Nitric oxide (NO) is one of the most important molecules in the body, involved in virtually every organ system. Perhaps its most important role is as a potent vasodilator (i.e. it makes blood vessels bigger). This is of huge importance because bigger blood vessels means more blood flow around the body without the pump (heart) working harder. Thus, insufficient NO can directly cause or contribute to multiple diseases.
The discovery of NO, a structurally simple, colourless and odorless gas, was viewed as so fundamentally important for human health and disease prevention that Science magazine named it as molecule of the year in 1992, and the Nobel Prize in Physiology or Medicine was awarded for its discovery in 1998.
NO is produced by an enzyme for an amino acid called L-Arginine. L-Arginine is found in many protein containing foods (e.g. legumes and nuts). However, one problem is that the enzyme doesn’t always work well and can be affected by smoking, getting older, etc. Another problem is that simply supplying more L-Arginine, either in diet or supplements, does not always increase NO production. Even worse, L-arginine supplementation has been demonstrated to be ineffective after long-term use and has been associated with less NO and excess death when given to patients after a heart attack.
Despite intense interest, there are unfortunately very few options to enhance NO bioavailability, including medications and surgery. Then…enter vegetables! Until recently, it was assumed that the enzyme discussed above was the only way to produce NO in humans. As dietary components, both nitrate and nitrite were considered unfavourable and potentially cancer causing. However, it has been shown that when humans ingest dietary nitrate, it is recirculated into the saliva where bacteria in the mouth convert it to nitrite. This nitrite is swallowed and can be further converted into NO either in the stomach, blood vessels, or within tissues (e.g. heart). Dietary nitrate is now recognised as a very significant precursor to NO in a dose-dependent manner in humans. In other words, more nitrate equals more NO—though there is a plateau at very high doses. Therefore, ingestion of dietary nitrate may increase NO and provide benefit in a number of diseases characterised by insufficient NO.
The bacteria in the mouth are crucial because humans can’t convert nitrate to nitrite; only the bacteria can. Killing these bacteria by using mouthwash or antibiotics has been shown to stop the production of NO from dietary nitrate! One study even got volunteers to consume nitrate and then drool and so lose the nitrate/nitrite in their saliva. This completely stopped the effect! Another important step in the production of NO from dietary nitrate is the acid within the stomach, which helps produce NO from nitrite. Therefore, decreasing stomach acid with certain medications (e.g. antacids and acid reducing medication like Losec) can also decrease NO production and its effects.
Is nitrite harmful?
You may have heard of nitrite previously. Nitrite is often used as a preservative and added to processed meats (e.g. bacon) to prevent spoilage (e.g. botulism) and to contribute to a pinky color. Plant foods are the primary sources of nitrate, while processed and cured meats are the primary sources of nitrites for humans. Plant foods generally contain little or no nitrite, while animal foods, even if cured, generally contain little or no nitrate. Processed meats have multiple negative health consequences, and nitrite has been thought to be one of the reasons why. But dietary nitrate seems to work by first being metabolised to nitrite. Does this mean that dietary nitrate can be dangerous? It’s complicated!
When added to processed meats, nitrites can react with the iron, fat and amino acids present to form harmful substances before the meat is even cooked or eaten. Further, it turns out that when humans consume nitrites, there is potential for additional cancer causing substances to form under certain conditions—for example, in the absence of phytochemicals and antioxidants The phyto– in phytochemical is Greek for “plant.” They are literally “plant chemicals. Phytochemicals and antioxidants are health promoting, disease fighting compounds found in abundance in whole plant foods. It seems that nitrite is not as much a problem as the nitrosamines formed when we eat nitrite in the form of processed meats. A review in the American Journal of Clinical Nutrition wrote that “If nitrite were, indeed, a carcinogen, we would be advised to avoid swallowing because saliva contains nitrite.” On the other hand, when nitrate (often produced from dietary nitrate in plant foods) is available in the presence of antioxidants and phytochemicals, NO is produced. Guess what nitrate containing plant foods also contain in abundance. Phytochemicals and antioxidants!
