In the previous blog entry Nitrates and nitrites – Part 1: bad for you I described  how there are two current contradictory views about the value of human consumption of nitrates/nitrites.  One view is that consumption of these substances, perhaps through drinking fertalizer-contaminated water, perhaps by eating processed meats, is dangerous and should be avoided.  The result could be incidences of cancer, Alzheimer’s disease, diabetes or premature aging.  The arguments for this “bad for you” view and research justification for this view are laid out in the previous blog entry.  This current blog entry lays out an opposite and contradictory view – that consumption of nitrates can be “good for you.”  I also comment on some critical differences between the “bad for you” and “good for you” studies and say where I am on the issue.

The question of whether dietary nitrates are friends or foes goes back at least ten years

For many decades nitrates in drinking water were seen to be serious threats to public health, as illustrated by several publication s quoted in the previous “nitrates and nitrites are bad for you” blog entry.  The 1999 review article Dietary nitrate in man: friend or foe? Was one of the first to throw this view into question.  “Based on the premise that dietary nitrate is detrimental to human health, increasingly stringent regulations are being instituted to lower nitrate levels in food and water. Not only does this pose a financial challenge to water boards and a threat to vegetable production in Northern Europe, but also may be eliminating an important non-immune mechanism for host defense. Until recently nitrate was perceived as a purely harmful dietary component which causes infantile methaemoglobinaemia, carcinogenesis and possibly even teratogenesis. Epidemiological studies have failed to substantiate this. It has been shown that dietary nitrate undergoes enterosalivary circulation. It is recirculated in the blood, concentrated by the salivary glands, secreted in the saliva and reduced to nitrite by facultative Gram-positive anaerobes (Staphylococcus sciuri and S. intermedius) on the tongue. Salivary nitrite is swallowed into the acidic stomach where it is reduced to large quantities of NO and other oxides of N and, conceivably, also contributes to the formation of systemic S-nitrosothiols. NO and solutions of acidified nitrite, mimicking gastric conditions, have been shown to have antimicrobial activity against a wide range of organisms. In particular, acidified nitrite is bactericidal for a variety of gastrointestinal pathogens such as Yersinia and Salmonella. NO is known to have vasodilator properties and to modulate platelet function, as are S-nitrosothiols. Thus, nitrate in the diet, which determines reactive nitrogen oxide species production in the stomach (McKnight et al. 1997), is emerging as an effective host defense against gastrointestinal pathogens, as a modulator of platelet activity and possibly even of gastrointestinal motility and microcirculation. Therefore dietary nitrate may have an important therapeutic role to play, not least in the immunocompromised and in refugees who are at particular risk of contracting gastroenteritides.”

A 2007 article with the same theme is Dietary nitrate increases gastric mucosal blood flow and mucosal defense. “Salivary nitrate from dietary or endogenous sources is reduced to nitrite by oral bacteria. In the acidic stomach, nitrite is further reduced to bioactive nitrogen oxides, including nitric oxide (NO). In this study, we investigated the gastroprotective role of nitrate intake and of luminally applied nitrite against provocation with diclofenac and taurocholate. Mucosal permeability ((51)Cr-EDTA clearance) and gastric mucosal blood flow (laser-Doppler flowmetry) were measured in anesthetized rats, either pretreated with nitrate in the drinking water or given acidified nitrite luminally. Diclofenac was given intravenously and taurocholate luminally to challenge the gastric mucosa. Luminal NO content and nitrite content in the gastric mucus were determined by chemiluminescence. The effect of luminal administration of acidified nitrite on the mucosal blood flow was also investigated in endothelial nitric oxide synthase-deficient mice. Rats pretreated with nitrate or given nitrite luminally had higher gastric mucosal blood flow than controls. Permeability increased more during the provocation in the controls than in the nitrate- and nitrite-treated animals. Dietary nitrate increased luminal NO levels 50 times compared with controls. Nitrate intake also resulted in nitrite accumulation in the loosely adherent mucous layer; after removal of this mucous layer, blood flow was reduced. Nitrite administrated luminally in endothelial nitric oxide synthase-deficient mice increased mucosal blood flow. We conclude that dietary nitrate and direct luminal application of acidified nitrite decrease diclofenac- and taurocholate-induced mucosal damage. The gastroprotective effect likely involves a higher mucosal blood flow caused by nonenzymatic NO production. These data suggest an important physiological role of nitrate in the diet.”

