Abstract

Continual nitric oxide (NO) synthesis is important in the regulation of vascular tone and thus blood pressure. Whereas classically NO is provided by the enzymatic oxidation of l-arginine via endothelial NO synthase, it is now clear that NO can also be generated in mammals from the reduction of nitrite and nitrate. Thus inorganic nitrate derived either from NO oxidation or from dietary sources may be an important storage form of reactive nitrogen oxides which can be reduced back to nitrite and NO when physiologically required or in pathological conditions. The very short half-life of NO and the ready availability of stored nitrite and nitrate make for a very sensitive and responsive blood pressure control system. This review will examine processes by which these storage forms are produced and how augmentation of dietary nitrate intake may have a beneficial effect on blood pressure and other vascular function in humans.

Introduction

Soon after the discovery of the l-arginine/nitric oxide (NO) pathway in 1987, it became clear that continual endothelial NO synthesis is important in controlling vascular tone and hence blood pressure in humans.1,2 Vallance et al.3 showed that infusion of l-N monomethyl arginine (LNMMA), an inhibitor of nitric oxide synthase (NOS), when infused into the human forearm causes a doubling of forearm vascular resistance. The surprising but clear conclusion4 from this study was that NO is continually being synthesized and released from arterial vascular endothelium, as LNMMA has no intrinsic vasoconstrictor activity. It was clear, however, that NO itself is short-lived, as it is rapidly oxidized to nitrite in aqueous solutions,4 and directly oxidized to nitrate in the presence of superoxide or oxyhaemoglobin. We now know that inorganic nitrate synthesis in humans (first proved by Mitchell in 1916)5 results (probably entirely) from NO oxidation and may be an important storage form of reactive nitrogen oxides, which can be reduced back to nitrite and then NO under certain physiological and pathological conditions. Importantly, this endogenous source of inorganic nitrate is supplemented in varying amounts by dietary intake of inorganic nitrate.

Nitrate/nitrite/NO cycling in humans

Under normal physiological conditions, nitrite, along with NO and nitrate, is part of a complex biological cycle in mammals. There are several pathways thought to be involved in the modulation of the cycling of nitrate, nitrite, and NO. These include oxidation or reduction by bacteria,6–8 haemoglobin and other heme proteins,9–13 xanthine oxidoreductase (XOR),14–18 NOS,19,20 hypoxia,9,21 acid catalysed,22–25 and indeed UV radiation.26 The relative contributions of each will vary considerably from the normal physiological state through times of severe cellular stress.

Dietary sources of nitrate

In the typical western diet, an individual will consume 1–2 mmols of nitrate per day27,28 which will rapidly and completely be absorbed in the upper gastrointestinal tract;29,30 60% of ingested nitrate is excreted in the urine within 48 h,31 with the fate of the remainder as yet unknown. The half-life of an oral dose of inorganic nitrate is surprisingly long, estimates ranging between 5 and 8 h.24,31 This is mainly because, although it readily passes through the glomerulus into the renal tubule, it is mostly reabsorbed by the proximal renal tubules. The urinary clearance of nitrate is only about 26 mL/min,31 consistent with the observation that the fractional reabsorption of nitrate by renal tubules is about 90% in dogs,32 by a transport mechanism which has not yet been characterized (Figure 1).

Figure 1

Simplified representation of the entero-salivary circulation of nitrate. Nitrate (represented by the blue arrows) derived from the diet is swallowed. It is rapidly and completely absorbed in the upper gastrointestinal tract. Approximately 25% is concentrated in the salivary glands and secreted into the mouth. Here it is reduced to nitrite (represented by the red arrows) by facultative anaerobes on the dorsum of the tongue and swallowed. Some of the nitrite undergoes acidic reduction to NO in the stomach, with the remainder being absorbed. The fate of nitrite is discussed in depth later. Sixty per cent of ingested nitrate is lost in the urine within 48 h.

Figure 1

Simplified representation of the entero-salivary circulation of nitrate. Nitrate (represented by the blue arrows) derived from the diet is swallowed. It is rapidly and completely absorbed in the upper gastrointestinal tract. Approximately 25% is concentrated in the salivary glands and secreted into the mouth. Here it is reduced to nitrite (represented by the red arrows) by facultative anaerobes on the dorsum of the tongue and swallowed. Some of the nitrite undergoes acidic reduction to NO in the stomach, with the remainder being absorbed. The fate of nitrite is discussed in depth later. Sixty per cent of ingested nitrate is lost in the urine within 48 h.

Endogenous production of nitrate

NO from the classical l-arginine NOS pathway is rapidly oxidized to nitrate in the presence of oxyhaemoglobin, which yields approximately 1 mmol nitrate per day.33,34 A by-product of this is methaemoglobin. In this oxidized state, haemoglobin is unable to bind oxygen and requires reduction back to functional haemoglobin by methaemoglobin reductase in order to function again.

graphic

Entero-salivary circulation of nitrate

Between ingestion or endogenous production and ultimate excretion, circulating nitrate, from whichever source, undergoes complex biological processing in the nitrate/nitrite/NO cycle. From circulating plasma, it is concentrated in the salivary glands and subsequently secreted into the mouth. Approximately 25% of circulating plasma nitrate will be taken up by the salivary glands so that salivary nitrate concentration is at least 10 times that of plasma. On the dorsum of the tongue facultative anaerobes, especially Vionella spp, which can use nitrate instead of oxygen as an alternative electron acceptor, reduce nitrate to nitrite.7 The resulting salivary nitrite concentration is more than 1000 times greater than that of plasma in the resting state.35 This nitrite is then swallowed. In the acidic conditions of the stomach, there is good evidence that nitrite can be reduced to NO, a reaction that occurs spontaneously in acid solutions.24 This intragastric NO production appears to play an important role in regulating gastric blood flow and mucus production36–38 as well as host defence against enteric pathogens.22,39

graphic

Evidence that some of the nitrite formed in the mouth is also absorbed into the circulation is provided by studies which show an increase in blood nitrite concentration following oral nitrate loading35,40 (Figure 2).

Figure 2

The effect of oral inorganic nitrate (from beetroot juice, administered at time 0) on plasma nitrite. Peak plasma nitrite concentrations occur 3 h following ingestion of nitrate.40

Figure 2

The effect of oral inorganic nitrate (from beetroot juice, administered at time 0) on plasma nitrite. Peak plasma nitrite concentrations occur 3 h following ingestion of nitrate.40

In addition to this pathway for nitrate reduction by tongue anaerobes, Bernheim and Dixon41 had demonstrated in 1928 that both rat muscle and ox liver could reduce nitrate to nitrite. In liver, this was thought in part due to XOR. This capability of mammals was largely overlooked until Lundberg and Weitzberg's group recently provided evidence for a functional mammalian nitrate reductase enzyme demonstrating elevated levels of nitrite following nitrate administration in germ-free and NOS knockout mice.42 The increased nitrite levels were associated with a significant fall in mean arterial pressure (MAP). The rise in nitrite observed was attenuated by allopurinol, suggesting a role for XOR (having excluded NOS and bacteria as potential sources).