Benefits of dietary nitrate
When humans ingest food we metabolise it in the presence of oxygen to produce a molecule called ATP (adenosine triphosphate). ATP produces energy at the cellular level. It has been thought that a certain and constant amount of oxygen was required to produce a molecule of ATP. Athletes, for example, can produce more ATP than non-athletes, but athletes have bigger, stronger lungs than non-athletes. They also have more oxygen carrying red blood cells and can take in more oxygen for ATP production.
Until recently, we knew very few ways to produce more ATP without increasing oxygen consumption. However, several trials have demonstrated that dietary nitrate can decrease the amount of oxygen need to produce ATP, i.e.more work can be performed with the same amount of oxygen. There are also reports that dietary nitrate improves the efficiency of human mitochondria, the energy producing units within our cells. Thus, dietary nitrates could prove to be beneficial for athletes, those living at high altitude (where oxygen is limited) and some disease states, such as lung disease or sleep disorders, where oxygen is limited.
Early studies demonstrated that dietary nitrate could even help improve performance in athletes. However, recent evidence with regard to athletes has been very inconsistent. Nevertheless, the effect of dietary nitrate on those with lower fitness levels and/or muscular/heart/lung impairments is more convincing. The effect of dietary nitrate on physical performance seems more pronounced in those with less fitness and with muscular/lung impairments. I headed a research team in Dublin, and we demonstrated increase exercise tolerance in patients with a serious lung disease called COPD and in those with a specific heart problem—non-ischemic, dilated cardiomyopathy.” Other research groups around the world have also reported benefit in COPD, heart failure and peripheral artery disease (also called intermittent claudication).
High blood pressure is one of the most common and life threatening issues in the world. Because NO causes blood vessels to dilate, increasing NO can decrease blood pressure. Therefore, dietary nitrate could increase NO and decrease blood pressure. Indeed, early studies showed that dietary nitrate could decrease blood pressure in young, healthy volunteers. More recent data show that dietary nitrate can also decrease blood pressure in more at-risk populations—those with high blood pressure. My research team in Dublin demonstrated that any blood pressure lowering effect was more pronounced in those with higher blood pressure, i.e. those who need it most!
One group of researchers wrote, “an additional strategy, based on intake of nitrate-rich vegetables, may prove to be both cost-effective, affordable and favourable for a public health approach to hypertension.”
Obstructive sleep apnoea (OSA) is a serious sleep disorder where a person stops breathing regularly during sleep. Each time the person stops breathing, oxygen levels fall and the person will wake up, usually briefly. At the clinic in Dublin, I remember one lady who had an OSA score of 150: she had stopped breathing 150 times in a single night and each time for at least ten seconds! OSA is associated with high blood pressure which is very difficult to treat. My research team has also demonstrated that dietary nitrate can decrease blood pressure in OSA.
Additional research has even shown that dietary nitrate can increase blood flow to the brain. This brings the intriguing question: can increasing dietary nitrate help improve brain disorders such as dementia?
When trials relating to dietary nitrate first started being published, scientists were sceptical. How could vegetables increase NO when many other therapies couldn’t? How could dietary nitrate lower blood pressure and increase exercise capacity in multiple groups? Eventually the volume of research convinced the majority that vegetables were in fact very effective! A 2008 editorial in the eminent journal Hypertension led with the headline, “Mother was right: eat your vegetables and do not spit!”
How can dietary nitrate affect so many processes?
Dietary nitrate increases NO production. Because NO is so important throughout the body, this means that nitrate can have wide ranging effects. Research has shown that dietary nitrate works by making blood vessels bigger, increasing the amount of blood with each heartbeat, increasing the amount of oxygen in muscles, and thus increasing muscle strength.
Who will benefit most?
In the scientific journal Current Opinion in Clinical Nutrition and Metabolic Care, I recently published a scientific review of the conditions that contribute to the effectiveness of dietary nitrate in increasing NO, lowering blood pressure, and improving exercise tolerance.