Oral bacteria appears to play an important role in converting ingested nitrates into nitrites

This point is made in the 2008 publication The increase in plasma nitrite after a dietary nitrate load is markedly attenuated by an antibacterial mouthwash.  “Recent studies surprisingly show that dietary inorganic nitrate, abundant in vegetables, can be metabolized in vivo to form nitrite and then bioactive nitric oxide. A reduction in blood pressure was recently noted in healthy volunteers after dietary supplementation with nitrate; an effect consistent with formation of vasodilatory nitric oxide. Oral bacteria have been suggested to play a role in bioactivation of nitrate by first reducing it to the more reactive anion nitrite. In a cross-over designed study in seven healthy volunteers we examined the effects of a commercially available chlorhexidine-containing antibacterial mouthwash on salivary and plasma levels of nitrite measured after an oral intake of sodium nitrate (10mg/kg dissolved in water). In the control situation the salivary and plasma levels of nitrate and nitrite increased greatly after the nitrate load. Rinsing the mouth with the antibacterial mouthwash prior to the nitrate load had no effect on nitrate accumulation in saliva or plasma but abolished its conversion to nitrite in saliva and markedly attenuated the rise in plasma nitrite. We conclude that the acute increase in plasma nitrite seen after a nitrate load is critically dependent on nitrate reduction in the oral cavity by commensal bacteria. The removal of these bacteria with an antibacterial mouthwash will very likely attenuate the NO-dependent biological effects of dietary nitrate.”

The salutatory effects of consuming nitrates seem to revolve around release of nitric oxide which improves blood flow.  Many other health benefits are reported in addition to protection against gastrointesinal pathogens.

Dietary nitrates are protective of the heart and other organs

The 2009 publication Dietary nitrate and nitrite modulate blood and organ nitrite and the cellular ischemic stress response relates “Dietary nitrate, found in abundance in green vegetables, can be converted to the cytoprotective molecule nitrite by oral bacteria, suggesting that nitrate and nitrite may represent active cardioprotective constituents of the Mediterranean diet. We therefore tested the hypothesis that dietary nitrate and nitrite levels modulate tissue damage and ischemic gene expression in a mouse liver ischemia-reperfusion model. We found that stomach content, plasma, heart, and liver nitrite levels were significantly reduced after dietary nitrate and nitrite depletion and could be restored to normal levels with nitrite supplementation in water. Remarkably, we confirmed that basal nitrite levels significantly reduced liver injury after ischemia-reperfusion. Consistent with an effect of nitrite on the posttranslational modification of complex I of the mitochondrial electron transport chain, the severity of liver infarction was inversely proportional to complex I activity after nitrite repletion in the diet. The transcriptional response of dietary nitrite after ischemia was more robust than after normoxia, suggesting a hypoxic potentiation of nitrite-dependent transcriptional signaling. Our studies indicate that normal dietary nitrate and nitrite levels modulate ischemic stress responses and hypoxic gene expression programs, supporting the hypothesis that dietary nitrate and nitrite are cytoprotective components of the diet.”

Nitrates and brain functioning

The 2010 publication Acute effect of a high nitrate diet on brain perfusion in older adults reports “AIMS  Poor blood flow and hypoxia/ischemia contribute to many disease states and may also be a factor in the decline of physical and cognitive function in aging. Nitrite has been discovered to be a vasodilator that is preferentially harnessed in hypoxia. Thus, both infused and inhaled nitrite are being studied as therapeutic agents for a variety of diseases. In addition, nitrite derived from nitrate in the diet has been shown to decrease blood pressure and improve exercise performance. Thus, dietary nitrate may also be important when increased blood flow in hypoxic or ischemic areas is indicated. These conditions could include age-associated dementia and cognitive decline. The goal of this study was to determine if dietary nitrate would increase cerebral blood flow in older adults. METHODS AND RESULTS In this investigation we administered a high vs. low nitrate diet to older adults (74.7 ± 6.9 years) and measured cerebral perfusion using arterial spin labeling magnetic resonance imaging. We found that the high nitrate diet did not alter global cerebral perfusion, but did lead to increased regional cerebral perfusion in frontal lobe white matter, especially between the dorsolateral prefrontal cortex and anterior cingulate cortex. CONCLUSION These results suggest that dietary nitrate may be useful in improving regional brain perfusion in older adults in critical brain areas known to be involved in executive functioning.”

