injury
Lefer, D. J., Bryan, N. S., & Organ, C. L. (2017) · Springer eBooks · doi:10.1007/978-3-319-46189-2_16 · Cited by 2
Nitrite and Nitrate in Ischemia-Reperfusion Injury
Lavu, M., Gundewar, S., & Lefer, D. J. (2011) · Humana Press eBooks · doi:10.1007/978-1-60761-616-0_14 · Cited by 2
“Endogenous NO derived from NOS plays a vital role in imparting protection during reperfusion injury; its absence leads to increased injury in the heart [17].”
BackgroundKowash, H. M., Tropea, T., Dilworth, M., Lundberg, J. O., Weitzberg, E., Nihlén, C., & Cottrell, E. C. (2025) · Nitric Oxide · doi:10.1016/j.niox.2025.06.002 · Cited by 1
Symeonidi, L., Nikolaou, P., Stathopoulos, P., Christodoulou, A., Svouraki, A., Efentakis, P., Chania, C., Choustoulaki, A., Xenaki, M., Agapaki, A., et al. (2026) · Phytotherapy Research · doi:10.1002/ptr.70391 · Cited by 1
“The eNOS phosphorylation and activation corroborates with nitrite levels in several settings of cardioprotection and atheroprotetion in agreement with our findings (Bradley et al. 2015; Bryan et al. 2008; Nguyen et al. 2023; Sharma et al. 2015).”
The Nitrate–Nitrite–Nitric Oxide Pathway in Traditional Herbal Medicine for Heart Disease
Geng, Y. (2011) · Humana Press eBooks · doi:10.1007/978-1-60761-616-0_15 · Cited by 1
“The described benefits of these ancient medications may be attributed to their inherent nitrate/nitrite content combined with their robust nitrate/nitrite reductase activity to generate NO independent of the l-arginine–NO pathway [19, 20, 27, 32].”
BackgroundGeng, Y. (2017) · Springer eBooks · doi:10.1007/978-3-319-46189-2_19 · Cited by 1
Metagenomics: Implications in oral health and disease
Prabhu, V. R., Bhavana, K., Deo, P. N., Suresh, A., Kamalakkannan, R., & Nagarajan, M. (2024) · Elsevier eBooks · doi:10.1016/b978-0-323-91631-8.00020-2 · Cited by 2
Beneficial Effects of Inorganic Nitrate/Nitrite on Vascular Function and Blood Pressure in Diabetes
Bahadoran, Z., Mirmiran, P., & Ghasemi, A. (2017) · Springer eBooks · doi:10.1007/978-3-319-60324-7_23 · Cited by 1
Curtis, K. (2016) · Spiral (Imperial College London) · doi:10.25560/44728 · Cited by 1
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Exercise-Induced Cardioprotection: More to k‘NO'w
Lira, V. A. (2015) · Cardiology · doi:10.1159/000375399
Is NO-eNOS a Target for C-Peptide Action and Its Protective Effects on Diabetic Nephropathy?
Kimura, K., & Kamikawa, A. (2011) · Humana Press eBooks · doi:10.1007/978-1-61779-391-2_6
Hoose, P. M. V. (2015) · ThinkIR: The University of Louisville's Institutional Repository (University of Louisville) · doi:10.18297/etd/2293
“protection against ischemia reperfusion injury (40, 71-73).”
Bryan, N. S., & Loscalzo, J. (2017) · Springer eBooks · doi:10.1007/978-3-319-46189-2_22
Nitrate, Nitrite and Type 2 Diabetes
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“However, it subsequently initiated a recovery phase, with a growth rate of 9.1 percent observed in the fiscal year 2022 (19).”
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Towards nitrite as a therapy in cardiovascular disease
Ormerod, J. O. M. (2011) · University of Birmingham Institutional Research Archive (University of Birmingham)
Metadata
- Authors
- Bryan, N. S., Calvert, J. W., Gundewar, S., & Lefer, D. J.
- Affiliations
- Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (US)
- Albert Einstein College of Medicine (US)
- Corresponding author
- Lefer, David J.
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2008-08
- Volume
- 45
- Issue
- 4
- Pages
- 468-474
- ISSN
- 0891-5849 (ISSN-L)
- PMC
- PMC2662396
- OpenAlex
- W2074088550
- Cited by
- 161
- References
- 57
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 9 · 2023: 8 · 2022: 9 · 2021: 6 · 2020: 5 · 2019: 4 · 2018: 6 · 2017: 15 · 2016: 10 · 2015: 11 · 2014: 12 · 2013: 13 · 2012: 6
- FWCI
- 9.93
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Diabetes Association
- National Heart, Lung, and Blood Institute (R01HL093579, 2R01 HL-6049, R01HL060849)
- National Institute of Diabetes and Digestive and Kidney Diseases (F32DK077380)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Health Sciences › Medicine › Biochemistry (medical) › Antioxidant Activity and Oxidative Stress
- Keywords
- dietary nitrite, nitric oxide homeostasis, endothelial nitric oxide synthase, nitrate, myocardial ischemia-reperfusion injury, cardioprotection, blood pressure, cardiovascular health, nitrite supplementation
- MeSH terms
- Animals, Diet, Homeostasis, Myocardium, Nitric Oxide, Nitrite Reductases, Nitrites, Mice, Knockout, Mice, Nitric Oxide Synthase Type III
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