Why should we care about the effects of mouth rinses on oral nitric oxide production?

Nitric oxide has been a major topic of discussion among my colleagues the last few years, especially as we become more deeply immersed in the science of oral-systemic connections, whole-body health, and biological patient care. While I was in dental hygiene school in the mid-1980s, researchers were discovering the biological significance of nitric oxide. Robert F. Furchgott, PhD, Louis J. Ignarro, PhD, and Ferid Murad, MD, PhD, were awarded the Nobel Prize in Physiology or Medicine in 1998 for their combined research on nitric oxide as a signaling molecule in the cardiovascular system.¹ Yet, I knew nothing about this amazingly important molecule until I learned of Nathan S. Bryan, Janet Zand, and Bill Gottlieb's book, The Nitric Oxide (NO) Solution in 2015.²

Nitric oxide's role in health

Nitric oxide is one of the most important molecules produced by our bodies, and it is vital for human health. It functions as a vasodilator, improving blood circulation by relaxing smooth muscle cells in blood vessels, and plays a key role in the cardiovascular, immunological, gastroenterological, pulmonary, nervous, reproductive, and musculoskeletal systems. It reduces blood pressure, inhibits platelet aggregation and leukocyte adhesion to endothelium, and decreases oxidative stress, inflammation, atherosclerosis, dyslipidemia, coronary artery disease, and stroke. It also acts as a neurotransmitter.³ Every chronic disease involves the loss of nitric oxide.

While the body synthesizes nitric oxide through various pathways, the oral cavity also contributes significantly to its production.⁴ This is called the enterosalivary pathway and it depends on a healthy, diverse microbiome, adequate saliva, and a diet rich in nitrates such as spinach, beets, and celery. These foods are converted to nitrites in the saliva by commensal aerobic bacteria, which secretes the nitrites into the saliva, concentrating nitrite levels in the mouth. This process is facilitated by a protein called sialin in the salivary glands. The saliva is swallowed, and if the stomach is the correct acidic pH, it is reduced to nitric oxide and enters the bloodstream through the small intestine.⁵

Why this matters in dentistry

Understanding the vital role that nitric oxide plays in the body and the importance of the oral microbiome in facilitating the production of nitric oxide is important for dental professionals. We often prescribe oral rinses or support the use of over-the-counter (OTC) rinses without fully realizing their possible deleterious effects on the oral microbiome and the processes we rely on it to complete.

For decades, the gold standard mouth rinse for reducing gingival inflammation was chlorhexidine gluconate,⁶ but in 1999 a study reported that chlorhexidine gluconate negatively affected gingival fibroblast proliferation, collagen and noncollagen protein production, and possibly wound healing.⁶ Yet even now some practices are unaware that the across-the-board recommendations to prescribe chlorhexidine gluconate for all surgical and periodontal patients is no longer the gold standard.

Chlorhexidine gluconate rinse not only interferes with wound healing as explained above, but its bactericidal effect can dramatically alter the oral microbiome.⁷ It can control pathogens but damages commensal bacteria as well, including those required for the synthesis of nitric oxide.⁷ Use of 0.12% chlorhexidine gluconate may destroy more than 90% of oral nitrate-reducing bacteria, resulting in an 85% reduction in the production of nitric oxide.⁷

If chlorhexidine gluconate is not an optimal choice for oral rinses, which-if any-should we recommend to our patients?

Best mouth rinses

Studies show that mouth rinses with antimicrobial activity against nitrate-reducing oral bacteria are capable of decreasing nitric oxide production and inducing adverse systemic effects.⁹ Rinses with antimicrobial ingredients such as chlorhexidine gluconate, hydrogen peroxide, cetylpyridinium chloride, chlorine dioxide, povidone iodine, and essential oils may all have negative systemic effects on nitric oxide and therefore should be used with caution.⁹

A proof-of-concept study showed that StellaLife, a homeopathic rinse, did not have cytotoxic effects on the oral microbiome but did have anti-inflammatory effects.¹⁰ Large-scale, randomized controlled research needs to be done, but this proof-of-concept study gives me confidence that a homeopathic product could be a safer choice when looking to reduce oral inflammation while protecting the oral microbiome and the enterosalivary pathway of nitric oxide production.

Regular use of antiseptic mouth rinses interferes with nitric oxide production and can have a negative effect on many other systemic processes as well. A longitudinal, three-year study demonstrated that daily use of OTC mouth rinses, irrespective of their active ingredients, represented an independent risk factor for the development of prediabetes, diabetes mellitus, and hypertension.⁷

For the future

We must ask ourselves if the cost of controlling pathogens and reducing inflammation with oral rinses is too high. Should we eliminate the use of oral rinses completely, or can we use specific rinses judiciously, for as short a time as possible (days? weeks?) to eradicate pathogens, and then switch to less harmful means (probiotics?) to restore a healthful and balanced microbiome? I don't have all the answers. I trust that research on this very important topic will continue and bring deeper insights.

References:

1. Ignarro LJ. Nitric oxide is not just blowing in the wind. Br J Pharmacol. 2019;176(2):131-134. doi:10.1111/bph

2. Bryan N, Zand J, Gottlieb B. The Nitric Oxide (NO) Solution. Neogenis Labs; 2010.

3. Rosselli M, Keller PJ, Dubey RK. Role of nitric oxide in the biology, physiology and pathophysiology of reproduction. Hum Reprod Update. 1998;4(1):3-24. doi:10.1093/humupd/4.1.3

4. Ambe K, Watanabe H, Takahashi S, et al. Production and physiological role of NO in the oral cavity. Jpn Dent Sci Rev. 2016;52(1):14-21. doi:10.1016/j.jdsr.2015.08.001.

5. Qu XM, Wu ZF, Pang BX, et al. From nitrate to nitric oxide: the role of salivary glands and oral bacteria. J Dent Res. 2016;95(13):1452-1456. doi:10.1177/0022034516673019

6. Mariotti AJ, Rumpf DA. Chlorhexidine-induced changes to human gingival fibroblast collagen and non-collagen protein production. J Periodontol. 1999;70(12):1443-8. doi: 10.1902/jop

7. Bescos R, Ashworth A, Cutler C, et al. Effects of chlorhexidine mouthwash on the oral microbiome. Sci Rep. 2020;10(1):5254. doi:10.1038/s41598-020-61912-4

8. Muniz FWMG, Cavagni J, Langa GPJ, et al. A systematic review of the effect of oral rinsing with H2O2 on clinical and microbiological parameters related to plaque, gingivitis, and microbes. Int J Dent. 2020;2020:8841722. doi:10.1155/2020/8841722

9. Woessner M, Smoliga JM, Tarzia B, et al. A stepwise reduction in plasma and salivary nitrite with increasing strengths of mouthwash following a dietary nitrate load. Nitric Oxide. 2016;54:1-7. doi:10.1016/j.niox.2016.01.002

10. Froum S, Estrin N. Mouth rinses, high blood pressure, and nitric oxide. Perio Implant Advisory. April 4, 2024.