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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    • "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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    • "The roles of nitrite and nitrate as exogenous NO sources have recently obtained increasing attention with respect to their potential beneficial effects in cardiovascular diseases [29], [30], [31]. Although the endogenous NOS system partially contributes to the changes of nitrite and nitrate levels, a few animal studies [32], [33], [34], in which low NOx diet was used for dietary nitrite and nitrate depletion, show that blood and tissue nitrite and nitrate levels were significantly reduced under the low NOx diet suggesting the remarkable contribution of diet to steady-state levels of nitrite and nitrate. "
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    ABSTRACT: Nitric oxide (NO) appears to play an important role in the regulation of thrombosis and hemostasis by inhibiting platelet function. The discovery of NO generation by reduction of nitrite (NO(2) (-)) and nitrate (NO(3) (-)) in mammals has led to increased attention to these anions with respect to potential beneficial effects in cardiovascular diseases. We have previously shown that nitrite anions at 0.1 µM inhibit aggregation and activation of human platelet preparations in vitro in the presence of red blood cells and this effect was enhanced by deoxygenation, an effect likely due to NO generation. In the present study, we hypothesized that nitrite and nitrate derived from the diet could also alter platelet function upon their conversion to NO in vivo. To manipulate the levels of nitrite and nitrate in mouse blood, we used antibiotics, NOS inhibitors, low nitrite/nitrate (NOx) diets, endothelial NOS knock-out mice and also supplementation with high levels of nitrite or nitrate in the drinking water. We found that all of these perturbations affected nitrite and nitrate levels but that the lowest whole blood values were obtained by dietary restriction. Platelet aggregation and ATP release were measured in whole blood and the results show an inverse correlation between nitrite/nitrate levels and platelet activity in aggregation and ATP release. Furthermore, we demonstrated that nitrite-supplemented group has a prolonged bleeding time compared with control or low NOx diet group. These results show that diet restriction contributes greatly to blood nitrite and nitrate levels and that platelet reactivity can be significantly affected by these manipulations. Our study suggests that endogenous levels of nitrite and nitrate may be used as a biomarker for predicting platelet function and that dietary manipulation may affect thrombotic processes.
    PLoS ONE 02/2013; 8(2):e55699. DOI:10.1371/journal.pone.0055699 · 3.23 Impact Factor
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