Dietary nitrates, metabolic syndrome and visceral fat accumulation

The 2010 publication Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice states “The metabolic syndrome is a clustering of risk factors of metabolic origin that increase the risk for cardiovascular disease and type 2 diabetes. A proposed central event in metabolic syndrome is a decrease in the amount of bioavailable nitric oxide (NO) from endothelial NO synthase (eNOS). Recently, an alternative pathway for NO formation in mammals was described where inorganic nitrate, a supposedly inert NO oxidation product and unwanted dietary constituent, is serially reduced to nitrite and then NO and other bioactive nitrogen oxides. Here we show that several features of metabolic syndrome that develop in eNOS-deficient mice can be reversed by dietary supplementation with sodium nitrate, in amounts similar to those derived from eNOS under normal conditions. In humans, this dose corresponds to a rich intake of vegetables, the dominant dietary nitrate source. Nitrate administration increased tissue and plasma levels of bioactive nitrogen oxides. Moreover, chronic nitrate treatment reduced visceral fat accumulation and circulating levels of triglycerides and reversed the prediabetic phenotype in these animals. In rats, chronic nitrate treatment reduced blood pressure and this effect was also present during NOS inhibition. Our results show that dietary nitrate fuels a nitrate-nitrite-NO pathway that can partly compensate for disturbances in endogenous NO generation from eNOS. These findings may have implications for novel nutrition-based preventive and therapeutic strategies against cardiovascular disease and type 2 diabetes.”

The amazing properties of beetroot juice

A number of recent publications have been concerned with the positive circulatory effects of consuming beetroot juice, a juice high in nitrates.  The nitrates convert in the mouth into nitrites which produce nitric oxide which dilates blood vessels reducing blood pressure and increasing circulation.

Nitrates reduce blood pressure

The 2010 publication Inorganic nitrate supplementation lowers blood pressure in humans: role for nitrite-derived NO reports “Ingestion of dietary (inorganic) nitrate elevates circulating and tissue levels of nitrite via bioconversion in the entero-salivary circulation. In addition, nitrite is a potent vasodilator in humans, an effect thought to underlie the blood pressure-lowering effects of dietary nitrate (in the form of beetroot juice) ingestion. Whether inorganic nitrate underlies these effects and whether the effects of either naturally occurring dietary nitrate or inorganic nitrate supplementation are dose dependent remain uncertain. Using a randomized crossover study design, we show that nitrate supplementation (KNO(3) capsules: 4 versus 12 mmol [n=6] or 24 mmol of KNO(3) (1488 mg of nitrate) versus 24 mmol of KCl [n=20]) or vegetable intake (250 mL of beetroot juice [5.5 mmol nitrate] versus 250 mL of water [n=9]) causes dose-dependent elevation in plasma nitrite concentration and elevation of cGMP concentration with a consequent decrease in blood pressure in healthy volunteers. In addition, post hoc analysis demonstrates a sex difference in sensitivity to nitrate supplementation dependent on resting baseline blood pressure and plasma nitrite concentration, whereby blood pressure is decreased in male volunteers, with higher baseline blood pressure and lower plasma nitrite concentration but not in female volunteers. Our findings demonstrate dose-dependent decreases in blood pressure and vasoprotection after inorganic nitrate ingestion in the form of either supplementation or by dietary elevation. In addition, our post hoc analyses intimate sex differences in nitrate processing involving the entero-salivary circulation that are likely to be major contributing factors to the lower blood pressures and the vasoprotective phenotype of premenopausal women.”

Nitrites are cardioprotective

The 2009 publication Myocardial protection by nitrite explains: “Nitrite has long been considered to be an inert oxidative metabolite of nitric oxide (NO). Recent work, however, has demonstrated that nitrite represents an important tissue storage form of NO that can be reduced to NO during ischaemic or hypoxic events. This exciting series of discoveries has created an entirely new field of research that involves the investigation of the molecular, biochemical, and physiological activities of nitrite under a variety of physiological and pathophysiological states. This has also led to a re-evaluation of the role that nitrite plays in health and disease. As a result there has been an interest in the use of nitrite as a therapeutic strategy for the treatment of acute myocardial infarction. Nitrite therapy has now been studied in several animal models and has proven to be an effective means to reduce myocardial ischaemia-reperfusion injury. This review article will provide a brief summary of the key findings that have led to the re-evaluation of nitrite and highlight the evidence supporting the cardioprotective actions of nitrite and also highlight the potential clinical application of nitrite therapy to cardiovascular diseases.”

