In this article I will cover the less well known, albeit highly significant, NO generating process, the nitrate-nitrite-NO pathway. This new NO producing pathway holds a lot of promise and supplements that target it will probably replace the current arginine based NO boosters in the near future[6, 7].
The nitrate-nitrite-NO pathway is especially interesting in that it not only has performance enhancing effects in healthy folks – as well as in people with risk factors – but also offers cardiovascular protection, regardless of baseline health status [7-10].
Nitric oxide production from the arginine-eNOS-NO pathway is dependent on the activity of the eNOS enzyme, which itself is controlled by other factors. In contrast to the arginine-eNOS-NO pathway, which forms the basis of current NO boosting supplements, nitrate-nitrite-NO pathway produces NO by a mechanism that does not involve the eNOS enzyme.
As indicated in figure 1, NO production via the nitrate-nitrite-NO pathway starts by conversion of nitrate to nitrite, which is carried out by bacteria in the oral cavity. Once nitrite is formed, several pathways exist (deoxygenated hemoglobin/myoglobin, xanthine oxidase, respiratory chain enzymes etc) which convert nitrite to NO [1, 2].
Figure 1: NO production via the nitrate-nitrite-NO pathway.
Many of the biochemical reactions that drive the nitrate-nitrite-NO pathway are greatly accelerated under hypoxic and acidic conditions, such as those occurring during high intensity exercise [3-5]. This is an important point because hypoxic conditions reduce the activity of the eNOS enzyme , which catalyzes the production of NO from L-aginine. The importance of the nitrate-nitrite-NO pathway has been underscored by the finding that nitrite supplementation restores NO supply and is cardio-protective in mice lacking the arginine-eNOS-NO pathway .
Thus, the nitrate-nitrite-NO pathway is complementing the better known arginine-eNOS-NO pathway for generation of NO when the arginine-eNOS-NO pathway isn’t running smoothly. And a growing number of studies are shown that the nitrate-nitrite-NO pathway appears to be far more effective in healthy people looking for a performance enhancing edge, than the arginine-eNOS-NO pathway.
Several studies have demonstrated that nitrate supplementation reduces the oxygen cost for a given exercise intensity [13-18]. This has practical implications because exercise economy affects tolerance to high-intensity exercise . Three recent studies confirm that nitrate supplementation increases tolerance to high-intensity exercise by enhancing muscle contractile efficiency and reducing metabolic perturbations in muscle [13, 16, 17]. Mechanistically, a central target for the effects of nitrate and its metabolites seems to be the mitochondrion .
In one study, healthy men were given 500 ml of a nitrate-rich beetroot juice providing 316 mg of nitrate, or placebo, 6 consecutive days. On the last 3 days they subjects completed low-intensity and high-intensity “step” exercise tests. On days 4-6, the nitrate-rich beetroot juice supplement resulted in a significant increase in blood nitrite levels that was more than double that seen with placebo. During low-intensity exercise, the nitrate-rich beetroot juice supplement attenuated the reduction in muscle phosphocreatine by 35% and reduced the exercise associated oxygen cost with 25%. During high-intensity exercise, time to exhaustion was 12 min 14 sec in the nitrate supplemented group, compared to 9 min 46 sec in placebo, which corresponds to a 25% increased performance. The total ATP turnover rate was significantly less for both low-intensity and high-intensity exercise in the nitrate supplemented group, compared to placebo. It was concluded that the reduced oxygen cost of exercise following nitrate-rich beetroot juice supplementation is due to a reduced ATP cost of muscle force production , and that the reduced muscle metabolic perturbation (as reflected in the extent of depletion of muscle phosphocreatine) allowed high-intensity exercise to be tolerated for a greater period of time .
Most studies also show that nitrate supplementation, when taken in amounts that sufficiently elevate blood nitrite levels, boosts performance in high-intensity exercise time trials [21-28]. More specifically, a study that investigated the effects of a single dose dietary nitrate supplementation on power output and performance during 2.5 and 10 mile cycling time trials . Club-level competitive male cyclists were assigned to consume 17 oz of beetroot juice (providing 384 mg nitrate) or 17 oz of nitrate-depleted beetroot juice as placebo, 2.5 h before the cycling trials. The results showed that the nitrate supplementation significantly increased power output during both the 2.5 and 10 mile cycling time trials, and improved 2.5 mile performance by 2.8% and 10 mile performance by 2.7%. The performance increase was attributed to an improved cycling economy, as demonstrated by a higher power output for the same oxygen consumption .