The fate of nitrite

A dose of nitrite administered to experimental animals rapidly disappears. A study in which nitrite was administered to rabbits showed a rapid reduction in plasma concentration from nearly 3000 nm to <1000 nm in <5 min, interpreted as a redistribution phase, but then a slower elimination phase with a half-life of 34 min.43 Kelm44 has shown that in humans the metabolism seems to be more linear with a half-life of 110 s. It was previously thought that reaction with oxyhaemoglobin resulted exclusively in nitrate, but this complex reaction has recently been more carefully studied, and it seems that nitrite can also be further reduced to NO by reaction with haemoglobin,45 which may have physiological importance.46

In plasma, in vitro, nitrite also has a short half-life because it is oxidized to nitrate. It is not yet clear what enzymatic or chemical process is involved in this oxidation reaction. Kim and Lancaster47 demonstrated that the catalysis of the oxidation of nitrite to nitrate in rat hepatocytes and hepatocyte extracts involves a mechanism which uses tetrahydrobiopterin. This would represent a means by which a cell can terminate the reversible reaction between NO and nitrite, thus limiting their activity.

Bryan and Feelisch's group provided some of the most revealing insights into the pharmacology of nitrite,48,49 initially demonstrating that concentrations of nitrite were much higher in vascular tissue than in plasma. Intraperitoneal nitrite injection in rats resulted in rapid absorption from the abdominal cavity with widespread distribution, steady state being achieved after approximately 5 min. A dose–response relationship was evident for the S-nitrosation and heme nitrosylation in all (plasma, red blood cell, heart, liver, kidney, lung) apart from two (brain and aorta) tissues studied. Oxidation to nitrate occurred rather more slowly and indeed a significant increase in nitrate levels was only observed following the highest nitrite dose. In contrast the administration of nitrate intraperitoneally did not produce the S-nitrosation or heme nitrosylation in the time period studied. Interestingly, under the physiological conditions studied there was no detectable formation of NO suggesting nitrite may have a direct signalling effect independent of NO. This may be due to post-translational protein modification by protein nitrosation. It is also possible that nitrite itself exerts a direct blood pressure lowering effect.

XOR has previously been discussed as a potential nitrate reductase. However, it is more conventionally thought of as a nitrite reductase. In tissues and tissue extracts, nitrite generates much more NO than would be expected at acidic pH, suggesting the presence of a catalyst (Figure 3). Nitrite added to the perfusate in a Langendorff heart preparation results in the formation of gaseous NO which is increased following ischaemia.15 The enzymatic mechanism by which nitrite reduction to NO is enhanced is likely to vary in different tissues. There is good evidence that in the rodent heart XOR is involved. Its activity in red blood cells and vascular endothelial cells under normal physiological conditions appears to be minimal and probably does not contribute in any meaningful way to the regulation of resting vascular tone.20 However, with falling pH and hypoxia there appears to be an increase in the nitrite reductase activity of XOR which makes it more important in the setting of ischaemia–reperfusion injury.15–17,20,50

Figure 3

The addition of rat heart homogenate enhances the release of NO from acidified nitrite.15

Figure 3

The addition of rat heart homogenate enhances the release of NO from acidified nitrite.15

Effects of inorganic nitrate and nitrite on blood pressure

The vasodilatory properties of organic nitrates and nitrites have been known and put to therapeutic use since the latter part of the nineteenth century, with amyl nitrite being used in the treatment of angina,51 and later nitroglycerin which was used by Alfred Nobel. The vasodilatory effect was short-lived, thus organic nitrate and nitrite therapy was limited to ‘paroxysmal' conditions. Attention would turn to inorganic nitrite compounds in the search for a longer lasting effect.52,53 Reichert's52 paper On the Physiological Action of Potassium Nitrite reviewed the action of potassium nitrite in a host of biological systems in both human and animal models. One surprising finding was that the administration of potassium nitrite salts would cause a transient rise in blood pressure before a blood pressure lowering effect supervened. Attempts to ascertain which nitrite-containing moieties produced the best therapeutic profile while minimizing potential adverse events continued into the early part of last century.54 One agent that appeared to offer a more controlled, predictable, and sustained hypotensive effect was bismuth subnitrate, which Stieglitz noted required reduction by Bacillus coli to nitrous acid allowing slow release of nitrite ions.55,56 This deduction, that bacterial reduction was a required step before nitrate could have a hypotensive effect, had been made some years earlier following investigations into a series of episodes of methaemoglobinaemia in infants who had been administered bismuth subnitrate as a radiological contrast agent.6 While the period of the turn of the last century was marked by a surge in awareness of the potential for nitrite to produce vasodilatation, concerns about methaemoglobinaemia and later nitrite's role as a putative agent in the development in neoplasia57 reduced interest in the vasodilatory component of nitrites pharmacological action. It is perhaps only in the last 20 years or so that nitrite's key role in normal physiological control of blood pressure among other beneficial effects has attracted renewed attention.

Nitrite and blood pressure

Early investigations had suggested that supra-physiological levels of nitrite had no vasodilatory effect.58 Subsequently the administration of nitrite has been shown to produce vasodilatation in numerous physiologically distinct vascular beds including pulmonary,59–61 cerebral,62–64 and other vascular beds.9,40 The cerebral circulation is worthy of specific consideration when considering the vasodilatory properties and therapeutic potential of nitrite given its autoregulatory system which is key to maintaining cerebral perfusion within desired parameters despite fluctuations in systemic blood pressure. Rifkind and colleagues during a 10 min nitrite infusion showed a biphasic fall in MAP with a falling cerebrovascular resistance which approximately mirrors the fall in MAP.64 Cerebral blood flow, however, is unaffected by the first drop in MAP. Following the second fall in MAP, cerebral blood flow begins to increase. Other studies have shown prevention of vasospasm in a primate subarachnoid haemorrhage model63 or increases in cerebral blood flow in cerebral ischaemia62 following nitrite infusion without any effect on systemic blood pressure. These provide further evidence of nitrite's capacity to produce vasodilatation where vasoconstriction may otherwise supervene and cause harm.

In the pulmonary circulation, whether nebulized61 or administered intravenously59,60 sodium nitrite vasodilates the pulmonary circulation. This attenuated pulmonary hypertension whether induced by hypoxia or infusion of U46619. Interestingly, in Ingram et al.60 study, the pulmonary vasodilation produced by nitrite infusion in man persisted for up to an hour after the nitrite infusion ceased and plasma nitrite had returned to baseline levels.

