Nitric Oxide: The Miracle Molecule

lizlaneyrdh
Apr 22
8 min read

With its antimicrobial, anti-inflammatory, and vasodilating properties, nitric oxide is a naturally occurring molecule that plays a crucial role in both oral and systemic health. Even so, it doesn't get nearly the attention it deserves in medicine, and even less so in dentistry.

The discovery of nitric oxide as a “miracle molecule” or “miracle messenger” won the Nobel Prize for medicine in 1998 [11].

Keep reading to review what makes this molecule so important, and what patients and providers can do to increase levels naturally to support overall health.

What is Nitric Oxide?

Not to be confused with nitrous oxide (i.e., laughing gas, N₂O) or nitrogen dioxide (i.e., an air pollutant, NO₂), nitric oxide (NO) is a gaseous molecule produced by the body that consists of one nitrogen atom and one oxygen atom.

Its primary role is to relax the blood vessels (vasodilation), which allows more blood, oxygen, and nutrients to flow through the body and nourish vital organs. However, it also functions as a neurotransmitter, signaling molecule, and bronchodilator.

[11]

Overall, NO helps protect the endothelium, the layer of cells that line the blood vessels [10].

Too little NO can lead to a condition called endothelial dysfunction, a condition that damages cells and increases the risk of cardiovascular disease [4].

Benefits of Nitric Oxide [11, 18]

Optimizes nutrient absorption
Increases oxygen delivery to muscles
Enhances exercise performance
Decreases oxidative stress
Triggers immune cells to kill bacteria and cancer cells

There are two ways the human body produces NO

Endogenous pathway (enzymatic pathway): Nitric Oxide Synthase (NOS)
Reductive pathway (non-enzymatic pathway): Nitrate-Nitrite-Nitric Oxide Pathway

Endogenous: Nitric Oxide Synthase (NOS) [3, 6, 12]

There are three main isoforms of this enzyme family that are crucial for nitric oxide production. These NOS enzymes follow an oxidative pathway using L-arginine, an amino acid, along with oxygen and a coenzyme, NADPH, to produce nitric oxide and citrulline (another amino acid).

[12]

Each NOS enzyme has important yet distinct roles:

Neuronal NOS (nNOS/NOS1) - Abundant in neurons of the brain and nervous system
- Acts as a neurotransmitter for synaptic plasticity, learning, memory, and other neuronal functions
- Neuroprotective
Inducible NOS (iNOS/NOS2) - Activated by inflammation as part of an immune response, particularly in macrophages
- Produces large amounts of NO during an immune response
- Fights off pathogens and mediates inflammatory responses
Endothelial NOS (eNOS/NOS3) - Main form of the NOS enzyme that is involved in the control of vascular function and vascular tone
- Primarily found in endothelial cells lining blood vessels
- Regulates blood vessel dilation (vasodilation)
- Prevents blood clot formation (platelet aggregation)
- Atherosclerosis prevention

eNOS and nNOS are always present, while iNOS is only induced during inflammation.

Reductive: The Nitrate-Nitrite-Nitric Oxide Pathway [17]

The nitrate-nitrite-nitric oxide pathway is an alternative route for NO production that involves the reduction of nitrate (NO₃-) to nitrite (NO₂-) to nitric oxide (NO) — primarily in the gut and other tissues — under specific conditions such as hypoxia (low oxygen conditions) and acidosis (when body fluids are too acidic).

This pathway plays a role in vasodilation, cellular metabolism, cellular signaling, and tissue protection during hypoxia

Nitrate sources in this pathway mainly center on dietary intake of nitrate-rich foods, such as [4]:

Beets
Garlic
Citrus Fruits
Leafy greens
Cabbage
Cauliflower
Carrots
Broccoli
Nuts and seeds

Enterosalivary circulation

Exogenous nitrate obtained from the diet is mixed with saliva in the oral cavity, travels along the gut, and is absorbed in the small intestine. Upon absorption, circulating nitrate is secreted via the salivary glands into the oral cavity, where it’s reduced to nitrite by the local microflora, especially by commensal bacteria found on the tongue [6]. From there, several pathways further reduce nitrate to bioactive NO [8].

The generation of NO via these pathways is enhanced during hypoxia and acidosis. This ensures NO levels are maintained during cellular and tissue hypoxic events [8].

[14]

Two additional ways in which the human body increases NO production include nasal breathing and exercise.

Nasal breathing [9]

The paranasal sinuses continuously produce and release nitric oxide when patent nasal breathing is occurring.

With nasal breathing, NO is carried into the lungs, where it dilates blood vessels and enhances circulation, thus improving oxygen transfer.
- This, in turn, can boost cognitive function, physical performance, and mood as well as protect against respiratory infections such as COVID-19.

It’s important to understand that mouth breathing interrupts this endogenous production and release of NO from the paranasal sinuses, which results in negative effects on several systemic functions.

