Click here to review Part 1.

Diagnosis

There is no standard blood test for testing nitric oxide deficiency. However, it has become a little easier to assess NO deficiency. There are oral test strips, first developed by Dr. Bryan, such as the one pictured here from Designs for Health, that measure if a patient has adequate levels. If saliva turns the strip a bright pink, then there is sufficient NO being produced. It can have some inaccuracies. One would be if someone has eaten within an hour. The other is if someone has an infection in their mouth. In both cases, you would find it falsely elevated. The immune system's reaction to the infection will cause NO to elevate in the mouth. I have been testing patients, and I have found that many are showing a deficiency of NO. The reasons for this are generally because the process of converting nitrates to nitric oxide is disturbed by one or more factors. One reason is the use of fluoridated mouthwash and toothpaste and the effect it has on the nitrate to nitrite pathway. Fluoride is antimicrobial, and the conversion process is dependent on bacteria in the mouth to accomplish this. More than two hundred million Americans use mouthwash daily. The application of fluoridated mouthwash could offset the positive effects of nitric oxide obtained from dietary intake and exercise. Finding an alternative to fluoridated toothpaste and mouthwash is especially important if you have any symptoms of nitric oxide deficiency.

Adequate hydrochloric acid from the stomach is important in nitric oxide production. It converts nitrate to nitrite, and it may be adversely influenced by commonly used medications, namely PPIs and SSRIs. Approximately 8.6% of Americans use proton pump inhibitors (PPIs) such as Nexium, Prilosec, and Prevacid, which lower hydrochloric acid production and interfere with the nitrate to nitrite pathway.

Bryan's book mentions large studies showing a 30-40% increased risk of heart attack and stroke in those using PPIs for 3-5 years. Similar analysis has suggested a roughly 35% increased relative risk of dementia with multi-year use. These studies have raised questions about potential long-term vascular effects of chronic gastric acid suppression. Dr. Bryan and other researchers suggest chronic PPI use may reduce nitric oxide bioavailability and cause endothelial dysfunction. This could be due to effects on oxidative stress and the production of ADMA, as discussed in part 1.

There are two other forms of nitric oxide that need to be discussed. One is inducible nitric oxide synthase (iNOS). During infections, acute or chronic, inflammatory cytokines prompt macrophages to generate inducible nitric oxide. This process aids in eliminating the infection. However, in the case of chronic infections, the arginine in the citrulline-arginine pathway can become depleted, leading to the elevation of inflammatory cytokines and mitochondrial disorders.

The second is nNOS, or neuronal nitric oxide. nNOS is protective of the brain and peripheral nerves; the opposite is true of iNOS, which has a neurotoxic effect on the brain and nervous system. SSRIs can inhibit the efficiency of the nNOS pathway. With approximately 16.6% taking selective serotonin reuptake inhibitors such as Lexapro, Zoloft, and Prozac a substantial portion of the U.S. is risking NO deficiency with long term use of these drugs.

Treatment for low NO

Foods rich in nitrates, such as beets, Swiss chard, and spinach, also contain elevated levels of oxalates. This combination can potentially form kidney stones, so moderate consumption is advised. Fermenting beets removes the oxalates. Increasing foods that contain chlorogenic acid also helps. Chlorogenic acid is an antioxidant that helps preserve the nitric oxide we produce. Green coffee beans are highest in chlorogenic acid.

We all know that breastfeeding a newborn provides more nutrients than formula. In one of Dr. Bryan’s studies, he found that colostrum, the first mother’s milk, contained the highest amount of nitrite of any food. After about a week, when the infant’s microbiome was established, breast milk production switched to nitrate, and then the infant’s oral bacteria were able to convert it to nitrite. The brilliance of Mother Nature!

Some people believe that consuming the amino acids citrulline alongside arginine is a crucial method for producing NO within the body. This theory is being challenged by experts such as Dr. Nathan Bryan, who believe this approach (except for young, healthy individuals) can be counterproductive. Dr. Bryan feels there are more effective treatments. Hawthorn berries have a long history in herbal medicine as being beneficial for the heart. Now, science has discovered that it has polyphenol compounds that boost nitrate-to-nitrite conversion by activating the nitrite reductase pathway. Using BH4 as a supplement is an important consideration in NO deficiency because a deficiency in BH4 results in NOS uncoupling and impaired NO production. This uncoupling means that instead of making NO, we make a free radical called superoxide, which combines with nitric oxide to form another free radical, peroxynitrite. Both free radicals will damage proteins, mitochondria, further limit BH4 availability and nitric oxide production, and age us prematurely. It may also present itself as peripheral neuropathy, such as pain and sensory disturbances.

Exposure to sunlight, infrared light, or an infrared sauna may also help to increase NO levels. An appropriate level of nitric oxide is also crucial for ATP generation in mitochondria.

Dr. Bryan estimates that our daily nitrate needs are 300-400 mg. Americans consume only around 150 mg daily, largely because they do not eat enough vegetables.

There are several products from different companies that increase NO too. Here is a list of several companies, their products, and the ingredients in them that stimulate NO production.

Except for the products from N1O1, I stock the other products.

Final Thoughts

Understanding nitric oxide's role in the cardiovascular system as a signaling molecule will revolutionize treatments for high blood pressure and heart disease. This is sorely needed because heart disease is the leading cause of death in America. Beyond heart issues, Dr. Bryan is collaborating with neurologist Dr. David Perlmutter. Their joint effort focuses on creating novel products and pharmaceutical treatments for Alzheimer's and other neurodegenerative conditions, using pharmaceutical-grade nitric oxide. Plus, products for diabetic ulcers, and a nitric oxide pharmaceutical for treating viral infections like COVID-19 are on tap too.

I want to thank Dr. Nathan Bryan for his decades of devotion to this important topic and for his excellent book. His research will no doubt help doctors and patients unlock the mechanisms behind many health problems that in previous decades were not well understood. His discoveries have led to patents and products from his company N1O1.