Dietary nitrite and nitrate: A review of potential mechanisms of cardiovascular benefits

Molecular Medicine Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
European Journal of Nutrition (Impact Factor: 3.47). 05/2011; 50(5):293-303. DOI: 10.1007/s00394-011-0192-5
Source: PubMed


In the last decade, a growing scientific and medical interest has emerged toward cardiovascular effects of dietary nitrite and nitrate; however, many questions concerning their mode of action(s) remain unanswered. In this review, we focus on multiple mechanisms that might account for potential cardiovascular beneficial effects of dietary nitrite and nitrate.
Beneficial changes to cardiovascular health from dietary nitrite and nitrate might result from several mechanism(s) including their reduction into nitric oxide, improvement in endothelial function, vascular relaxation, and/or inhibition of the platelet aggregation. From recently obtained evidence, it appears that the longstanding concerns about the toxicity of oral nitrite or nitrate are overstated.
Dietary nitrite and nitrate may have cardiovascular protective effects in both healthy individuals and also those with cardiovascular disease conditions. A role for nitrite and nitrate in nitric oxide biosynthesis and/or in improving nitric oxide bioavailability may eventually provide a rationale for using dietary nitrite and nitrate supplementation in the treatment and prevention of cardiovascular diseases.

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    • "In mammals in particular, nitrite is formed through the oxidation of NOS-derived nitric oxide [12]. In addition, nitrite in the body also originates from processed food (in which it is used as preservative [13]) but from vegetables [14], as well as from the reduction of nitrate by commensal bacteria in the digestive system [13]. "
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    ABSTRACT: Ingestion of dietary nitrites lowers arterial blood pressure in experimental animals and in humans. However, the exact mechanism underlying the hypotensive effect of nitrite remains unclear. The present study compared nitrite-induced responses in rings (with or without endothelium) of aortae of 18-20 weeks old Wistar-Kyoto Rats (WKY) and spontaneously hypertensive (SHR) rats and investigated the underlying mechanism. Relaxations of aortae from WKY and SHR to increasing concentrations (1 nM - 100μM) of sodium nitrite (NaNO2) were determined during sustained contractions to phenylephrine, in the absence and presence of pharmacological agents. The nitrite-induced relaxations were concentration-dependent and larger in SHR than in WKY aortic rings. Inhibition of endothelial nitric oxide synthase (eNOS) and absence of endothelium decreased nitrite-induced relaxations in both WKY and SHR aortae, indicating the role of endothelium-derived nitric oxide (NO) in the response. The involvement of eNOS was further confirmed by increases in phosphorylation of eNOS at ser1177 in HUVEC cells following treatment with sodium nitrite. The presence of NO scavengers decreased the relaxation to nitrite in both WKY and SHR preparations while inhibition of soluble guanylyl cyclase (sGC) abolished the response, indicating that besides producing NO, nitrite also induces relaxation by directly activating the enzyme. Thus, the present study demonstrates that the sensitivity to exogenous nitrite is increased in the aorta of the SHR compared to that of the WKY. The endothelium-dependent component of the relaxation to nitrite involves activation of eNOS with production of endothelium-derived NO, while the endothelium-independent component is due to stimulation of sGC. Copyright © 2015. Published by Elsevier Inc.
    Vascular Pharmacology 06/2015; DOI:10.1016/j.vph.2015.05.014 · 3.64 Impact Factor
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    • "Nitric oxide (NO) plays a key contributing role in the modulation of blood vessel tone at rest and under conditions of increased metabolic demand, such as exercise (Heinonen et al. 2011; Joyner and Casey 2009; Joyner and Tschakovsky 2003). As a result, there has been a growing interest in the use of dietary interventions that increase bioavailable NO as both cardiovascular healthpromoting (Kapil et al. 2010; Lundberg et al. 2011; Machha and Schechter 2011) and ergogenic aids (Bailey et al. 2009; Bescos et al. 2012; Jones et al. 2011; Lansley et al. 2011; Vanhatalo et al. 2011). In particular, dietary supplementation with inorganic salts or highnitrate containing foods (e.g., beetroot juice) has recently grown "
