Nitric Oxide: A Remarkable Molecule That Can Transform Your Health

James Odell, OMD, ND, LAc

A Remarkable Molecule

Nitric oxide (NO) is a remarkable molecule that plays a pivotal role in human physiology, but is often overlooked despite its extraordinary significance. Far more than just a simple chemical compound, nitric oxide serves as a crucial messenger and regulator within our bodies, interacting with nearly every major physiological system.

It is so critical that its absence would have severe, widespread consequences across multiple systems. The complete absence of nitric oxide would be essentially incompatible with life. It's so fundamental to our physiological processes that our body would rapidly experience multiple systemic failures.

This tiny molecule, composed of just one nitrogen and one oxygen atom, is a gas that is one of the principal oxides of nitrogen. What makes it so special is that NO is a free radical as it has an unpaired electron. This makes it easy to interact with other molecules to initiate signaling pathways. Often free radicals are given a bad reputation but they can be beneficial at low to moderate concentrations. Furthermore, they can also be mitigated with the right amount of antioxidants. 

Nitric oxide can occur naturally both outside and inside the body, and is often referred to as a "miracle molecule".

By optimizing this incredible molecule through diet and supplements, you can  promote overall wellness at the cellular level. 

NO’s Wide Ranging Roles Throughout the Body

• Research has shown that NO plays a role in neurotransmission, or information sharing between neurons, which helps functions in the nervous system, such as digestion and memory. 

• It affects the release of hormones, including growth hormones and insulin. 

• In addition, NO plays a key role in cell metabolism and is instrumental in coordinating tissue energy demand with supply. 

• Among numerous other functions, NO supports the immune system, helps maintain healthy sexual function in men, and encourages healthy brain function.1, 2

NO’s Role in the Vascular System 

Inside the body NO is one of the critical molecules of the vasculature system, regulating key signaling pathways in health. In micro vessels, NO functions to suppress cell inflammation as well as adhesion. In this way, it inhibits blood clots (thrombosis) and promotes blood flow. 

It also limits vessel constriction and vessel wall remodeling, thus preventing atherosclerotic plaque. 

In micro vessels and particularly capillaries, NO and growth factors are important in promoting new vessel formation, a process termed angiogenesis. 

By relaxing blood vessels and helping maintain their elasticity, nitric oxide facilitates healthy blood flow and helps maintain healthy blood pressure.

The endothelium (inner lining) of blood vessels uses nitric oxide to signal the surrounding smooth muscle to relax, resulting in vasodilation and increasing blood flow. 

NO is a cornerstone of a healthy endothelium, the functioning layer of cells that lines the inside of blood vessels, including arteries and veins. A healthy endothelium helps maintain vascular tone, allowing for smooth blood flow. An optimally functioning endothelium is an important contributing factor to one's overall heart health.3 

NO Dysregulation

With age and cardiovascular disease, NO can become dysregulated at multiple levels including decreased production, decreased tissue half-life, and decreased potency. NO deficiency has also been implicated in diseases that are related to neurotransmission and cancer. 

Noble Prize Related to a Nitric Oxide Discovery

The 1998 Nobel Prize in Physiology or Medicine was awarded for discovering nitric oxide's role as a cardiovascular signaling molecule.4, 5 The discovery of NO as a signaling molecule revolutionized our understanding of cellular biology and physiology. It is a bioproduct in almost all types of organisms, including bacteria, plants, fungi, and animal cells. 

How Our Bodies Create Nitric Oxide

Our bodies create nitric oxide from the essential amino acid L-arginine, with the help of a specific enzyme called nitric oxide synthase (NOS).6, 7, 8 Intracellular arginine availability is a rate-limiting factor in cellular NO production, and argininosuccinate lyase that converts citrulline back to arginine is important to synthesize not only intracellular arginine but also to utilize extracellular arginine for NOS-dependent NO synthesis.9

Nutritional and Supplemental Strategies for Increasing Nitric Oxide

This review will outline nutritional and supplemental strategies such as L-arginine for increasing NO and improving its vital function. Diet is a safe and inexpensive way of increasing NO bioavailability.10, 11

Polyphenols

Polyphenols are a class of chemical compounds that occur naturally in plants and are available in standardized doses in supplement form. Many polyphenols have antioxidant properties, protecting our cells from free radicals. Polyphenols can also encourage NO levels, supporting endothelial function and cardiovascular health.12, 13

Teas 

Black, green, oolong, or white tea polyphenols, including epigallocatechin gallate, promote catalytic NOS activity.14 Additionally, tea consumption may reverse endothelial dysfunction and beneficially affect weight control and insulin sensitivity 15, 16

Red Wine

Red wine polyphenols, including resveratrol, quercetin, and gallic acid, upregulate NOS expression and NO production.17 This, in turn, can significantly enhance the function of circulating endothelial progenitor cells (EPCs) that are capable of forming new blood vessels.18

Cocoa

Flavonol-rich cocoa consumption increases circulating NO with vasculoprotective, insulin-sensitizing impact.19

Other Various Polyphenol Sources

Other examples of polyphenol sources that support NO are aronia berry, pomegranate, and pycnogenol, an extract of French maritime pine bark. 

