I have been listening to Dr. Nathan Bryan for over a year on different podcasts and finally got around to reading this book by him. Although nitric oxide was discovered in the 1700s, its role as a signaling molecule for the cardiovascular system was discovered in 1980. In 1998, Lou Ignarro, Robert Furchgott, and Ferid Murad received the Nobel Prize in Physiology or Medicine for their research on it. This led Dr. Bryan to apply their discovery to practical knowledge for physicians and patients about the importance of nitric oxide (NO) to improve health outcomes. With over ninety-five research articles to his credit, Dr. Bryan’s book explains his 20-year investigation into understanding why this molecule is so important to our health.
From this chart you can see that nitric oxide (NO), which is a gas, is important for nearly every facet of human physiology. It is important for the cardiovascular system, in helping to lower blood pressure, and reducing the risk of clotting. The nervous system needs NO to maintain cognitive function. The immune system needs NO for killing viruses and bacteria, and the respiratory system for helping bronchial dilation. For the urogenital system, it is needed for sexual arousal and fertility. The excretory system and the kidneys, and the endocrine system for hormone production all need NO. Since the 1870s, we have used diluted nitroglycerin to treat angina and atherosclerosis in patients to increase blood flow. It is believed that it is nitric oxide in the nitroglycerin that enables it to work. We now know that through a series of reactions, nitroglycerin and nitric oxide are both metabolized into another substance called cyclic guanosine monophosphate (cGMP) which causes smooth muscle relaxation and results in dilation of blood vessels. Nitric oxide also prevents the deterioration of the telomeres of our DNA and potentially extends our lifespan. NO helps with mitochondrial and stem cell function. Adequate NO is vital to improving insulin resistance and diabetes. Glucose transporter protein (GLUT4) brings glucose into the cell. Dr. Bryan found that diabetic mice given sodium nitrite in their drinking water had lower insulin and fasting glucose levels because of the activation of GLUT4 than those mice that did not have the sodium nitrite. For those who have trouble acclimating to altitude, there is evidence that NO can help with that too because of its ability to increase oxygen to tissues and the brain with the dilation of blood vessels.
With NO being so important, you might be wondering how we get NO. The production of NO occurs in two ways.
One pathway is called the nitrate to nitrite pathway. In this pathway, NO is made by beneficial bacteria in saliva by the conversion of nitrate rich foods into nitrite. Nitrate rich foods would include arugula, celery seeds, and beets. We also can get nitrates from cured meats. There is a perception that nitrates from cured meats are bad for us, but that assumption can be challenged. The major benefits of NO are the effects it has on interior of an artery called the endothelium. Endothelium NO is also called eNOS. The nitrite made in the mouth is subsequently stored in the salivary glands or in the blood. It can then act upon the arterial walls by expanding it and improving blood flow. Dr. Bryan’s research tested organic versus conventional produce and surprisingly found that organic produce had lower levels of nitrates. Conventional non-organic farming uses artificial inputs such as nitrogen fertilizers that result in higher levels of nitrates. This is not a recommendation to switch to non-organic produce; I am just stating the facts. Conventional foods with pesticides have their own problems.
The second pathway is called the Nitric Oxide Synthase pathway (NOS pathway) or L-Arginine pathway. Some call it the citrulline-arginine pathway. This pathway requires the amino acid arginine. Arginine is plentiful in our diet, with the typical American ingesting about 4.5 grams of arginine each day. A rare genetic disorder would be one of the few reasons someone would be deficient in arginine. Arginine goes through a 5-step process using nitric oxide synthase to convert arginine to nitric oxide. However, the nitric oxide synthase enzyme needs about five nutrients for that pathway to work efficiently. It is the absence of one, BH4 (tetrahydrobiopterin), that is most considered to be the rate-limiting factor in making NO.
BH4 (tetrahydrobiopterin) is essential for proper nitric oxide synthase (NOS) function. We need folinic acid and vitamin C to make BH4. BH4 not only helps produce nitric oxide, but it is also essential for making neurotransmitters like dopamine and serotonin.
When BH4 levels are insufficient, NOS becomes “uncoupled.” Instead of converting arginine into nitric oxide, the enzyme begins generating superoxide, increasing oxidative stress. Elevated oxidative stress can impair the enzyme responsible for breaking down ADMA (asymmetric dimethylarginine), allowing ADMA levels to rise. Higher ADMA concentrations inhibit nitric oxide synthase and are associated with atherosclerosis, hypertension, heart failure, and increased all-cause mortality.
At the same time, when nitric oxide production is impaired, arginine may be diverted toward alternative metabolic pathways such as arginase, which produces urea. The combined effect is reduced nitric oxide availability and increased oxidative stress — a pattern linked to vascular dysfunction and cellular aging processes.
We also produce NO from exercise. Aerobic exercise, such as walking, and anaerobic exercise, such as sprinting or lifting weights, are both effective in raising NO levels in the body. However, this production is within the second pathway, the L-arginine pathway.
As we age, it becomes more difficult to maintain adequate nitric oxide levels. By age 40-50 we make 40-50% less than what we did when we were younger, and by age 60 it decreases by 85%.
Final Thoughts
This is just the beginning of the discussion of nitric oxide. In Part 2, I will discuss how to diagnose nitric oxide deficiency and how to treat it