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    ABSTRACT: Despite the popularity of dietary nitrate supplementation and the growing evidence base of its potential ergogenic and vascular health benefits, there is no direct information about its effects on exercising limb blood flow in humans. We hypothesized that acute dietary nitrate supplementation from beetroot juice would augment the increases in forearm blood flow, as well as the progressive dilation of the brachial artery, during graded handgrip exercise in healthy young men. In a randomized, double-blind, placebo-controlled crossover study, 12 young (22 ± 2 years) healthy men consumed a beetroot juice (140 mL Beet-It Sport, James White Juice Company) that provided 12.9 mmol (0.8 g) of nitrate or placebo (nitrate-depleted Beet-It Sport) on 2 study visits. At 3 h postconsumption, brachial artery diameter, flow, and blood velocity were measured (Doppler ultrasound) at rest and during 6 exercise intensities. Nitrate supplementation raised plasma nitrate (19.5-fold) and nitrite (1.6-fold) concentrations, and lowered resting arterial pulse wave velocity (PWV) versus placebo (all p < 0.05), indicating absorption, conversion, and a biological effect of this supplement. The supplement-associated lowering of PWV was also negatively correlated with plasma nitrite (r = -0.72, p = 0.0127). Despite these systemic effects, nitrate supplementation had no effect on brachial artery diameter, flow, or shear rates at rest (all p ≥ 0.28) or during any exercise workload (all p ≥ 0.18). These findings suggest that acute dietary nitrate supplementation favorably modifies arterial PWV, but does not augment blood flow or brachial artery vasodilation during nonfatiguing forearm exercise in healthy young men.
    Applied Physiology Nutrition and Metabolism 10/2014; 40(2). DOI:10.1139/apnm-2014-0228 · 2.34 Impact Factor
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    • "Nitrite can be further reduced to NO by several pathways including deoxyhemoglobin [8], [9], deoxymyoglobin [10], xanthine oxidase [11], [12], and non-enzymatic reduction in the presence of protons [13], [14] or ascorbic acid [15]. Since nitrate and nitrite can be easily obtained from our diet, the potential NO-related bioactivities of those anions are getting more attention with regard to the cardiovascular benefits [16], [17]. We previously reported that nitrite could inhibit platelet aggregation and activation in the presence of erythrocytes through its reduction to NO and this inhibitory effect was promoted by deoxygenation since deoxyhemoglobin reduces nitrite to NO [18]. "
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    ABSTRACT: Nitric oxide (NO), a small gas molecule, has long been known to be a potent inhibitor of platelet function but the physiological and pathological implications of platelet inhibition by NO have not been well clarified. We recently showed that the addition of nitrite to platelet-rich plasma in the presence of erythrocytes could inhibit platelet aggregation and this inhibitory effect of nitrite + erythrocytes was enhanced by deoxygenation of erythrocytes as measured by P-selectin expression and cGMP production. In order to study the nitrite effect on platelets at different oxygen levels, we used the flow cytometric assays to detect platelet membrane surface markers upon activation. The P-selectin and activated gpIIb/IIIa expression on platelet membranes in response to ADP, collagen and thrombin stimulation was measured at various hematocrit and oxygen levels. Nitrite (0.1 to 1.0 μM) significantly decreased the percentage of these surface markers on the platelet membrane at the hematocrit values above 23% and oxygen levels lower than 49 mmHg. The inhibitory effect of nitrite was augmented by increasing hematocrit values and decreasing oxygen saturation. C-PTIO (an NO scavenger) prevented the platelet inhibition by nitrite + erythrocytes whereas the inhibitors of NO synthase and xanthine oxidoreductase had no effect. These results support the proposal that circulating nitrite decreases platelet reactivity in the presence of partially deoxygenated erythrocytes through its reduction to NO, which may also explain certain differences between arterial and venous thrombosis and support directly the role of deoxyhemoglobin in this process. We believe that our flow cytometric assays offer a possibility to identify the individual molecular process involved in these effects.
    PLoS ONE 03/2014; 9(3):e92435. DOI:10.1371/journal.pone.0092435 · 3.23 Impact Factor
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