Review focus on inorganic nitrite and nitrate in cardiovascular health and disease
Open accessAbstract
This editorial refers to the following review articles in the issue which are part of a Review Focus on Inorganic Nitrite and Nitrate: M. Gilchrist et al.7, pp. 492–498;J.W. Calvert10, pp. 499–506;R.P. Patel et al.12, pp. 507–515;Q. Yu et al.16, pp. 516–524;J.O. Lundberg et al.17, pp. 525–532;C.B. Patillo et al.19, pp. 533–541;B.S. Zuckerbraun et al.23, pp. 542–552;A. Cauwels and P. Brouckaert24, pp. 553–559. Reviews and original articles in this focused issue of Cardiovascular Research address the topic of inorganic nitrite and nitrate in cardiovascular pathophysiology. It is well accepted that nitric oxide (NO) is a critical regulator of cardiovascular health that is routinely depleted during vascular disease and dysfunction.1,2 Since the original discovery of NO as a mediator of cardiovascular health, thousands of studies have focused on mechanisms of NO generation and function, largely addressing NO synthase (NOS) activity and NO-dependent signalling responses (e.g. soluble guanylate cyclase and nitrosylation reactions).3,4 From the beginning, a physiological role for inorganic nitrite or nitrate in mediating the biological effects of NO was briefly considered; however, early experimental data did not support a compelling role for these molecules in participating in NO physiology. Over the last decade, a handful of investigators have challenged this dogma through studies re-examining the relationship between NO, nitrite, and nitrate and have elucidated the newly described nitrite/nitrate/NO endocrine system. In the current review papers, the authors discuss how nitrite/nitrate serve as an important reservoir for NO and detail how under specific conditions nitrite/nitrate can be reduced back to NO to increase its bioavailability independent of classical NOS activity. The importance and mechanisms of this unique feature of nitrite/nitrate anion are further detailed with respect to cardiovascular health and potential therapeutic uses. Historical and new, emerging evidence suggests that inorganic nitrite/nitrate can significantly alter blood pressure.5,6 In the article by Gilchrist et al.,7 the authors discuss pharmacokinetic and pharmacodynamic properties of inorganic nitrite and nitrate consumption as well as elaborate on the entero-salivary circulation of nitrate, which can augment plasma nitrite levels through consumption of nitrate-rich foods. The authors also provide an update on the effect of nitrite/nitrate on blood pressure regulation and the possible importance of dietary nitrate contribution to cardiovascular health. Finally, the risk-to-benefit ratio for nitrate consumption is discussed, including the contribution of nitrate to carcinogenesis, which is presently equivocal. Physical activity through regular exercise has long been associated with increased cardiovascular health and resistance to disease.8,9 In his review, John Calvert discusses how regimented exercise contributes to increased eNOS expression and activation, thus enhancing NO bioavailability and plasma nitrite levels.10 This article also posits the idea that nitrite generation and sequestration in tissues due to exercise may be a biologically important mechanism behind the cardioprotective effects of exercise, possibly by invoking preconditioning through an increase in antioxidant defences, heat-shock responses, or alteration of signalling mechanisms. This compelling idea could help explain the significant cardiovascular benefits of a healthy lifestyle consisting of the consumption of green leafy vegetables coupled with regular exercise. While several details of the link between nitrite and exercise remain unknown, the author clearly identifies important questions to consider that will undoubtedly expand our knowledge of the mechanisms behind exercise and cardiovascular protection. Nitrite reduction back to NO is now known to occur in multiple tissues through several different mechanisms.11 However, the initial appreciation and understanding of a one-electron reduction of nitrite anion came from studies identifying deoxyhaemoglobin as an effective nitrite reductase. In the article by Patel et al.,12 the authors recount this discovery as well as provide new insight into specific reductase mechanisms of deoxyhaemoglobin. The authors also discuss the conundrum around NO escape from the red cell after nitrite reduction, which still remains a strongly debated and poorly understood topic. Nonetheless, it is clear from numerous studies that haemoglobin-mediated nitrite reduction influences vascular tone in ex vivo experimental settings, reinforcing the idea that much work is needed to better understand the mechanisms of red cell-dependent, nitrite-mediated vasodilation. Defective NO bioavailability is now well accepted as an aetiological factor contributing to metabolic and cardiovascular dysfunction during diabetes.13–15 The review by Yu et al.16 delivers clear and succinct insight into insulin regulation of eNOS activation and NO produc
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Low doses of nitrite limiting ischemia-reperfusion infarction suggests that nitrite may modulate critical pathophysiological stress responses, particularly those involved during tissue ischemia.
“The potent effect of low doses of nitrite on limiting ischemia-reperfusion infarction suggests that nitrite may modulate critical pathophysiological stress responses, particularly those involved during tissue ischemia [47, 161].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [161]
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- Authors
- Kevil, C. G., & Lefer, D. J.
- Affiliations
- Louisiana State University (US)
- Emory University (US)
- Corresponding author
- Kevil, C. G.
- Venue
- Cardiovascular Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-12-23
- Volume
- 89
- Issue
- 3
- Pages
- 489-491
- ISSN
- 0008-6363 (ISSN-L)
- PMC
- PMC3028981
- OpenAlex
- W2168817383
- Cited by
- 32
- References
- 27
- Citations by year
- 2025: 1 · 2023: 2 · 2022: 3 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 2 · 2017: 3 · 2016: 2 · 2015: 1 · 2014: 2 · 2013: 1 · 2012: 4
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cardiovascular Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Emory University
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL-80482, R01HL093579, R01HL092141, R01HL080482)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01 DK-43785, P01DK043785)
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- inorganic nitrite, nitrate, nitric oxide, nitric oxide bioavailability, nitrite reductase, blood pressure regulation, cardiovascular disease, nitrate therapy, nitrate tolerance
- MeSH terms
- Animals, Cardiovascular Diseases, Cardiovascular System, Humans, Nitrates, Nitrites
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