Another study tested whether 6 days of nitrate supplementation would improve competitive time-trial performance in trained cyclists, as it does after a single dose. Male cyclists ingested 140 ml/day of concentrated beetroot juice (496 mg nitrate per day) or a placebo (nitrate-depleted beetroot juice) for 6 d. After supplementation on day 6, subjects performed 60 min of submaximal cycling (2×30 min at 45% and 65% Wmax, respectively), followed by a 6.2 mile time trial. It was found that the nitrate supplementation lowered sub-maximal oxygen consumption, and increased time-trial performance with 12 seconds (1.2%) and power output by 2 % .
Intake of 200 mg baked beetroot (providing 500 mg nitrate) has been shown in healthy fit men and women to increase running speed by 5% during the last 1.1 miles (1.8 km) of a 3.1 mile (5 km) treadmill run, and also reduce ratings of perceived exertion during that same exercise segment . This finding supports the mechanistic theory that the nitrate-nitrite-NO pathway kicks in when that arginine-eNOS-NO pathway flakes out.
As of this writing, there are yet no long-term studies on the potential effects of nitrate supplementation in conjunction with resistance exercise training. But since the hypoxia and acidity stimulates the activity of the nitrate-nitrite-NO pathway, and knowing that nitrate supplementation improves muscle contractile efficiency, there are good reasons to believe that it may boost anaerobic muscle performance and enhance training outcomes related to muscle growth and strength.
It is especially exciting when performance enhancing supplements also confer health benefits. Nitrate, which is found in most vegetables and is particularly abundant in leafy greens and beetroot, has emerged as being one of the compounds that contribute to the cardiovascular and metabolic health benefits associated with high vegetable consumption [20, 29-38].
Nitrite, the conversion product of nitrate, is more abundant in meant (see below). While most studies on nitrite appear to show that its effects occur via generation of NO, there are also indications that nitrite itself may act as a signaling molecule and regulator of gene expression , and be an endocrine mediator of NO-based cellular signaling [40, 41]. Nitrite itself can also perform many actions that were previously attributed to NO .
The most notable and widely relevant cardiovascular protection seen with nitrate and nitrite intake is its well documented salutary impact on blood pressure and vascular function [2, 37, 43-48]. Elevated blood pressure is an established risk factor for coronary artery disease, stroke, kidney disease, all-cause mortality, and shortened life expectancy [49, 50]. Furthermore, the relation between blood pressure and health consequences is progressive throughout the non-hypertensive range . Given these considerations, and the high prevalence of both hypertension and pre-hypertension (30% and 66% respectively, pre-hypertension defined as 120-139/80-89) [52, 53], even a small decrease in blood pressure may have a significant health effect. It is notable that two thirds of the American population has pre-hypertension, and that over a third of those are undiagnosed . This is an important issue since hypertension causes premature aging of endothelial function and thereby accelerates development of age-related cardiovascular disease .
Thus, dietary modification and/or supplementation to increase nitrate and nitrite intake in order to ramp up the nitrate-nitrite-NO pathway hold tremendous benefit for the vast majority of people, of all ages (more on that below). In addition, dietary nitrite and nitrate have been shown to reduce inflammation, restore endothelial function, lower C-reactive protein levels, and protect from heart attack, stroke and type-2 diabetes [20, 55, 56]. Nitrate intake, in a dose that corresponds to a large intake of vegetables, has also been shown to reverse features of metabolic syndrome . Long term nitrate ingestion may even reduce abdominal (visceral) fat and lower blood fats (triglycerides) .
Our diet is the main contributor to the body’s pool of nitrate and nitrate, with vegetables accounting for 60-85% of daily nitrate intake [30, 36]. Meats (both processed and unprocessed), the second food source, contain more nitrite than vegetables. Processed meat contains a little more nitrite and nitrate than un-processed meat, but the difference is much less than what is often claimed in media .