Deoxyhaemoglobin can reduce nitrite to NO65 resulting in the arterial–venous gradient of plasma nitrite noted by Gladwin's et al.66 This reduction of nitrite, in concentrations found under normal physiological conditions, to NO by deoxyhaemoglobin results in vasodilatation and increased blood flow in the human forearm.9 Considering that metabolism of plasma nitrite increases with falling oxygen tension, Maher et al.21 postulated that this effect would be greatest in the venous circulation under resting conditions. They found that under normoxic conditions low-dose nitrite infusions produced venodilation with no apparent effect on the arterial circulation. As the nitrite dose increased, arterial dilation and an increase in forearm blood flow (FBF) became apparent. Under hypoxic conditions, there was little change to the degree of venodilation. In contrast FBF significantly increased. In the resting state, up to 70% of the circulating blood volume may be in the venous capacitance vessels. Thus, small changes in venous tone may have dramatic effects on systemic blood pressure by decreasing right atrial and ventricular end-diastolic pressure. Venous dilatation and concomitant arterial constriction following administration of nitrite has previously been observed in a study looking into the mechanism behind nitrite-induced circulatory collapse in 1937.67

A significant obstacle to nitrite's vasodilatory activity under aerobic conditions, such as would be expected in the arterial circulation under normal physiological conditions, is the very efficient NO scavenging effect of oxyhaemoglobin.68

Zweier's group showed nitrite reduction to NO and subsequent vasodilatation was mediated by sGC or other heme proteins in the vessel wall.12 Reduction of nitrite by effectors in the vessel wall is an attractive pathway for two reasons: first, this mechanism does not rely on the escape of NO from the red blood cell; and secondly, the concentration of nitrite in vascular tissue is far greater than in plasma.49 Indeed, plasma levels under normal physiological conditions are insufficient to produce arterial dilatation.

Cao and colleagues suggest that nitrite has an indirect effect in promoting vascular NO synthesis. They demonstrated that under hypoxic conditions nitrite promotes ATP synthesis and release by erythrocytes.69 The ATP released under these conditions stimulates endothelial nitric oxide synthase (eNOS) in the vessel wall to produce NO70 with vasodilatation. Nitroglycerin has been reported to have a similar but more modest effect on red blood cell ATP release.71

Interestingly, during Bryan and Feelish's pharmacokinetic study,48 a rise in blood pressure was observed when low doses of nitrite were administered. Other investigators have noted a similar rise in blood pressure when lower doses of nitrite are administered or at the start of an infusion.52,72 Vasoconstriction by sodium nitrite has also been demonstrated in an isolated dog liver model by Geumei et al.73 Bryan and Feelish suggest the rise in blood pressure they observed may represent a feedback mechanism whereby increasing concentrations of nitrite initially inhibit eNOS production of NO before a threshold is reached and a vasorelaxant effect supervenes.

Evidence that nitrate may be the important factor in high vegetable diet and blood pressure reduction

Decreased production of NO is evident in essential hypertension and other conditions associated with elevated blood pressure such as diabetes, hypercholesterolemia, and chronic kidney disease.33,74–78

A diet rich in fruit and vegetables has been shown to be effective in reducing blood pressure.79,80 In addition, it lowers the risk of morbidity and mortality from cardiovascular disease81–83 as diet exhibits such tremendous intra- and inter-individual variation, elucidating which components of such a diet are responsible for this effect is difficult. There is a growing weight of evidence from both human and animal studies that nitrate and nitrite derived from the diet can serve as a source for NO, particularly where it is deficient.84 Indeed, the greatest protective effect on cardiovascular disease is to be found in those diets with the greatest consumption of green leafy and cruciferous vegetables,82,83 which typically have high nitrate contents.85

Using an L-NAME-induced hypertensive rat model, Tsuchiya et al.86,87 demonstrated the ability of dietary nitrite-derived NO to attenuate the ensuing hypertension and ameliorate the renal injury in rats treated with L-NAME for 8 weeks.

Larsen et al.88 showed a significant fall in diastolic and mean arterial blood pressure associated with a rise in plasma nitrite following the administration of oral sodium nitrate to healthy volunteers. Webb et al.,40 using beetroot juice as a source of inorganic nitrate, showed a significant reduction in blood pressure with a maximum effect at 3 h with a strong inverse correlation with plasma nitrite levels. That reduction of nitrate by oral commensal bacteria to nitrite is required to procure a blood pressure lowering effect was demonstrated by the abolition of the rise in plasma nitrite and associated fall in blood pressure if no saliva was swallowed in the 3 h following an oral nitrate load. The administration of an antibacterial mouthwash has a similar effect.89,90 These effects lend strong support to the hypothesis that it is the nitrate content of a diet rich in fruit and vegetables which confers a significant proportion of the cardiovascular benefits of such a diet.80,91

Ahluwalia's group recently demonstrated comparable blood pressure lowering effects between nitrate doses whether administered with beetroot juice or KNO3 capsules.84 These effects were also not apparent when a KCl control was administered. Interestingly, they also demonstrated significant elevations in cGMP concentrations in association with elevated plasma nitrite. NO's effects are known to be mediated by the activation of cGMP.92 This finding provides further evidence to suggest nitrite's effects are mediated via conversion to NO.

Sunlight, nitrite, and blood pressure

The significant concentrations of nitrate in sweat from skin stores from which NO is generated following reduction by skin commensals to nitrite93 which are thought to play a role in host defence94 may have another purpose. A perhaps overlooked aspect of the regulation of blood pressure is the role of UVA radiation, which may partly explain seasonal variations in blood pressure noted by some investigators.95 The first suggestion this might be so is from in vitro work by Matsunaga and Furchgott96 who demonstrated light-mediated relaxation of rabbit aorta in the presence of inorganic nitrite. Oplander et al.26 showed that whole body UVA irradiation resulted in a maximum fall in MAP of 11.9±1.8% from baseline 15 min after UVA exposure with a residual effect up to 1h later. This was accompanied by significant increases in FBF and flow-mediated vasodilatation. Like the complex chemistry observed in the stomach, the reactions taking place in the dermis are complex with numerous potential intermediates and putative effectors. NO gas is liberated from the skin following UV irradiation. There were significant rises in plasma nitroso compound (RX-NO) species in plasma which highly correlated with the fall in blood pressure and a significant rise in plasma nitrite which did not. In addition, there was a significant increase in intracutaneous S-nitrosothiols. Previous work by Mowbray et al.97 suggests that nitrate is the likely storage form of NO in skin, with nitrite as the photo-reactive intermediate with concentrations of S-nitrosothiols being comparatively far lower and thought to be of less significance.

Risk/benefit of increasing nitrate intake to reduce blood pressure

Although nitrates and nitrites have been used medicinally and for curing meat for many centuries (reviewed in a recent paper by Butler and Feelisch98), acute toxic effects have only been encountered at very high doses. The toxicity reported has been principally methaemoglobinaemia, but only when several grams of nitrate salt are administered.99 It has been suggested that some early studies may have shown methaemoglobinaemia with lower doses of nitrate due to contamination with nitrite. Nitrite causes acute toxicity in much smaller doses. The LD 50 of inorganic nitrite in laboratory animals is about 2.6 mmol/kg. If extrapolated to man this equates to a dose of 12 g. In fact is likely to be lower at about 4 g100 with significant methaemoglobinaemia occurring with as little as 1 g (14 mmol).