The 2009 publication Emerging role of nitrite in myocardial protection relates “Nitrite has long been considered an inert oxidative metabolite of nitric oxide (NO). However, recent experimental findings strongly suggest that nitrite is a critical storage form of NO that is converted back into NO during ischemic or hypoxic events as well as under physiological conditions. Thus, the conversion of nitrite into NO during cellular stress may be an evolutionarily conserved and redundant means for NO generation at a time when endothelial nitric oxide synthase is non-functional. As a result of the recent revelation that the nitrite anion serves an important biological function a large number of studies have been performed to characterize both the physiological actions and therapeutic potential of nitrite under diverse conditions. While the earliest experiments characterized the vasodilatory effects of nitrite in both animal models and humans, more recent research efforts have focused on the potential benefits of nitrite in a number of pathological states. Nitrite therapy has now been studied in numerous animal models and has proven to be an effective means to ameliorate myocardial ischemia-reperfusion (I/R) injury. This review will focus on recent experimental findings related to the cytoprotective actions of nitrite therapy in the setting of myocardial I/R injury.”

Dietary nitrates make exercise more efficient

A very-recent (December 2010) report A toast to health and performance! Beetroot juice lowers blood pressure and the O2 cost of exercise relates “Dietary nitrate administered in the form of beetroot juice decreases resting systolic blood pressure (SBP) and O(2) consumption during walking and running. The effects of dietary nitrate are thought to be mediated via reduction to biologically active nitrite and nitric oxide (NO) molecules. Potential mechanisms for dietary nitrate effects on O(2) cost of exercise are improved matching of O(2) delivery and consumption of active motor units, increased efficiency of mitochondrial oxidative phosphorylation, and stoichiometry of calcium transport to ATP hydrolysis by the sarcoplasmic reticulum calcium-ATPase.”

The 2010 study Acute and chronic effects of dietary nitrate supplementation on blood pressure and the physiological responses to moderate-intensity and incremental exercise relates “Dietary nitrate (NO(3)(-)) supplementation with beetroot juice (BR) over 4-6 days has been shown to reduce the O(2) cost of submaximal exercise and to improve exercise tolerance. However, it is not known whether shorter (or longer) periods of supplementation have similar (or greater) effects. We therefore investigated the effects of acute and chronic NO(3)(-) supplementation on resting blood pressure (BP) and the physiological responses to moderate-intensity exercise and ramp incremental cycle exercise in eight healthy subjects. Following baseline tests, the subjects were assigned in a balanced crossover design to receive BR (0.5 l/day; 5.2 mmol of NO(3)(-)/day) and placebo (PL; 0.5 l/day low-calorie juice cordial) treatments. The exercise protocol (two moderate-intensity step tests followed by a ramp test) was repeated 2.5 h following first ingestion (0.5 liter) and after 5 and 15 days of BR and PL. Plasma nitrite concentration (baseline: 454 ± 81 nM) was significantly elevated (+39% at 2.5 h postingestion; +25% at 5 days; +46% at 15 days; P < 0.05) and systolic and diastolic BP (baseline: 127 ± 6 and 72 ± 5 mmHg, respectively) were reduced by ∼4% throughout the BR supplementation period (P < 0.05). Compared with PL, the steady-state Vo(2) during moderate exercise was reduced by ∼4% after 2.5 h and remained similarly reduced after 5 and 15 days of BR (P < 0.05). The ramp test peak power and the work rate at the gas exchange threshold (baseline: 322 ± 67 W and 89 ± 15 W, respectively) were elevated after 15 days of BR (331 ± 68 W and 105 ± 28 W; P < 0.05) but not PL (323 ± 68 W and 84 ± 18 W). These results indicate that dietary NO(3)(-) supplementation acutely reduces BP and the O(2) cost of submaximal exercise and that these effects are maintained for at least 15 days if supplementation is continued.” 