A typical US diet usually provides around 40–100 mg nitrate/day [58, 59] and 1-5 mg nitrite/day [60, 61]. On the basis of a conservative recommendation to consume 400 g of different fruits and vegetables per day at average nitrate concentrations, the dietary intake of nitrate would be 157 mg/day .
Ingested nitrate and nitrite is rapidly and completely be absorbed in the small intestine and taken up in the blood [62-65]. About 25% of blood nitrate is then absorbed by the salivary glands, of which 20% is converted to nitrite by commensal bacteria in the oral cavity [66, 67]. This nitrite is then swallowed and enters the blood circulation, where it becomes a precursor to NO generation via the nitrate-nitrite-NO pathway [37, 64].
Without this so called “entero-salivary circulation” of nitrate, which is dependent on oral bacteria, nitrate would leave the body unmodified as this chemically stable anion cannot be metabolized by mammalian enzymes. One can say that the entero-salivary circulation is a round-about-way of getting nitrite from nitrate, and up to 30% of the general population may not have the right oral bacteria to convert nitrate to nitrite  (which means they will not get any benefit from nitrate rich foods). Further, the necessary oral bacteria, when present, can easily be killed by anti-bacterial mouthwash . Therefore it may be better to supplement with nitrite directly . Nitrite can be seen as an NO donor, or storage form of NO (which decomposes in milliseconds after it has been liberated from its salt) [3, 29, 71], and is now at the forefront of NO biology . However, warnings have been issued regarding supplementation with nitrite salts . I will cover this debate on nitrite supplementation (commonly in the form of sodium nitrite) in a separate upcoming article…
Even though nitrate is less toxic than nitrite , very large amounts of nitrite (2000-3000 mg) needs to be ingested before toxicity sets in . While veggies contain most nitrate and meat most nitrite, in this context intake of veggies should be prioritized because they also provide tons of other health promoting substances, which not only themselves confer health benefits, but also enhance the NO generation from dietary nitrite (regardless of whether this nitrite came from meat or veggies) .
Despite the beneficial effects of dietary nitrate and nitrite, conservative governmental institutions and regulations perceive that these are harmful dietary substances. The purported health risks of exposure to nitrite and nitrate are based on reports about met-hemoglobinemia in infants – “blue baby syndrome” – caused by drinks or food prepared with nitrate-rich and bacterially contaminated well water, as well as contaminated vegetables (such as spinach, celery, and carrots), occupational intoxication, increasing nitrate levels in soil and lakes as a result of fertilizer overuse, and the formation of potentially carcinogenic N-nitrosamines. Also, some epidemiological studies have shown a weak association between cured and processed meats, which contain nitrite and nitrate, and cancer .
This gave nitrite and nitrate a negative image, and as a result efforts have been made to remove as much nitrite and nitrate as possible from our drinking water and food. The Joint Food and Agricultural Organization/World Health Organization has set the Acceptable Daily Intake (ADI) for the nitrate at 1.7 mg/lb body weight (3.7 mg/kg) and for nitrite at 0.03 mg/lb body weight (0.06 mg/kg) . Likewise, the Environmental Protection Agency (EPA) has set a daily Reference Dose for nitrate at 3.2 mg/lb body weight (7 mg/kg). This amounts to 222-420 mg nitrate and 3.6 mg nitrite for a 132 lb (60-kg) individual, which is below the doses that have been used in studies showing performance enhancing effects – around 500 mg nitrate  – as well as health promoting effects [7-10].
Figure 2: The nitrogen cycle - how nitrate and nitrite enters the natural ecosystem.
All the media scare about the purported hazards if nitrate and nitrite may make it appear as if dietary nitrate and nitrite are unnatural dangerous chemicals added by the industry. This is wrong; while cultivation and fertilization does add nitrate and nitrite to produce, vegetables also naturally contain nitrate and nitrite which enters the ecosystem via the nitrogen cycle, as illustrated in figure 2 . Thus, dietary nitrate and nitrite are part of our natural diet, in the same way as are vitamins and minerals.
The weak and inconclusive data on the cancer risk of nitrite and nitrate [77, 78] are far outweighed by the well documented health benefits of supplementing the NO pool with dietary nitrate (and to a lesser extent nitrite). Nitrate has actually been shown to have beneficial health effects at intakes that traditionally have been considered to be toxic .