While the benefits of a diet rich in vegetables, and therefore by extension rich in nitrate, in terms of effect on blood pressure and reduced cardiovascular risk appear clear at a population level, it is prudent to remember that any substance with a pharmacological effect will produce undesirable effects in some. Concern emerged in the 1970s as a result of Tannenbaum and Spiegelhalder's work on the potential of dietary nitrate to form N-nitrosamines.101,102

Both nitrous acid and dinitrogen trioxide which are formed from acidification of nitrite are well-known nitrosating agents.103 Nitrosation of secondary amines present in foodstuffs or drugs104 could lead to the formation of carcinogenic N-nitrosamines (see below) which are known, in animal studies, to predispose to gastric and liver cancers.105

graphic

It should be noted, however, that there are problems in extrapolating toxicology studies from these small laboratory animals to man. While generally true for most chemical entities, it is especially relevant in any discussion about potential health risks of nitrate. For example, rats do not appear to have the same mechanisms as humans to concentrate nitrate, iodide, and thiocyanate in salivary glands, a feature of nitrate metabolism in man which is key to any potential benefits or harms.106,107

It had been shown by Magee in 1956 that N-nitrosamines could cause hepatic tumours in rats by forming DNA adducts.108 Numerous studies since have attempted to find a positive correlation between nitrate intake or exposure and cancer. However, most are epidemiologically weak and inconclusive.109 Indeed in 2003, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) concluded: ‘Overall, the epidemiological studies showed no consistently increased risk for cancer with increasing consumption of nitrate. These data, combined with the results of the epidemiological studies considered by the Committee at its 44th meeting, do not provide evidence that nitrate is carcinogenic to humans'.110 Furthermore, it has been suggested that it would be surprising from an evolutionary point of view that nitrate would be recovered from glomerular filtrate and actively excreted into the mouth at high concentration if it were a toxic molecule.35

It remains possible that certain subgroups of the human population may be at increased risk of cancer if subject to high levels of dietary nitrate. Winter et al.'s111 paper elegantly demonstrated the formation of nitrosamines in an in vivo system in the human oesophagus. While the ability of a given nitrosamine to induce cancer has considerable inter-species and inter-tissue variation within a species, this is a potentially important finding. Human oesophageal cells can metabolize and activate nitrosamines via the cytochrome p450 enzyme pathway resulting in binding of these metabolites with DNA.112–114 Alcohol, the excessive consumption of which is known to be a risk factor for upper gastrointestinal cancer, inhibits first pass metabolism of nitrosamines by the liver resulting in increased exposure of extra-hepatic organs.115 Thus, for individuals with gastro-oesophageal reflux, the generation of potential carcinogens within the oesophageal lumen in addition to increased circulating nitrosamines may put them at increased risk. It seems reasonable to postulate that those who have subsequently developed dysplasia will be at greater risk still.

Outwith these specific circumstances, nitrite and NO generated in the gastric lumen have a clear role in gastro-protection by increasing gastric blood flow and gastric mucous production.36–38 It also inhibits ulcer formation whether by NSAIDs or in association with H-pylori infection.116,117

Conclusion

Nitrate and nitrite play a key role in modulating blood pressure in both health and disease states. The vast array of surprisingly diverse mechanisms by which NO can be generated from nitrite serve to underline its vital role in regulating vascular tone. Its physiological handling appears to be designed to deliver NO to the point of greatest need with evidence that nitrite reduction increases with increasing hypoxia and falling pH—an effect perhaps most evident in certain disease states. In addition, evidence is emerging that nitrite may have a direct vasoactive effect independent of its role as a precursor for NO.

Conflict of interest: N.B. is a cofounder of Heartbeet Ltd, a non-profit making organization set up to promote the health benefits of dietary nitrate.

References

1
Ignarro
LJ
Byrns
RE
Buga
GM
Wood
KS
Endothelium-derived relaxing factor from pulmonary artery and vein possesses pharmacologic and chemical properties identical to those of nitric oxide radical
Circ Res
 , 
1987
, vol. 
61
 (pg. 
866
-
879
)
2
Palmer
RM
Ferrige
AG
Moncada
S
Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor
Nature
 , 
1987
, vol. 
327
 (pg. 
524
-
526
)
3
Vallance
P
Collier
J
Moncada
S
Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man
Lancet
 , 
1989
, vol. 
334
 (pg. 
997
-
1000
)
4
Ignarro
L
Endothelium-derived nitric oxide: actions and properties
FASEB J
 , 
1989
, vol. 
3
 (pg. 
31
-
36
)
5
Mitchell
HH
Shonle
HA
Grindley
HS
The origin of nitrates in urine
J Biol Chem
 , 
1916
, vol. 
24
 (pg. 
461
-
90
)
6
Böhme
A
Über Nitritvergiftung nach interner Darreichung von Bismuthum subnitricum
Naunyn Schmiedebergs Arch Pharmaco
 , 
1907
, vol. 
57
 (pg. 
441
-
454
)
7
Doel
JJ
Benjamin
N
Hector
MP
Rogers
M
Allaker
RP
Evaluation of bacterial nitrate reduction in the human oral cavity
Eur J Oral Sci
 , 
2005
, vol. 
113
 (pg. 
14
-
19
)
8
Lundberg
JO
Weitzberg
E
Cole
JA
Benjamin
N
Nitrate, bacteria and human health
Nat Rev Microbiol
 , 
2004
, vol. 
2
 (pg. 
593
-
602
[Erratum appears in Nat Rev Microbiol 2004;2:681]
9
Cosby
K
Partovi
KS
Crawford
JH
Patel
RP
Reiter
CD
Martyr
S
, et al.  . 
Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation
Nat Med
 , 
2003
, vol. 
9
 (pg. 
1498
-
1505
)
10
Huang
Z
Shiva
S
Kim-Shapiro
DB
Patel
RP
Ringwood
LA
Irby
CE
, et al.  . 
Enzymatic function of hemoglobin as a nitrite reductase that produces NO under allosteric control
J Clin Invest
 , 
2005
, vol. 
115
 (pg. 
2099
-
2107
)
11
Shiva
S
Huang
Z
Grubina
R
Sun
J
Ringwood
LA
MacArthur
PH
, et al.  . 
Deoxymyoglobin is a nitrite reductase that generates nitric oxide and regulates mitochondrial respiration
Circ Res
 , 
2007
, vol. 
100
 (pg. 
654
-
661
)
12
Alzawahra
WF
Talukder
MA
Liu
X
Samouilov
A
Zweier
JL
Alzawahra
WF
, et al.  . 
Heme proteins mediate the conversion of nitrite to nitric oxide in the vascular wall
Am J Physiol Heart Circ Physiol
 , 
2008
, vol. 
295
 (pg. 
H499
-
H508
)
13
Vitturi
DA
Teng
X
Toledo
JC
Matalon
S
Lancaster
JR
Jr
Patel
RP
Regulation of nitrite transport in red blood cells by hemoglobin oxygen fractional saturation
Am J Physiol Heart Circ Physiol
 , 
2009
, vol. 
296
 (pg. 
H1398
-
H1407
)
14
Zhang
Z
Naughton
DP
Blake
DR
Benjamin
N
Stevens
CR
Winyard
PG
, et al.  . 
Human xanthine oxidase converts nitrite ions into nitric oxide (NO)
Biochem Soc Trans
 , 
1997
, vol. 
25
 pg. 
524S
 