The 2009 publication Dietary nitrate supplementation reduces the O2 cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans reports “Pharmacological sodium nitrate supplementation has been reported to reduce the O2 cost of submaximal exercise in humans. In this study, we hypothesized that dietary supplementation with inorganic nitrate in the form of beetroot juice (BR) would reduce the O2 cost of submaximal exercise and enhance the tolerance to high-intensity exercise. In a double-blind, placebo (PL)-controlled, crossover study, eight men (aged 19-38 yr) consumed 500 ml/day of either BR (containing 11.2 +/- 0.6 mM of nitrate) or blackcurrant cordial (as a PL, with negligible nitrate content) for 6 consecutive days and completed a series of “step” moderate-intensity and severe-intensity exercise tests on the last 3 days. On days 4-6, plasma nitrite concentration was significantly greater following dietary nitrate supplementation compared with PL (BR: 273 +/- 44 vs. PL: 140 +/- 50 nM; P < 0.05), and systolic blood pressure was significantly reduced (BR: 124 +/- 2 vs. PL: 132 +/- 5 mmHg; P < 0.01). During moderate exercise, nitrate supplementation reduced muscle fractional O2 extraction (as estimated using near-infrared spectroscopy). The gain of the increase in pulmonary O2 uptake following the onset of moderate exercise was reduced by 19% in the BR condition (BR: 8.6 +/- 0.7 vs. PL: 10.8 +/- 1.6 ml.min(-1).W(-1); P < 0.05). During severe exercise, the O2 uptake slow component was reduced (BR: 0.57 +/- 0.20 vs. PL: 0.74 +/- 0.24 l/min; P < 0.05), and the time-to-exhaustion was extended (BR: 675 +/- 203 vs. PL: 583 +/- 145 s; P < 0.05). The reduced O2 cost of exercise following increased dietary nitrate intake has important implications for our understanding of the factors that regulate mitochondrial respiration and muscle contractile energetics in humans.”

The November 2010 publication Dietary nitrate supplementation reduces the O2 cost of walking and running: a placebo-controlled study reports “Dietary supplementation with beetroot juice (BR) has been shown to reduce resting blood pressure and the O(2) cost of sub-maximal exercise and to increase the tolerance to high-intensity cycling. We tested the hypothesis that the physiological effects of BR were consequent to its high nitrate content, per se, and not to the presence of other potentially bioactive compounds. We investigated changes in blood pressure, mitochondrial oxidative capacity (Q(max)), and the physiological responses to walking, moderate-intensity running and severe-intensity running following dietary supplementation with BR and nitrate-depleted beetroot juice (PL). Following control (non-supplemented) tests, nine healthy, physically-active male subjects were assigned in a randomized, double-blind, cross-over design to receive BR (0.5 L(.)d(-1); containing ~6.2 mmol of nitrate) and PL (0.5 L(.)d(-1); containing ~0.003 mmol of nitrate) for six days. Subjects completed treadmill exercise tests on days four and five, and knee-extension exercise tests for the estimation of Q(max) (using (31)P-MRS) on day six of the supplementation periods. Relative to PL, BR elevated plasma [nitrite] (PL: 183±119 vs. BR: 373±211 nM, P<0.05) and reduced systolic blood pressure (PL: 129±9 vs. BR: 124±10 mmHg; P<0.01). Q(max) was not different between PL and BR (PL: 0.93±0.05 vs. BR: 1.05±0.22 mM(.)s(-1)). The O(2) cost of walking (PL: 0.87±0.12 vs. BR: 0.70±0.10 L(.)min(-1); P<0.01), moderate-intensity running (PL: 2.26±0.27 vs. BR: 2.10±0.28 L(.)min(-1); P<0.01), and severe-intensity running (End-exercise V(O2); PL: 3.77±0.57 vs. BR: 3.50±0.62 L(.)min(-1); P<0.01) was reduced by BR, and time-to-exhaustion during severe-intensity running was increased by 15% (PL: 7.6±1.5 vs. BR: 8.7±1.8 min; P<0.01). In contrast, relative to control, nitrate-depleted beetroot juice did not alter plasma [nitrite], blood pressure or the physiological responses to exercise. These results indicate that the positive effects of 6 days of BR supplementation on the physiological responses to exercise can be ascribed to the high nitrate content per se.”

Perhaps the vasoprotective effects of eating certain vegetables is due to nitrates/nitrites and the production of NO.   

