Nitric oxide: The miracle molecule

Nitric oxide (NO), a gas that is enzymatically produced in the saliva, has proven to be a molecule of immense benefit to a patient’s oral and systemic health. With its antibacterial properties, vasodilatory abilities, and role in immune system stimulation, it is no wonder that this miraculous molecule is continuing to be researched at length.^1,2

However, the amount of NO available in the oral cavity varies among patients, and low levels have even been proposed as a risk factor for cardiovascular health and caries incidence. The role of the oral health-care provider is critical when it comes to product recommendations, oral hygiene instruction, and completing risk assessments for patients.² This article discusses the etiology of NO and how oral health-care professionals can assist with increasing levels of available NO in the mouth to support oral-systemic wellness.

What is nitric oxide?

The chemical compound nitrate is found in both saliva and through diet. Dietary nitrate makes up 80% of nitrate intake and is most prevalent in green, leafy vegetables such as spinach, celery, beetroot, and lettuce. On the contrary, salivary nitrate makes up a smaller percentage and is found in posterior areas of the tongue.² We’ll focus mostly on salivary nitrate, as this chemical compound is critical when it encounters the oral bacteria, Veillonella spp., Staphylococcus aureas, and Nocardia sp.²

When nitrate contacts these nitrate-reducing organisms, an acidic environment is created, and the enzyme nitrate reductase reduces nitrate into nitrite. The acidic environment around nitrite converts nitrite into nitrous oxide, which is the familiar gas found in dental settings. Unstable on its own, nitrous oxide will then spontaneously convert to NO.^1-3 This gas molecule becomes more prevalent in an acidic environment and is even more effective at lower pH levels, which suggests that NO and its antibacterial properties could be protective in patients with high caries risk and active periodontitis.⁴

NO is a powerful defense mechanism in the mouth. This gas molecule is a broad-spectrum antimicrobial and antiviral that can penetrate mature biofilm.⁴ Studies have shown that NO levels increase during plaque deposition in patients with periodontal disease in an effort to reduce the subgingival microbial load and disrupt these biofilms before they initiate a larger inflammatory response.⁴ Not only does NO play a role in inhibiting bacterial growth and signaling a host immune response, but its vasodilatory properties also have a direct correlation with risks for prehypertension and hypertension.³

Nitric oxide and cardiovascular health

One out of every three Americans has hypertension, and only about half of those on medication are truly managing their blood pressure.⁵ NO is a natural vasodilator and without it, vasoconstriction has the potential to occur, placing individuals at higher risk for hypertension.²

Studies suggest extraneous factors such as overuse of antibiotics and chronic mouth rinse could be contributing to the eradication of nitrate- and nitrite-reducing bacteria. However, allowing the nitrate- and nitrite-reducing bacteria to recolonize in the mouth and help produce NO could potentially assist in normalizing blood pressure.⁵ Independent from other risk factors such as smoking and diet, reduced nitrite levels in healthy humans have an inverse relationship with increased systolic and diastolic blood pressure.^5,6

One study looked at those who used over-the-counter mouthwash twice daily or more. At baseline, they had an 85% higher risk of physician-diagnosed hypertension compared to less frequent users. When compared to non-mouthwash users, these study participants had more than twice the risk of physician-diagnosed hypertension over a three-year follow-up of people free of hypertension.⁶

With alterations in the oral microbial environment, a shift is seen with lower levels of nitrate-reducing bacteria and increased levels of harmful, disease-causing bacteria. It is well understood that the effects of NO allow smooth muscle tissue to relax, which leads to vasodilation.⁵ This dysbiosis between nitrate-reducing organisms and pathologic oral bacteria is leading researchers to believe that reduced levels of NO are a risk factor for hypertension.

Nitric oxide and caries risk 

When discussing risks for caries and bacteria that contribute to the development of carious lesions, species Streptococcus mutans is typically at the forefront. We know that high-caries-risk individuals have increased amounts of S. mutans, but what we also know through research is that nitrite in the saliva has the potential to destroy S. mutans in an acidic environment.² The direct role of NO production in caries prevention is still unknown, as some reports show positive correlations with reduced caries incidence, while others show no correlation.