15
Webb
A
Bond
R
McLean
P
Uppal
R
Benjamin
N
Ahluwalia
A
Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage
Proc Natl Acad Sci USA
 , 
2004
, vol. 
101
 (pg. 
13683
-
13688
)
16
Lu
P
Liu
F
Yao
Z
Wang
C-Y
Chen
D-D
Tian
Y
, et al.  . 
Nitrite-derived nitric oxide by xanthine oxidoreductase protects the liver against ischemia-reperfusion injury
Hepatobiliary Pancreat Dis Int
 , 
2005
, vol. 
4
 (pg. 
350
-
355
)
17
Baker
JE
Su
J
Fu
X
Hsu
A
Gross
GJ
Tweddell
JS
, et al.  . 
Nitrite confers protection against myocardial infarction: role of xanthine oxidoreductase, NADPH oxidase and K(ATP) channels
J Mol Cell Cardiol
 , 
2007
, vol. 
43
 (pg. 
437
-
444
)
18
Golwala
NH
Hodenette
C
Murthy
SN
Nossaman
BD
Kadowitz
PJ
Vascular responses to nitrite are mediated by xanthine oxidoreductase and mitochondrial aldehyde dehydrogenase in the rat
Can J Physiol Pharmacol
 , 
2009
, vol. 
87
 (pg. 
1095
-
1101
)
19
Gautier
C
van Faassen
E
Mikula
I
Martasek
P
Slama-Schwok
A
Endothelial nitric oxide synthase reduces nitrite anions to NO under anoxia
Biochem Biophys Res Commun
 , 
2006
, vol. 
341
 (pg. 
816
-
821
)
20
Webb
AJ
Milsom
AB
Rathod
KS
Chu
WL
Qureshi
S
Lovell
MJ
, et al.  . 
Mechanisms underlying erythrocyte and endothelial nitrite reduction to nitric oxide in hypoxia: role for xanthine oxidoreductase and endothelial nitric oxide synthase
Circ Res
 , 
2008
, vol. 
103
 (pg. 
957
-
964
)
21
Maher
AR
Milsom
AB
Gunaruwan
P
Abozguia
K
Ahmed
I
Weaver
RA
, et al.  . 
Hypoxic modulation of exogenous nitrite-induced vasodilation in humans
Circulation
 , 
2008
, vol. 
117
 (pg. 
670
-
677
)
22
Benjamin
N
O'Driscoll
F
Dougall
H
Duncan
C
Smith
L
Golden
M
, et al.  . 
Stomach NO synthesis
Nature
 , 
1994
, vol. 
368
 pg. 
502
 
23
Duncan
C
Dougall
H
Johnston
P
Green
S
Brogan
R
Leifert
C
, et al.  . 
Chemical generation of nitric oxide in the mouth from the enterosalivary circulation of dietary nitrate
Nat Med
 , 
1995
, vol. 
1
 (pg. 
546
-
551
)
24
McKnight
GM
Smith
LM
Drummond
RS
Duncan
CW
Golden
M
Benjamin
N
Chemical synthesis of nitric oxide in the stomach from dietary nitrate in humans
Gut
 , 
1997
, vol. 
40
 (pg. 
211
-
214
)
25
Lundberg
JO
Weitzberg
E
Lundberg
JM
Alving
K
Intragastric nitric oxide production in humans: measurements in expelled air
Gut
 , 
1994
, vol. 
35
 (pg. 
1543
-
1546
)
26
Oplander
C
Volkmar
CM
Paunel-Gorgulu
A
van Faassen
EE
Heiss
C
Kelm
M
, et al.  . 
Whole body UVA irradiation lowers systemic blood pressure by release of nitric oxide from intracutaneous photolabile nitric oxide derivates
Circ Res
 , 
2009
, vol. 
105
 (pg. 
1031
-
1040
)
27
Bonnell
A
Nitrate concentrations in vegetables. Epidemiological studies in humans
Proceedings of the International Workshop on Health Aspects of Nitrate and its Metabolites (Particularly Nitrite)
 , 
1995
Strasbourg
European Commission
 