For example, the well-known health promoting and blood pressure-lowering DASH diet can provide over 1200 mg nitrate due to its high vegetable content, which exceeds the World Health Organization’s Acceptable Daily Intake for nitrate by 540% for a 132 lb (60-kg) adult. Further support comes from the traditional Japanese diet, which naturally provides 8.6 mg nitrate per lb body weight per day (1135 mg nitrate per day for a 132 lb individual) . If nitrate really was that bad, the traditional Japanese diet wouldn’t be nourishing a population with the longest worldwide longevity.
These data call into question the rationale of recommendations to limit nitrate consumption from plant foods. Further, an effect of nitrite intake on cancer also seems less likely because significant amounts of nitrite are formed in the body. Fasting saliva contains 2 mg nitrite/L, and after consumption of an amount of nitrate equivalent to 7 oz of spinach (roughly 1400 mg nitrate), the nitrite concentration in saliva may rise as high as 72 mg/L . That is much higher than the EPA standard for drinking water of 4.4 mg nitrite/L or the WHO Acceptable Daily Intake of 4.2 mg nitrite/d. Thus, the fuss and warnings about nitrate and nitrite need revision in the face of the undisputed health benefits of nitrate-enriched diets.
The potential health implications of increasing nitrate and nitrite intakes to fuel the nitrate-nitrite-NO pathway is critically important for health and function in older adults, in whom the arginine-eNOS-NO pathway is inefficient and/or dysfunctional [80-86].
Intake of nitrite is especially important in the elderly, who often have altered oral bacteria populations, dry mouth, and who take medications that affect stomach acidity and intestinal motility . This is underscored by the finding that a large dose nitrate supplementation may be required to elevate blood levels of nitrate and nitrite in elderly, even among those who consume high-nitrate foods .
Aging is also characterized by endothelial dysfunction [83, 88], which is caused by disturbances in the arginine-eNOS-NO pathway and NO bioavailability, among other things [89-98]. The importance of nitrite in elderly adults is underscored by the fact that endothelial dysfunction is associated with reduced blood nitrite levels, and both reduced blood nitrite levels and endothelial dysfunction are correlated with an increasing numbers of cardiovascular risk factors [99, 100].
Thereby, an increased nitrite intake may provide a first line of defense against cardiovascular disease, especially in older people . Moreover, the increased exercise tolerance seen after nitrate supplementation is greatly beneficial for elderly, who often cite exhaustion/fatigue as a critical barrier that prevents them from partaking in regular exercise [101, 102]. In this regard, nitrite/nitrate supplementation can indirectly help to prevent sarcopenia and frailty, which are deleterious age related conditions that primarily arise as a consequence from a sedentary lifestyle [103-106].
Several prominent scientists are actively reevaluating the health and performance effects of food sources of nitrates and nitrites [2, 11, 13, 15-17, 29-37, 43-47, 55, 64, 107-111]; hopefully these new results be reflected in upcoming regulatory and public health guidelines for dietary nitrite and nitrate exposures.
There is a major paradigm shift occurring in regards to the health and nutritional value of nitrate and nitrite. In the right context, they can provide enormous benefit to people in all walks of life. It has even been suggested that dietary nitrate and nitrite have a role in the diet as indispensable nutrients that many people are deficient in [30, 112].
Nitrate supplementation, by ramping up the nitrate-nitrite-NO pathway, has in most studies been shown to significantly increase performance and exercise tolerance, and reduce blood pressure and confer health promoting cardiovascular effects.
The nitrate-nitrite-NO pathway complements the better known L-arginine-NO pathway. One major difference is that production of NO from the nitrate-nitrite-NO pathway is greatly enhanced during hypoxia (low oxygen availability) and low pH, such as during exercise, which is when the L-arginine-NO pathway performs poorly. Thereby it kicks in when we need it the most.
What’s interesting is that the major supply of nitrate and nitrite in our bodies comes from our everyday diet. Thus, this alternative NO generating pathway can be harnessed therapeutically for prevention and treatment of diseases, while boosting performance and exercise capacity. Pretty good deal!
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