Aronia berries, or black chokeberries, are small, edible pea-sized berries that grow on shrubs native to North America. Chokeberry extract is a rich source of polyphenols and is included in some NO supplements. These polyphenols can promote the activity of endothelial NO synthase, the enzyme responsible for producing nitric oxide in the body.20 

Pomegranate is a nutrient-dense fruit with many unique compounds that benefit our health. One of its most impressive benefits is its support for blood vessel health. It supports healthy cardiovascular endothelial function.21, 22

Pycnogenol is an extract that comes from the bark of the French maritime pine tree and is available in supplement form. It has been shown to promote a healthy functioning endothelium and arterial blood flow. Pycnogenol also provides powerful protection against oxidative stress and helps promote a healthy inflammatory response. Through these actions, pycnogenol supports healthy blood flow throughout the body.23

Flavonoids

Flavonoids are a subclass of polyphenolic compounds found in a variety of supplements and occur naturally in various plants and plant-based foods and beverages. Like other polyphenols, they support nitric oxide levels by enhancing its production. Some examples of flavonoid supplements are Kaempferia parviflora extract, quercetin, and hesperidin.

Thai Black Ginger

Kaempferia parviflora extract, also known as Thai black ginger, is native to Southeast Asia and has been studied for male sexual health support for years. It works by promoting NO synthesis which helps maintain healthy blood vessels and promotes healthy blood flow, vital to a healthy sexual response.24

Quercetin

Quercetin is a flavonoid found in many plants and foods, such as onions, black tea, red wine, apples, and berries. It supports a healthy inflammatory response and offers antioxidant protection.25, 26 If taking a quercetin supplement, choose a bioavailable formula. One concern raised by many studying the potential uses of phytochemicals like quercetin is that they do not seem to be absorbed well by our bodies at levels capable of producing health benefits. However, like most flavonols, quercetin is most often found in a form known as a glycosylated conjugate—in non-technical terms, a compound of quercetin molecules bound to sugar molecules. Fortunately, tests show that this most prevalent form of quercetin is the easiest for our bodies to absorb, making its powerful positive effects bioavailable to our cells.

Hesperidin

Hesperidin is a compound derived from citrus peels that helps maintain blood vessel and circulatory health by boosting endothelial production of NO.27 

In a randomized controlled trial, 500 mg of sweet orange peel extract encouraged flow-mediated dilation, an indicator of healthy endothelial function. It also promoted a healthy inflammatory response.28

Dietary Nitrate and Beets

The discovery that dietary nitrate has important vascular effects came from the relatively recent realization of the ‘nitrate-nitrite-nitric oxide (NO) pathway’. Dietary nitrate has been demonstrated to have a range of beneficial vascular effects, including reducing blood pressure, inhibiting platelet aggregation, preserving or improving endothelial dysfunction, and enhancing exercise performance in healthy individuals and patients with peripheral arterial disease. Oral beet nitrate supplementation has been shown to increase plasma nitrate [NO3−] and nitrite [NO2−] consequently enhancing nitric oxide production.29, 30 

In one small study, 38 adults consuming a beet juice supplement increased nitric oxide levels by 21% after just 45 minutes.31 Numerous companies are marketing beet powder, beet crystals, and tablets as it is often difficult to consume enough beets in the diet to make a difference in the NO levels. 

Amino Acids - L-arginine and L-citrulline

L-arginine

L-arginine supplements are the most basic type of nitric oxide supplement. They contain the amino acid L-arginine which is a precursor to nitric oxide and can be converted to NO in the body. L-arginine supplements encourage healthy levels of endothelial NO production, promoting blood flow and circulatory health. They also provide other health benefits, such as maintaining healthy tissue and bones, promoting healthy sexual function and exercise performance, and supporting a healthy immune system.32, 33

However, regular L-arginine only stays in your blood for a short amount of time. So, there are high-quality supplementation formulas designed to support blood L-arginine levels for a longer time. Because these supplements stay in your blood longer, they provide additional vascular support.

Some supplements may combine arginine with other ingredients, like ornithine (another amino acid), for additional benefits relating to athletic performance. These formulations combine protein-building amino acids to promote muscle health and recovery post-exercise.

L-citrulline

Another amino acid that is often mentioned when talking about NO supplements is L-citrulline. That's because L-citrulline is a precursor to L-arginine (just as L-arginine is a direct precursor to nitric oxide). However, since L-citrulline needs to be converted to L-arginine, many prefer to skip the middleman and take L-arginine.34

Conclusion

Nitric oxide is synthesized from L-arginine by NO synthase (NOS). As an endothelium-derived relaxing factor, a mediator of immune responses, a neurotransmitter, a cytotoxic free radical, and a signaling molecule, NO plays crucial roles in virtually every cellular and organ function in the body. Increasing evidence over the past decade shows that many dietary factors, including protein, amino acids such as L-arginine and citrulline, polyphenols, and flavonoids can increase NO production.

References

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