Reports of the Scientific Committee for Food
28
ECETOC
Nitrate and Drinking Water
 , 
1988
Brussels
European Chemical Industry Ecology and Toxicolgy Centre
29
Florin
TH
Neale
G
Cummings
JH
The effect of dietary nitrate on nitrate and nitrite excretion in man
Br J Nutr
 , 
1990
, vol. 
64
 (pg. 
387
-
397
)
30
van Velzen
AG
Sips
AJAM
Schothorst
RC
Lambers
AC
Meulenbelt
J
The oral bioavailability of nitrate from nitrate-rich vegetables in humans
Toxicol Lett
 , 
2008
, vol. 
181
 (pg. 
177
-
181
)
31
Wagner
DA
Schultz
DS
Deen
WM
Young
VR
Tannenbaum
SR
Metabolic fate of an oral dose of 15N-labeled nitrate in humans: effect of diet supplementation with ascorbic acid
Cancer Res
 , 
1983
, vol. 
43
 (pg. 
1921
-
1925
)
32
Godfrey
M
Majid
DS
Renal handling of circulating nitrates in anesthetized dogs
Am J Physiol
 , 
1998
, vol. 
275
 (pg. 
F68
-
F73
)
33
Forte
P
Copland
M
Smith
LM
Milne
E
Sutherland
J
Benjamin
N
Basal nitric oxide synthesis in essential hypertension
Lancet
 , 
1997
, vol. 
349
 (pg. 
837
-
842
)
34
Forte
P
Kneale
BJ
Milne
E
Chowienczyk
PJ
Johnston
A
Benjamin
N
, et al.  . 
Evidence for a difference in nitric oxide biosynthesis between healthy women and men
Hypertension
 , 
1998
, vol. 
32
 (pg. 
730
-
734
)
35
Lundberg
JO
Govoni
M
Inorganic nitrate is a possible source for systemic generation of nitric oxide
Free Radic Biol Med
 , 
2004
, vol. 
37
 (pg. 
395
-
400
)
36
Wallace
JL
Miller
MJ
Nitric oxide in mucosal defense: a little goes a long way
Gastroenterology
 , 
2000
, vol. 
119
 (pg. 
512
-
520
)
37
Bjorne
HH
Petersson
J
Phillipson
M
Weitzberg
E
Holm
L
Lundberg
JO
Nitrite in saliva increases gastric mucosal blood flow and mucus thickness
J Clin Invest
 , 
2004
, vol. 
113
 (pg. 
106
-
114
[erratum appears in J Clin Invest 2004 Feb;113:490]
38
Petersson
J
Phillipson
M
Jansson
EA
Patzak
A
Lundberg
JO
Holm
L
Dietary nitrate increases gastric mucosal blood flow and mucosal defense
Am J Physiol Gastrointest Liver Physiol
 , 
2007
, vol. 
292
 (pg. 
G718
-
G724
)
39
Dykhuizen
RS
Frazer
R
Duncan
C
Smith
CC
Golden
M
Benjamin
N
, et al.  . 
Antimicrobial effect of acidified nitrite on gut pathogens: importance of dietary nitrate in host defense
Antimicrob Agents Chemother
 , 
1996
, vol. 
40
 (pg. 
1422
-
1425
)
40
Webb
AJ
Patel
N
Loukogeorgakis
S
Okorie
M
Aboud
Z
Misra
S
, et al.  . 
Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite
Hypertension
 , 
2008
, vol. 
51
 (pg. 
784
-
790
)
41
Bernheim
F
Dixon
M
The reduction of nitrates in animal tissues
Biochem J
 , 
1928
, vol. 
22
 (pg. 
125
-
134
)
42
Jansson
EA
Huang
L
Malkey
R
Govoni
M
Nihlen
C
Olsson
A
, et al.  . 
A mammalian functional nitrate reductase that regulates nitrite and nitric oxide homeostasis
Nat Chem Biol
 , 
2008
, vol. 
4
 (pg. 
411
-
417
)
43
Ishibashi
T
Nishizawa
N
Nomura
M
Liu
S
Yang
M
Miwa
T
, et al.  . 
Arteriovenous differences in NO2- kinetics in anesthetized rabbits
Biol Pharm Bull
 , 
2009
, vol. 
32
 (pg. 
399
-
404
)
44
Kelm
M
Nitric oxide metabolism and breakdown
Biochim Biophys Acta
 , 
1999
, vol. 
1411
 (pg. 
273
-
289
)
45
Kim-Shapiro
DB
Gladwin
MT
Patel
RP
Hogg
N
The reaction between nitrite and hemoglobin: the role of nitrite in hemoglobin-mediated hypoxic vasodilation
J Inorg Biochem
 , 
2005
, vol. 
99
 (pg. 
237
-
246
)
46
Chen
K
Piknova
B
Pittman
RN
Schechter
AN
Popel
AS
Nitric oxide from nitrite reduction by hemoglobin in the plasma and erythrocytes
Nitric Oxide
 , 
2008
, vol. 
18
 (pg. 
47
-
60
)
47
Kim
Y-M
Lancaster
JR
Jr.
Tetrahydrobiopterin-dependent nitrite oxidation to nitrate in isolated rat hepatocytes
FEBS Lett
 , 
1993
, vol. 
332
 (pg. 
255
-
259
)
48
Bryan
NS
Fernandez
BO
Bauer
SM
Garcia-Saura
MF
Milsom
AB
Rassaf
T
, et al.  . 
Nitrite is a signaling molecule and regulator of gene expression in mammalian tissues
Nat Chem Biol
 , 
2005
, vol. 
1
 (pg. 
290
-
297
)
49
Rodriguez
J
Maloney
RE
Rassaf
T
Bryan
NS
Feelisch
M
Chemical nature of nitric oxide storage forms in rat vascular tissue
Proc Natl Acad Sci USA
 , 
2003
, vol. 
100
 (pg. 
336
-
341
)
50
Tripatara
P
Patel
NSA
Webb
A
Rathod
K
Lecomte
FMJ
Mazzon
E
, et al.  . 
Nitrite-derived nitric oxide protects the rat kidney against ischemia/reperfusion injury in vivo: role for xanthine oxidoreductase
J Am Soc Nephrol
 , 
2007
, vol. 
18
 (pg. 
570
-
580
)
51
Brunton
T
On the use of nitrite of amyl in angina pectoris
Lancet
 , 
1867
, vol. 
2
 (pg. 
97
-
98
)
52
Reichert
ET
On the physiological action of potassium nitrite
Am J Med Sci
 , 
1880
, vol. 
80
 (pg. 
158
-
180
)
53
Collier
W
A case of angina pectoris treated with nitrite of sodium: remarks
Lancet
 , 
1883
, vol. 
122
 pg. 
901
 
