Nitric oxide is a compound consisting of a nitrogen group attached to an oxygen molecule, but its simple structure is deceptive compared to the myriad functions it performs in the human body. The recognition of the many essential health effects of NO led to its being named “Molecule of the Year” by Science magazine in 1992. Six years later three scientists shared the Nobel Prize in physiology and medicine for their work on NO metabolism.
For many years scientists actually found NO to be elusive, since it’s an ephemeral gas and degrades in three seconds after it’s produced. What scientists did know was that something produced in the endothelium, which is the lining of blood vessels, caused the smooth muscles in the endothelium to relax instantly. That not only increased blood flow, but also lowered elevated blood pressure. Without actually isolating the enigmatic blood vessel product, the scientists named it “endothelial relaxation factor.” The three scientists who won the Nobel Prize in 1998 identified endothelial relaxation factor as nitric oxide and also produced evidence of its potent effects on cardiovascular function.
While NO is important for that cardiovascular function and for its ability to lower blood pressure, it also plays a role in numerous other functions. One example is that NO appears to encourage neurogenesis, which is the production of new nerve cell connections in the brain. When overproduced, however, NO has a reverse effect in that it starts to destroy brain cells. That’s the general pattern with NO—when released in small amounts, it exerts beneficial effects, but larger amounts are toxic. For one thing, NO is a free radical with a tendency to turn into an even more potent free radical known as peroxynitrite that is very toxic to cells. If you’re unfortunate enough to get septicemia, or blood poisoning, the cause of death is often septic shock. It turns out that the degree of septic shock is related to a large release of NO.
One reason that exercise can help you survive a heart attack was explained in a recent study published in the journal Circulation Research. The researchers found that exercise itself generates NO and allows it to be stored in the form of a precursor called nitrate and also in a sulfur form called nitrosothiol in the blood and heart following exercise. The body can rapidly convert those NO precursors back into NO, increasing blood flow and oxygen delivery to the heart, which would minimize or possibly even prevent heart muscle damage after a heart attack. Exercise boosts the primary enzyme nitric oxide synthetase, which regulates the NO production.
What about exercise and NO? The plethora of alleged NO–boosting supplements on the market offers mute testimony to the suggested benefits of increasing it. The reasoning is that elevating NO will increase blood flow, muscle pump and oxygen delivery to working muscles, and that, in turn, will enable you to train harder and more efficiently.
Since NO is also involved in anabolic hormone release, including growth hormone, it may also play a role in stimulating recovery after intensive training. As if that’s not enough, NO boosts the activity of muscle satellite cells, muscle stem cells that are required for muscle repair and growth.
In most of the available NO–boosting supplements, the amino acid arginine is the primary ingredient. That’s because L-arginine is the immediate precursor of NO synthesis in the body. Lesser known, however, is that it’s not the arginine that’s the limiting factor in NO synthesis but the activity of the NO–synthesizing enzymes located in the endothelium and elsewhere. In fact, people who have damaged endothelial tissue—for example caused by long-term high blood pressure—have a depressed ability to convert arginine to NO because of the failure of the NO–synthesizing enzymes. For them, getting extra arginine may encourage a more normal production of NO.
When people have cardiovascular disease, they produce a substance called asymmetric dimethylarginine in larger amounts than normal. That interferes with the activity of NO–synthesizing enzymes. Once again, however, the cure is to supply a higher-than-usual intake of arginine. Small wonder that arginine is considered to be a “conditionally essential amino acid.”
Even if your problem isn’t a damaged endothelial lining, you still face another barrier to NO production from arginine—the existence of the enzyme arginase in the liver and intestinal lining. Arginase degrades arginine, and the larger the dose of arginine you take, the greater the arginase activity. In fact, the studies that have shown a significant increase in NO production from arginine involved an intravenous administration of large doses, averaging 20 to 30 grams. Trying to duplicate that intake orally wouldn’t work, since oral arginine doses above 10 grams usually bring on severe gastrointestinal distress and nausea. You wouldn’t want a huge surge of NO anyway, since, as noted, large amounts are highly toxic and lead to cell death.
Also as noted, regular exercise alone is enough to boost NO production. That occurs because of the shearing effect on the endothelium induced by the more intensive blood flow typical of exercise. In effect, exercise creates its own pump. Those with more exercise experience produce more NO than those who don’t exercise regularly. Considering the protective role that NO plays in cardiovascular function, it’s no surprise that working out is one of the most important things you can do to encourage good health. Even so, since NO is just a gas and disappears so quickly after it appears, how do we know what boosts it in the body?
The answer is that we can measure the blood and urine contents of NO by-products like nitrites and nitrates, which are stable. They’re also found in food, particularly certain vegetables, and evidence shows that they can convert into NO in the body. In fact, a recent series of studies showed that eating beets or drinking beet juice, perhaps the richest natural source of nitrites, increases exercise intensity as well as oxygen delivery to muscles by way of increased NO production. One study found that taking in nitrites dramatically improves the function of mitochondria, cell structures responsible for energy production and fat oxidation. That route of NO production bypasses the usual enzmatic conversion of arginine into NO.1
Other substances besides arginine can boost NO production. Examples include garlic, which has long-acting sulfur precursors of NO. The amino acid citrulline, which is found in watermelon, among other sources, also bypasses the arginine barrier by being converted in the kidneys back into arginine and then into NO. It would be a better choice for NO–boosting supplements than arginine.
Cocoa also boosts NO production, likely because of its potent content of antioxidant polyphenols, which prevent the premature breakdown of NO. Glycine propionyl L-carnitine in doses of 4.5 grams taken 90 minutes before training has also been shown to boost NO, as evidenced by increased amounts of nitrates in the blood.
A new study discusses a proprietary supplement composed of beetroot and hawthorn herb. As noted, beetroot is the richest natural source of nitrites, while hawthorn contains an enzyme that helps to convert nitrites into nitrates, then into NO. Giving it to human subjects it led to a significant drop in elevated blood fats, a cardiovascular risk factor. More important, it bypasses the arginine barrier completely.
There are other points to keep in mind regarding optimizing NO production. For one thing, it’s important to eat a high-protein diet because of arginine. Glutamine, another popular amino acid supplement, interferes with NO synthesis and should not be taken with any NO supplement. Large doses of the amino acid lysine interfere with arginine uptake, which can lower NO production. Taurine boosts NO production in some tissues but lowers it in others because of its effects on NO–synthesizing enzymes. Homocysteine, a product of the metabolism of the essential amino acid methionine, lowers NO synthesis. Hyperglycemia, or elevated blood glucose, as occurs during insulin resistance, inhibits NO, as does fructose. Too much saturated fat intake impairs NO production in blood vessels, while unsaturated fats, including omega-3 and 6, boost NO production. Interestingly, monounsaturated fat, usually considered healthful, lowers NO production.
NO synthesis is also increased by vitamins C, A, E, K and folic acid as well as carotenoids because of their antioxidant activity. Minerals that boost NO include calcium, iron, zinc and magnesium. Glucosamine, a popular supplement used to treat joint pain, interferes with NO synthesis, while isoflavones in soy boost it. A recent study found that a flavonoid found in citrus fruits called hesperidin potently boosts NO synthesis.2
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1 Zand, J.,et al. (2011). All-natural nitrite and nitrate containing dietary supplement promotes nitric oxide production and reduces triglycerides in humans. Nut Res. 31:262-269.
2 Rizza, S., et al. (2011). Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome. J Clin Endocrin Metab. 96:782-92.