One study looked at changes in NO levels before and after treatment of carious lesions. Their results proved statistically significant, with levels of NO increasing by 20 micrograms 15 days after treatment and 44 micrograms 30 days after treatment. This could be due to the bactericidal properties of NO inhibiting the growth of cariogenic bacteria.² We know that increased cariogenic bacteria in patients leads to a more acidic environment, which is favorable when discussing the production of NO. At increased levels, NO has the potential to be a host defense mechanism against dental caries.² Including a screening for NO as part of a caries risk assessment could become commonplace as more research behind NO and its role in caries prevention is further understood.

Harmful habits

NO clearly has significant benefits to a patient’s oral-systemic health, but what could be contributing to lower levels of NO production? We know that NO production is dependent on the nitrate-reducing microorganisms found in the oral cavity. However, studies are examining the negative implications of consistent over-the-counter antibacterial and antiseptic mouthwash use on the inhibition of these critical microbes.^4,5 “Studies suggest that disruption of oral microflora by antibacterial mouthwash may have detrimental effects by lowering nitric oxide bioavailability.”⁶

Research pointing to chronic use of OTC rinses proposes that these ingredients have the intent of disrupting harmful biofilms, but the chemical properties of antibacterial and antiseptic rinses also disrupt the biological environment of the mouth, which includes the nitrate-reducing organisms critical to NO production.^4,5 With 99% of mouthwashes containing some antibacterial agent, it begs the question of which OTC rinses are most suitable to promote optimal oral health without compromising the “good” bacteria that we want to help thrive?⁶

More about nitric oxide … Mouth rinses, high blood pressure, and nitric oxide

Alternatively, instead of recommending chronic use of antiseptic rinses, should clinicians incorporate more nutritional counseling to reflect diets that are rich in foods and vegetables with nitrate and nitrite?⁵ Understanding a patient’s oral microbial blueprint will be imperative to providing individualized care plans and oral hygiene regimens. As previously demonstrated, incorrect product use could be detrimental to nitrate-reducing organisms that oral and systemic health are dependent upon.

Oral-systemic wellness begins at the microbial level

Now, more than ever, it is critical to understand the specific microbes that make up a patient’s oral microbiome. Creating an optimal environment for oral nitrate reduction to occur is critical for NO production. If levels of nitrate-reducing organisms are at suboptimal levels, research suggests that restoring homeostasis of NO availability in the mouth could have a significant influence on disease prevention.⁵ Achieving true oral-systemic wellness begins at the microbial level. Working with patients as a care partner to fully understand their medical and dental history will help guide product and treatment recommendations that support an oral environment that allows health-benefiting microbes to flourish adequately.

References

1. Esfehani M, Keshavarzi Z, Mirzadeh M, et al. Salivary nitric oxide levels in adults with different DMFT scores in a selected Iranian population: a cross-sectional study. Acta Stomatol Croat. 2023;57(2):113-120. doi:10.15644/asc57/2/2
2. Jindal M, Sogi S, Shahi P, Ramesh A, Nautiyal MP, Jindal T. Salivary nitric oxide levels before and after treating caries in children: a comparative study. Int J Clin Pediatr Dent. 2023;16(Suppl 2):133-137. doi:10.5005/jp-journals-10005-2659
3. Barbadoro P, Ponzio E, Coccia E, et al. Association between hypertension, oral microbiome and salivary nitric oxide: a case-control study. Nitric Oxide. 2020;106:66-71. doi:10.1016/j.niox.2020.11.002
4. Bright LME, Garren MRS, Ashcraft M, et al. Dual action nitric oxide and fluoride ion-releasing hydrogels for combating dental caries. ACS Appl Mater Interfaces. 2022;14(19):21916-21930. doi:10.1021/acsami.2c02301
5. Bryan NS, Tribble G, Angelov N. Oral microbiome and nitric oxide: the missing link in the management of blood pressure. Curr Hypertens Rep. 2017;19(4):33. doi:10.1007/s11906-017-0725-2
6. Joshipura K, Muñoz-Torres F, Fernández-Santiago J, Patel RP, Lopez-Candales A. Over-the-counter mouthwash use, nitric oxide and hypertension risk. Blood Press. 2020;29(2):103-112. doi:10.1080/08037051.2019.1680270

Annie Walters, MSDH, RDH, attended Northern Arizona University, where she spent time caring for individuals in Guatemala and Indian Health Service. She has a special interest in advancing access to care for individuals with specialized health-care needs. She’s a member of ADHA, and received her MS from the University of New Mexico, where she developed a chairside resource for RDHs to use for patients with specialized needs. She practices in Flagstaff, Arizona, and serves as part-time faculty at her alma mater. Contact her at [email protected].