54
Wallace
GB
Ringer
AI
The lowering of blood pressure by the nitrite group
JAMA
 , 
1909
, vol. 
LIII
 (pg. 
1629
-
1630
)
55
Stieglitz
EJ
Bismuth subnitrate in the therapy of hypertension
J Pharmacol Exp Ther
 , 
1927
, vol. 
32
 (pg. 
23
-
35
)
56
Stieglitz
EJ
Bismuth subnitrate in the treatment of arterial hypertension
JAMA
 , 
1930
, vol. 
95
 (pg. 
842
-
846
)
57
Nitrites, nitrosamines, and cancer
Lancet
 , 
1968
, vol. 
291
 (pg. 
1071
-
1072
)
58
Lauer
T
Preik
M
Rassaf
T
Strauer
BE
Deussen
A
Feelisch
M
, et al.  . 
Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action
Proc Natl Acad Sci USA
 , 
2001
, vol. 
98
 (pg. 
12814
-
12819
)
59
Casey
DB
Badejo
AM
Jr
Dhaliwal
JS
Murthy
SN
Hyman
AL
Nossaman
BD
, et al.  . 
Pulmonary vasodilator responses to sodium nitrite are mediated by an allopurinol-sensitive mechanism in the rat
Am J Physiol Heart Circ Physiol
 , 
2009
, vol. 
296
 (pg. 
H524
-
H533
)
60
Ingram
TE
Pinder
AG
Bailey
DM
Fraser
AG
James
PE
Low-dose sodium nitrite vasodilates hypoxic human pulmonary vasculature by a means that is not dependent on a simultaneous elevation in plasma nitrite
Am J Physiol Heart Circ Physiol
 , 
2010
, vol. 
298
 (pg. 
H331
-
H339
)
61
Hunter
CJ
Dejam
A
Blood
AB
Shields
H
Kim-Shapiro
DB
Machado
RF
, et al.  . 
Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator
Nat Med
 , 
2004
, vol. 
10
 (pg. 
1122
-
1127
)
62
Jung
K-H
Chu
K
Ko
S-Y
Lee
S-T
Sinn
D-I
Park
D-K
, et al.  . 
Early intravenous infusion of sodium nitrite protects brain against in vivo ischemia-reperfusion injury
Stroke
 , 
2006
, vol. 
37
 (pg. 
2744
-
2750
)
63
Pluta
RM
Dejam
A
Grimes
G
Gladwin
MT
Oldfield
EH
Nitrite infusions to prevent delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage
JAMA
 , 
2005
, vol. 
293
 (pg. 
1477
-
1484
)
64
Rifkind
JM
Nagababu
E
Barbiro-Michaely
E
Ramasamy
S
Pluta
RM
Mayevsky
A
, et al.  . 
Nitrite infusion increases cerebral blood flow and decreases mean arterial blood pressure in rats: a role for red cell NO
Nitric Oxide
 , 
2007
, vol. 
16
 (pg. 
448
-
456
)
65
Doyle
MP
Pickering
RA
DeWeert
TM
Hoekstra
JW
Pater
D
Kinetics and mechanism of the oxidation of human deoxyhemoglobin by nitrites
J Biol Chem
 , 
1981
, vol. 
256
 (pg. 
12393
-
12398
)
66
Gladwin
MT
Shelhamer
JH
Schechter
AN
Pease-Fye
ME
Waclawiw
MA
Panza
JA
, et al.  . 
Role of circulating nitrite and S-nitrosohemoglobin in the regulation of regional blood flow in humans
Proc Natl Acad Sci USA
 , 
2000
, vol. 
97
 (pg. 
11482
-
11487
)
67
Wilkins
RW
Haynes
FW
Weiss
S
The role of the venous system in circulatory collapse induced by sodium nitrite
J Clin Invest
 , 
1937
, vol. 
16
 (pg. 
85
-
91
)
68
Joshi
MS
Ferguson
TB
Jr
Han
TH
Hyduke
DR
Liao
JC
Rassaf
T
, et al.  . 
Nitric oxide is consumed, rather than conserved, by reaction with oxyhemoglobin under physiological conditions
Proc Natl Acad Sci USA
 , 
2002
, vol. 
99
 (pg. 
10341
-
10346
)
69
Cao
Z
Bell
JB
Mohanty
JG
Nagababu
E
Rifkind
JM
Nitrite enhances RBC hypoxic ATP synthesis and the release of ATP into the vasculature: a new mechanism for nitrite-induced vasodilation
Am J Physiol Heart Circ Physiol
 , 
2009
, vol. 
297
 (pg. 
H1494
-
H503
)
70
Bogle
RG
Coade
SB
Moncada
S
Pearson
JD
Mann
GE
Bradykinin and ATP stimulate l-arginine uptake and nitric oxide release in vascular endothelial cells
Biochem Biophys Res Commun
 , 
1991
, vol. 
180
 (pg. 
926
-
932
)
71
Garcia
JI
Seabra
AB
Kennedy
R
English
AM
Nitrite and nitroglycerin induce rapid release of the vasodilator ATP from erythrocytes: relevance to the chemical physiology of local vasodilation
J Inorg Biochem
 , 
2010
, vol. 
104
 (pg. 
289
-
296
)
72
Ingram
TE
Pinder
AG
Bailey
DM
Fraser
AG
James
PE
Low-dose sodium nitrite vasodilates hypoxic human pulmonary vasculature by a means that is not dependent on a simultaneous elevation in plasma nitrite
Am J Physiol Heart Circ Physiol
 , 
2010
, vol. 
298
 (pg. 
H331
-
H339
)
73
Geumei
A
Issa
I
Mahfouz
M
Intra-hepatic vascular response to sodium nitrite
Br J Pharmacol
 , 
1969
, vol. 
35
 (pg. 
456
-
459
)
74
Schmidt
RJ
Baylis
C
Total nitric oxide production is low in patients with chronic renal disease
Kidney Int
 , 
2000
, vol. 
58
 (pg. 
1261
-
1266
)
75
Blum
M
Yachnin
T
Wollman
Y
Chernihovsky
T
Peer
G
Grosskopf
I
, et al.  . 
Low nitric oxide production in patients with chronic renal failure
Nephron
 , 
1998
, vol. 
79
 (pg. 
265
-
268
)
76
Scherrer
U
Sartori
C
Defective nitric oxide synthesis: a link between metabolic insulin resistance, sympathetic overactivity and cardiovascular morbidity
Eur J Endocrinol
 , 
2000
, vol. 
142
 (pg. 
315
-
323
)
77
Shiode
N
Nakayama
K
Morishima
N
Yamagata
T
Matsuura
H
Kajiyama
G
Nitric oxide production by coronary conductance and resistance vessels in hypercholesterolemia patients
Am Heart J
 , 
1996
, vol. 
131
 (pg. 
1051
-
1057
)
78
Lind
L
Lind
L
Lipids and endothelium-dependent vasodilation—a review
Lipids
 , 
2002
, vol. 
37
 (pg. 
1
-
15
)
79
Rouse
IL
Beilin
LJ
Armstrong
BK
Vandongen
R
Blood-pressure-lowering effect of a vegetarian diet: controlled trial in normotensive subjects
Lancet
 , 
1983
, vol. 
1
 (pg. 
5
-
10
)
80
Appel
LJ
Moore
TJ
Obarzanek
E
Vollmer
WM
Svetkey
LP
Sacks
FM
, et al.  . 
A clinical trial of the effects of dietary patterns on blood pressure
N Engl J Med
 , 
1997
, vol. 
336
 (pg. 
1117
-
1124
)
81
Bazzano
LA
He
J
Ogden
LG
Loria
CM
Vupputuri
S
Myers
L
, et al.  . 
Fruit and vegetable intake and risk of cardiovascular disease in US adults: the first National Health and Nutrition Examination Survey Epidemiologic Follow-up Study
Am J Clin Nutr
 , 
2002
, vol. 
76
 (pg. 
93
-
99
)
82
Joshipura
KJ
Hu
FB
Manson
JE
Stampfer
MJ
Rimm
EB
Speizer
FE
, et al.  . 
The effect of fruit and vegetable intake on risk for coronary heart disease
Ann Intern Med
 , 
2001
, vol. 
134
 (pg. 
1106
-
1114
)
83
Joshipura
KJ
Ascherio
A
Manson
JE
Stampfer
MJ
Rimm
EB
Speizer
FE
, et al.  . 
Fruit and vegetable intake in relation to risk of ischemic stroke
JAMA
 , 
1999
, vol. 
282
 (pg. 
1233
-
1239
)
84
Kapil
V
Milsom
AB
Okorie
M
Maleki-Toyserkani
S
Akram
F
Rehman
F
, et al.  . 
Inorganic nitrate supplementation lowers blood pressure in humans: role for nitrite-derived NO
Hypertension
 , 
2010
, vol. 
56
 (pg. 
274
-
281
)
85
Nitrate in Vegetables
1998
UK
Ministry of Agriculture Food and Fisheries
86
Tsuchiya
K
Kanematsu
Y
Yoshizumi
M
Ohnishi
H
Kirima
K
Izawa
Y
, et al.  . 
Nitrite is an alternative source of NO in vivo
Am J Physiol Heart Circ Physiol
 , 
2005
, vol. 
288
 (pg. 
H2163
-
H2170
)
87
Tsuchiya
K
Tomita
S
Ishizawa
K
Abe
S
Ikeda
Y
Kihira
Y
, et al.  . 
Dietary nitrite ameliorates renal injury in l-NAME-induced hypertensive rats
Nitric Oxide
 , 
2010
, vol. 
22
 (pg. 
98
-
103
)
88
Larsen
FJ
Ekblom
B
Sahlin
K
Lundberg
JO
Weitzberg
E
Effects of dietary nitrate on blood pressure in healthy volunteers
N Engl J Med
 , 
2006
, vol. 
355
 (pg. 
2792
-
2793
)
89
Govoni
M
Jansson
Weitzberg
E
Lundberg
JO
The increase in plasma nitrite after a dietary nitrate load is markedly attenuated by an antibacterial mouthwash
Nitric Oxide
 , 
2008
, vol. 
19
 (pg. 
333
-
337
)
90
Petersson
J
Carlström
M
Schreiber
O
Phillipson
M
Christoffersson
G
Jägare
A
, et al.  . 
Gastroprotective and blood pressure lowering effects of dietary nitrate are abolished by an antiseptic mouthwash
Free Radic Biol Med
 , 
2009
, vol. 
46
 (pg. 
1068
-
1075
)
91
Lundberg
JO
Feelisch
M
Bjorne
H
Jansson
EA
Weitzberg
E
Cardioprotective effects of vegetables: is nitrate the answer
Nitric Oxide
 , 
2006
, vol. 
15
 (pg. 
359
-
362
)
92
Hobbs
AJ
Soluble guanylate cyclase: the forgotten sibling
Trends Pharmacol Sci
 , 
1997
, vol. 
18
 (pg. 
484
-
491
)
93
Weller
R
Pattullo
S
Smith
L
Golden
M
Ormerod
A
Benjamin
N
Nitric oxide is generated on the skin surface by reduction of sweat nitrate
J Invest Dermatol
 , 
1996
, vol. 
107
 (pg. 
327
-
331
)
94
Weller
R
Price
RJ
Ormerod
AD
Benjamin
N
Leifert
C
Antimicrobial effect of acidified nitrite on dermatophyte fungi, Candida and bacterial skin pathogens
J Appl Microbiol
 , 
2001
, vol. 
90
 (pg. 
648
-
652
)
95
Minami
J
Kawano
Y
Ishimitsu
T
Yoshimi
H
Takishita
S
Seasonal variations in office, home and 24 h ambulatory blood pressure in patients with essential hypertension
J Hypertens
 , 
1996
, vol. 
14
 (pg. 
1421
-
1425
)
96
Matsunaga
K
Furchgott
RF
Interactions of light and sodium nitrite in producing relaxation of rabbit aorta
J Pharmacol Exp Ther
 , 
1989
, vol. 
248
 (pg. 
687
-
695
)
97
Mowbray
M
McLintock
S
Weerakoon
R
Lomatschinsky
N
Jones
S
Rossi
AG
, et al.  . 
Enzyme-independent NO stores in human skin: quantification and influence of UV radiation
J Invest Dermatol
 , 
2009
, vol. 
129
 (pg. 
834
-
842
)
98
Butler
AR
Feelisch
M
Therapeutic uses of inorganic nitrite and nitrate: from the past to the future
Circulation
 , 
2008
, vol. 
117
 (pg. 
2151
-
2159
)
99
Tarr
L
Transient methemoglobinemia due to ammonium nitrate
Arch Intern Med
 , 
1933
, vol. 
51
 (pg. 
38
-
44
)
100
Sofos
JN
Raharjo
S
Maga
JA
Tu
AT
Curing agents
Food Additive Toxicology
 , 
1995
New York: Taylor Francis
(pg. 
235
-
268
)
101
Spiegelhalder
B
Eisenbrand
G
Preussmann
R
Influence of dietary nitrate on nitrite content of human saliva: possible relevance to in vivo formation of N-nitroso compounds
Food Cosmet Toxicol
 , 
1976
, vol. 
14
 (pg. 
545
-
548
)
102
Tannenbaum
SR
Weisman
M
Fett
D
The effect of nitrate intake on nitrite formation in human saliva
Food Cosmet Toxicol
 , 
1976
, vol. 
14
 (pg. 
549
-
552
)
103
Williams
D.
Nitrosation Reactions and the Chemistry of Nitric Oxide
 , 
2004
Elsevier;
104
Deshpande
S
Toxicants resulting from food processing
Handbook of Food Toxicology
 , 
2002
New York: Marcel Decker
(pg. 
285
-
320
)
105
WHO. Some N-Nitroso Compounds. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, vol. 17. Zurich: World Health Organisation
1998
 