This theory is put forward in the 2008 publication  Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite (2008).   “Diets rich in fruits and vegetables reduce blood pressure (BP) and the risk of adverse cardiovascular events. However, the mechanisms of this effect have not been elucidated. Certain vegetables possess a high nitrate content, and we hypothesized that this might represent a source of vasoprotective nitric oxide via bioactivation. In healthy volunteers, approximately 3 hours after ingestion of a dietary nitrate load (beetroot juice 500 mL), BP was substantially reduced (Delta(max) -10.4/8 mm Hg); an effect that correlated with peak increases in plasma nitrite concentration. The dietary nitrate load also prevented endothelial dysfunction induced by an acute ischemic insult in the human forearm and significantly attenuated ex vivo platelet aggregation in response to collagen and ADP. Interruption of the enterosalivary conversion of nitrate to nitrite (facilitated by bacterial anaerobes situated on the surface of the tongue) prevented the rise in plasma nitrite, blocked the decrease in BP, and abolished the inhibitory effects on platelet aggregation, confirming that these vasoprotective effects were attributable to the activity of nitrite converted from the ingested nitrate. These findings suggest that dietary nitrate underlies the beneficial effects of a vegetable-rich diet and highlights the potential of a “natural” low cost approach for the treatment of cardiovascular disease.”By now, you should be getting the picture that nitrates and nitrites and substances that contain these like beetroot juice are definitely beneficial – the opposite message of that conveyed in the previous blog entry. 

Beetroot juice could possibly be useful in the treatment of obesity

The 2009 study In vitro effects of beetroot juice and chips on oxidative metabolism and apoptosis in neutrophils from obese individuals  relates “Oxidative stress and inflammation are involved in the development of obesity. Beetroot (Beta vulgaris var. rubra) is a food ingredient containing betalain pigments that show antioxidant activity. The in vitro effect of beetroot juice and chips on oxidative metabolism and apoptosis in neutrophils from obese individuals has been investigated. Fifteen obese women (aged 45 +/- 9 years, BMI >30 kg/m2) and nine healthy controls (women, aged 29 +/- 11 years, BMI = 22.2 +/- 1.6 kg/m2) were examined. –. Neutrophils from obese individuals had a significantly higher ROS production compared with the controls (p < 0.05). Beetroot products inhibited neutrophil oxidative metabolism in a concentration-dependent manner. Also observed were the pro-apoptotic effects of beetroot at a concentration range of 0.1-10% in 24 h culture of stimulated neutrophils. These natural products (in both the liquid and solid state) have antioxidant and antiinflammatory capacity, and could be an important adjunct in the treatment of obesity.”

Nitrites play a role in hypoxic signaling

 One if the alternative theories of aging described in my treatise is Declining hypoxic response.  I speculate there that keeping the hypoxic response turned on can possibly contribute to longevity. 

The 2009 paper Nitrite as regulator of hypoxic signaling in mammalian physiology relates: “In this review we consider the effects of endogenous and pharmacological levels of nitrite under conditions of hypoxia. In humans, the nitrite anion has long been considered as metastable intermediate in the oxidation of nitric oxide radicals to the stable metabolite nitrate. This oxidation cascade was thought to be irreversible under physiological conditions. However, a growing body of experimental observations attests that the presence of endogenous nitrite regulates a number of signaling events along the physiological and pathophysiological oxygen gradient. Hypoxic signaling events include vasodilation, modulation of mitochondrial respiration, and cytoprotection following ischemic insult. These phenomena are attributed to the reduction of nitrite anions to nitric oxide if local oxygen levels in tissues decrease. Recent research identified a growing list of enzymatic and nonenzymatic pathways for this endogenous reduction of nitrite. Additional direct signaling events not involving free nitric oxide are proposed. We here discuss the mechanisms and properties of these various pathways and the role played by the local concentration of free oxygen in the affected tissue.”

I note that VIAGRA® (sildenafil citrate), CIALIS® (tadalafil) and other drugs for erectile dysfunction work through release of nitric oxide (NO) from nerve terminals and endothelial cells and consequent dilation of arteries and increase of blood flow.  These drugs appear to be useful for treating a number of other conditions where enhancing circulation is important, for example relieving pulmonary arterial hypertension and symptoms of scleroderma. While not nitrates or nitrites in themselves, their circulatory functions appear to be quite similar.  In fact, some blogs have suggested that beetroot juice might be an alternative to VIAGRA or CIALIS, though i have seen no research to that effect. 