Dietary nitrate may be most relevant to those with muscular, lung, or blood vessel impairments, for example low muscle mass, breathing problems, or high blood pressure. Increasing dietary nitrate also seems most beneficial in less fit individuals and those with a previously low dietary nitrate intake. Interestingly, longer term intake of dietary nitrate appears more beneficial than short term, i.e. regular consumption of green, leafy vegetables, for life! Finally, and perhaps most specific to athletes, dietary nitrate seems to be more effective in those engaging in short-term, intense exercise as opposed to longer term, low-moderate intensity.
How can I increase my nitrate intake?
Nitrate is present at trace levels in our environment, as well as in plant tissues. Therefore, all whole plant foods contain nitrate, though the levels vary depending on the type of plant and the quality of the soil in which it’s grown.
Vegetables are the main source of nitrate, contributing around 85 % of daily nitrate intake.. Most of the remaining nitrate comes from drinking water. Analyses of a range of foodstuffs indicate that the highest levels occur in green, leafy vegetables such as cabbage, lettuce, chard, and particularly arugula (rocket), while beetroot and rhubarb are moderate sources. Other vegetables such as carrots contain lesser amounts.
National dietary data surveys show average daily nitrate intakes in the USA and Europe to be 0.5-3 mmol/day).. This low nitrate intake reflects low vegetable intake. However, vegetarian as well as traditional Mediterranean and Japanese diets and the DASH diet contain far more vegetables and hence more nitrate than standard Western diets, with levels of up to 20 mmol/day being reported.
It is possible to get inorganic nitrate in a pharmaceutical form. However, the pharmaceutical form may have safety issues while nitrate from the diet does not. Additionally, nitrate from the diet has shown superior results, possibly due to synergistic effect of phytochemicals and other antioxidants.
Factors known to affect nitric oxide generation from dietary nitrate
As stated above, more nitrate equals more NO, and the dose of nitrate appears to be the most significant predictor of biochemical and physiological response to nitrate. However, it should be noted that a threshold effect has been suggested. For example, one study reported no effect of 4.2mmol/day but higher doses of 8.4 and 16.8mmol/day improved exercise performance. However, 16.8mmol achieved no additional benefit compared to 8.4mmol/day. Existing evidence suggests a maximum benefit of around 10 mmol/day, and this can easily be achieved with daily consumption of a variety of plant foods like green leafy vegetables, rhubarb, and beetroot. Other factors that can increase NO production from dietary nitrate include exercise and some medications (e.g. statins). Factors known to decrease NO production from dietary nitrate include smoking, aging, high cholesterol, inflammation, and low oxygen conditions (e.g. high altitude, some lung diseases).
The effects of dietary nitrate seem to be highest about three hours after consumption. After this, there is still a benefit but the effect lessens. After 24 hours, the effect is mostly gone. Therefore, humans should ideally aim to eat nitrate rich foods at least once per day and possibly more. Eat vegetables every day…sound familiar?
Is dietary nitrate safe?
Although dietary nitrate (consumed as vegetables!) seems remarkably safe and remarkably effective, some caution is warranted. The American Academy of Pediatrics and American Academy of Pediatrics Committee does not recommend dietary nitrate for infants under three months of age. Also, green vegetables contain vitamin K and are not recommended for those taking certain medications (e.g. Coumadin/Warfarin). Some sources of dietary nitrate (e.g. beetroot) can be high in oxalates, which can contribute to kidney stones in susceptible individuals. Many of the recent trials used beetroot juice as a convenient, standardised source of dietary nitrate. Beetroot consumption does have one interesting side effect: red/purple urine and stools! This is completely harmless, simply due to the colorful pigments in beetroot and affects about 15% of people. In fact, beetroot causing red/purple urine is so well known it has a medical term: beeturia!
Green, leafy vegetables are consistently reported as one of the healthiest varieties of plant foods, including with regards to protection against heart disease, diabetes, and cancer. Some have suggested that nitrate explains a lot of this benefit. Either way, the practicalities are clear: For most people looking to optimize their NO levels and overall health, the consumption of green, leafy vegetables regularly as well as beetroot and rhubarb can be recommended.
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