Although highly beneficial, the benefits of nasal breathing go far beyond the production and release of NO. Check out my other blog posts here to find out more

Exercise [5]

There are various ways in which exercise impacts NO levels, including the following:

Improved eNOS expression & function
- Regular physical activity upregulates eNOS expression and activity & reduces oxidative stress, which protects NO from being broken down by free radicals
Shear stress on blood vessels
- During exercise, increased blood flow creates shear stress on endothelial cells, which stimulates eNOS to produce more nitric oxide from L-arginine
Mitochondrial & muscle adaptations
- Skeletal muscle contraction enhances local NO production, which helps regulate oxygen delivery to muscles, glucose uptake, and mitochondrial biogenesis
- Supports endurance and metabolic health
Dietary Nitrate Pathway
- Exercise can improve circulation in the oral cavity and gut, enhancing the conversion of dietary nitrate into nitrite and then NO

Best types of exercise for improved NO levels [1]

Aerobic exercise (running, cycling, swimming): Strongest and most consistent boost in NO due to sustained blood flow
High-intensity interval training (HIIT): Enhances endothelial function and NO production, sometimes more efficiently than moderate steady-state exercise
Resistance training: Also boosts NO, though effects are somewhat smaller compared to aerobic exercise

[5]

Overall Effects of Exercise on NO [2, 15]

Vasodilation: Better blood flow and reduced blood pressure
Improved Oxygen Delivery: Supports endurance by enhancing oxygen utilization in muscles
Metabolic Health: Increases insulin sensitivity and glucose uptake
Cardiovascular Protection: Reduces risk of atherosclerosis by preventing platelet aggregation and smooth muscle proliferation

As we age, the bioavailable amount of NO decreases, which increases endothelial dysfunction and thus increases the risk of cardiovascular diseases and other systemic diseases.

It's important to note that the endothelium's responsiveness to NO doesn't change, just the level of NO available and the body's ability to generate NO declines, especially around the age of 40 [18].

[18]

By the time we reach 40 years of age, studies have shown that we only produce about half or less of the nitric oxide we did at age 20 [11].

By 40, men produce about 50% of the nitric oxide they did in their teens and 20s [11]. Women, however, at age 50 only produce about 35% of what they did in their 20s [11].

Many people are deficient in nitric oxide. Symptoms are caused by decreased blood circulation and may include [4]:

Fatigue
Erectile dysfunction
Elevated blood sugar
High blood pressure
Poor wound healing
Muscle soreness
Memory loss

Beyond the above-listed symptoms, bioavailable levels of NO also have a huge impact on oral health

Oral Health Benefits of NO

Antimicrobial Action [7]
- NO exhibits broad-spectrum antimicrobial properties
- Can penetrate biofilms and inhibit the growth of periodontal pathogens such as Porphyromonas gingivalis and Fusobacterium nucleatum
  - May reduce the risk of periodontal disease
Enhanced Circulation
- By dilating blood vessels, NO improves blood flow to oral tissues
  - Enhanced circulation supports the delivery of oxygen and nutrients, promoting gum health and aiding in the healing of oral wounds
Anti-Inflammatory Effects [13]
- NO helps modulate the inflammatory response, which can reduce gingival inflammation
Improved Oral Microbiome Balance [16]
- The production of NO from dietary nitrates promotes the growth of beneficial bacteria while suppressing harmful ones, contributing to a healthier oral environment

Recommendations for Oral Health and Nitric Oxide Preservation

To preserve the oral microbiome as a whole — including oral and systemic NO levels to support optimal health — review the following recommendations, and talk with your oral healthcare provider about individualized changes you can make in your daily routines.

Limit the use of antimicrobial mouthwashes, especially those containing chlorhexidine, essential oils & alcohol, to preserve beneficial oral bacteria
- Read more here about the harmful effects of antimicrobial mouthwash
Incorporate nitrate-rich foods like leafy greens and beets into your diet to support the natural production of nitric oxide
Practice good oral hygiene through regular brushing, flossing, tongue scraping, and the use of oral probiotics to maintain a healthy balance of oral bacteria
Consult with a healthcare professional before making significant changes to your oral care routine, particularly if you have underlying health conditions

NOTE: Although nitric oxide supplements are available, excessive NO intake can be harmful. Please consult with a licensed healthcare professional before making any lifestyle changes. None of the content within this blog is to be taken as direct medical advice and is provided for informational purposes only.

Final Thoughts

Whether you're a patient or a healthcare provider, understanding the importance of nitric oxide can be the missing piece you need to optimize both oral and systemic health parameters, including the prevention and improved support of various diseases such as periodontal diseases, cardiovascular diseases, and others.

Check out my other blog posts to learn more about oral-systemic health!

For links and discounts on products mentioned in this post, check out my Resources page.

Talk soon,

Liz Laney, BSDH, RDH

Oral-Systemic RDH & Educator

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