There is an explosion of research in the areas of nitrites-based signaling, physiology and medical applications.  Some of the many additional relevant publications are:

Nitrite as a physiological source of nitric oxide and a signalling molecule in the regulation of the cardiovascular system in both mammalian and non-mammalian vertebrates, The emerging role of nitrite as an endogenous modulator and therapeutic agent of cardiovascular function,The role of nitrite in nitric oxide homeostasis: a comparative perspective, Protective effect of red beetroot against carbon tetrachloride- and N-nitrosodiethylamine-induced oxidative stress in rats, Clinical translation of nitrite therapy for cardiovascular diseases, Mechanisms of nitrite reduction to nitric oxide in the heart and vessel wall, A mammalian functional nitrate reductase that regulates nitrite and nitric oxide homeostasis, Nitrite as a vascular endocrine nitric oxide reservoir that contributes to hypoxic signaling, cytoprotection, and vasodilation, Nitrite in nitric oxide biology: cause or consequence?, A systems-based review, Nitrite modulates contractility of teleost (Anguilla anguilla and Chionodraco hamatus, i.e. the Antarctic hemoglobinless icefish) and frog (Rana esculenta) hearts, Beta-adrenergic receptors and nitric oxide generation in the cardiovascular system, .

, Role of the anion nitrite in ischemia-reperfusion cytoprotection and therapeutics, ,Nitrite exerts potent negative inotropy in the isolated heart via eNOS-independent nitric oxide generation and cGMP-PKG pathway activation, Nitrite reductase activity of cytochrome c, Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues,  Dietary nitrite restores NO homeostasis and is cardioprotective in endothelial nitric oxide synthase-deficient mice,  and Nitrite-dependent vasodilation is facilitated by hypoxia and is independent of known NO-generating nitrite reductase activities.

My take on dietary nitrates and nitrites

Reviewing the research described in this blog entry and in the previous blog entry, I frankly am unable at this time to come down on one side or the other on the question of health benefits of ingesting nitrates/nitrites or supplements containing them like beetroot juice.  The arguments on both sides of the ledger seem compelling.  Hopefully it has been valuable to readers to review both sides of the issue.  I can make a few comments, however.

1.     The cell-level and body-level research relating to the beneficial effects of nitrates/nitrites and NO is generally newer and there seems to be much more of it at the moment than corresponding research on the negative effects. Yet, publications on both sides of the good/bad ledger are continuing to appear.

2.     Some of the arguments relating to the negative health effects of nitrates and nitrites seems to be circumstantial, e.g., incidences of diabetes increasing concurrently with drinking water nitrites levels.  Other arguments seem to be well-founded.  E.g. under certain circumstances nitrites are converted to nitrosamines, and these are definitely carcinogenic. 

3.     Some of the “bad for you” research reports are based on very large multi-year population studies involving hundreds or thousands of people, while the “good for you” studies are typically based on theoretical knowledge and experimental studies with relatively small numbers of subjects.

4.     The two categories of studies tend to measure very different things and could possibly be both essentially valid.  E.g. it could be the case that consuming beetroot juice could improve circulation, exercise, cardiovascular and cognitive performance and at the same time increase susceptibility to cancers and neurodegenerative diseases and accelerate biomarkers of aging.   The situation could be similar to that of taking HGH shots where there may be immediate improvements in body morphology and exercise capability but the long-term effects are likely to be life-shortening(ref).   

5.     The “good for you” and the “bad for you” researchers seem to be pursuing different agendas and largely ignore each other’s work. 

6.     Some of the “good for you” researchers point out that the levels of consumption of nitrates and nitrites or even beetroot juice associated with eating plenty of vegetables is too small to be concerned with negative health effects.

7.     The “good for you” researchers have focused on nitrate/nitrite-inducing supplements like beetroot juice and, insofar as I have seen, have avoided talking about processed meat which contains nitrites.  They have also avoided discussing nitrosamines.

I am waiting to see how this seeming-conflict in an important area of health and aging plays out.  Particularly I am awaiting more studies of relating NO levels to the hypoxic and other longevity-related gene-activation pathways.  Meanwhile I intend to consume generous amounts of vegetables but for now I am holding off on the beetroot juice as a regular supplement.