http://monographs.iarc.fr/ENG/Monographs/vol17/volume17.pdf (last accessed 13 May 2010)
106
Cohen
B
Myant
NB
Concentration of salivary iodide: a comparative study
J Physiol
 , 
1959
, vol. 
145
 (pg. 
595
-
610
)
107
Logothetopoulos
JH
Myant
NB
Concentration of radio-iodide and 35S-thiocyanate by the salivary glands
J Physiol
 , 
1956
, vol. 
134
 (pg. 
189
-
194
)
108
Magee
P
Barnes
J
The production of malignant primary hepatic tumours in the rat by feeding dimethylnitrosamine
Br J Cancer
 , 
1956
, vol. 
10
 (pg. 
114
-
122
)
109
Milkowski
A
Garg
HK
Coughlin
JR
Bryan
NS
Nutritional epidemiology in the context of nitric oxide biology: a risk-benefit evaluation for dietary nitrite and nitrate
Nitric Oxide
 , 
2010
, vol. 
22
 (pg. 
110
-
119
)
110
Speijers
G
van den Brandt
PA
Nitrate
Food Additives Series
 , 
2003
Geneva
Joint FAO/WHO Expert Committee on Food Additives
111
Winter
JW
Paterson
S
Scobie
G
Wirz
A
Preston
T
McColl
KEL
N-nitrosamine generation from ingested nitrate via nitric oxide in subjects with and without gastroesophageal reflux
Gastroenterology
 , 
2007
, vol. 
133
 (pg. 
164
-
174
)
112
Autrup
H
Stoner
GD
Metabolism of N-nitrosamines by cultured human and rat esophagus
Cancer Res
 , 
1982
, vol. 
42
 (pg. 
1307
-
1311
)
113
Godoy
W
Albano
RM
Moraes
EG
Pinho
PRA
Nunes
RA
Saito
EH
, et al.  . 
CYP2A6/2A7 and CYP2E1 expression in human oesophageal mucosa: regional and inter-individual variation in expression and relevance to nitrosamine metabolism
Carcinogenesis
 , 
2002
, vol. 
23
 (pg. 
611
-
616
)
114
Harris
CC
Autrup
H
Stoner
GD
Trump
BF
Hillman
E
Schafer
PW
, et al.  . 
Metabolism of benzo(a)pyrene, N-nitrosodimethylamine, and N-nitrosopyrrolidine and identification of the major carcinogen-DNA adducts formed in cultured human esophagus
Cancer Res
 , 
1979
, vol. 
39
 (pg. 
4401
-
4406
)
115
Swann
PF
The possible role of nitrosamines in the link between alcohol consumption and esophageal cancer in man
Toxicol Pathol
 , 
1984
, vol. 
12
 (pg. 
357
-
360
)
116
Dykhuizen
RS
Fraser
A
McKenzie
H
Golden
M
Leifert
C
Benjamin
N
Helicobacter pylori is killed by nitrite under acidic conditions
Gut
 , 
1998
, vol. 
42
 (pg. 
334
-
337
)
117
Jansson
EA
Petersson
J
Reinders
C
Sobko
T
Bjorne
H
Phillipson
M
, et al.  . 
Protection from nonsteroidal anti-inflammatory drug (NSAID)-induced gastric ulcers by dietary nitrate
Free Radic Biol Med
 , 
2007
, vol. 
42
 (pg. 
510
-
518
)

Author notes

This article is part of the Review Focus on: Inorganic Nitrite and Nitrate in Cardiovascular Health and Disease