Research on nitric oxide used to be in the realm of obscure scientists. All that changed in 1998 when the Nobel prize for physiology and medicine was awarded to three men who explained how production of this powerful natural compound—a gas called nitric oxide—is used by the body to fight off infection, reduce blood pressure, prevent abnormal blood clots, assure proper neurological function, and even to attain and maintain erections. It plays a role in our memory, sense of smell, and how the muscles in our intestines contract to move food along in the digestive process.

Dr. Robert Furchgott, Dr. Louis J. Ignarro, and Dr. Ferid Murad were American pharmacological researchers who did not work together, but each played a role in figuring out exactly why nitric oxide is so important, and how it works in the body.

Nitric oxide is a cousin of a better known compound called nitrous oxide, often used in dental offices. Prior to the work of these pharmacologists, most didn’t believe nitric oxide activity in the body was very important. After all, it is highly unstable and stays in its original form for only 10 seconds or less.

In fact, the Nobel awards committee is quoted as stating, “this was the first discovery that a gas can act as a signal molecule in the organism.” The discovery was startling because “nitric oxide is totally different from any other known signal molecule and so unstable that it is converted to nitrate and nitrite within 10 seconds.”

This discovery in the medical world has led to new treatments for erectile dysfunction, heart and lung disease, and physiological shock. But understanding of how nitric oxide, or NO, works in the body has major implications in natural medicine and botanical research, because many supplements have been shown to increase the creation of NO in the body.

NO is very popular with weight-lifters and other athletes because it supports circulation by dilating the blood vessels. Many people are aware of the cardiovascular benefits of NO but other biological activities include supporting the neurological system and communication between nerve cells by increasing oxygen delivery, aiding the immune system, assisting with blood pressure regulation, reducing inflammation, enhancing sleep, maintaining peristalsis (healthy gut motility), and many other crucial processes within the body.

The most common cardiovascular disease is called atherosclerosis, which is the build up of plaque and calcifications in artery walls which inhibits blood flow and can trap clots. If a blood clot is trapped for a long period of time, the tissue that blood vessel feeds starts to die. When this happens in the brain, this ic called a cerebrovascular accident (CVA) or stroke. When it happens in the vessels that nourish the heart muscle, it is called a heart attack. NO is important in cardiovascular health as it relaxes tight blood vessels and greatly enhances blood flow. The NO in our blood vessel walls offers protection from potential cardiovascular complications like high blood pressure, diabetic changes and plaque build-ups. One of the biggest challenges facing our cardiovascular system is atherosclerosis. If we want to live well and healthy to a ripe old age, we need to limit our risk of cardiovascular diseases, meaning we need to prevent and control atherosclerosis. One of the best ways to keep atherosclerosis in check is by maintaining optimal NO production in the body.

Amino Acids

In the human body, NO is synthesized from the amino acids L-arginine and L-citrulline. One theory on how to increase NO production in the body is to supplement with these amino acids in the hope that providing more raw materials will yield more of the desired end product.

The research shows that this can be useful. In an animal study, mice were given L-arginine for a week and infected with the parasite Plasmodium yoelii. The mouse group supplemented with L-arginine showed an increase in iNOS (inducible nitric oxide synthase) and subsequently NO production. This increase in NO equates to an enhanced immune response and greater protection from parasitic infections (Zheng 2015). In a human study, L-arginine supplementation over a six-month time period was shown to improve coronary endothelial function, even in the smallest blood vessels (Lerman A 1998). An animal study on the combination of oral L-citrulline and L-arginine also showed favorable results. This study demonstrated that the combination enhanced NO bioavailability, even with acute dosing (Morita 2014). Another combination study using L-citrulline and reduced glutathione exhibited synergistic effects on NO production (McKinley-Barnard 2015).

In addition to amino acids, botanicals have been found to stimulate NO production. Therefore, it should not be surprising that some of the best known herbal medicines for heart health also show significant impact on the NO system.

Grape Seed Extract

Offering support for cardiovascular issues, weight management, diabetes and immune function, grape seed extract’s (GSE) benefits are very far-reaching. One of the ways in which it supports the cardiovascular system may be through its connection to NO. GSE has been shown to increase NO levels in the body and is also a super potent antioxidant, simultaneously reducing reactive oxygen species (Feng 2010). A rat study done just this year demonstrated GSE’s ability to reduce blood pressure after only a single dose. One of the mechanisms for blood pressure regulation by GSE involves an increase in endothelial NO production (Pons 2015). The production of NO in the lining of the blood vessels (the endothelium) is critical for preventing atherosclerosis.

One challenge with GSE has to do with standardization. The key compounds that exert medicinal effects are called polyphenols, and the most powerful form in GSE are oligomeric proanthocyanins, or OPCs. A quality product should be standardized to a percentage of both polyphenols and OPCs. One standard would be a minimum of 90 percent total polyphenols and of that, a minimum of 80 percent that are actually OPCs. Another challenge has to do with size. OPCs come in a variety of sizes, and the largest, often called tannins, are too large to be absorbed, though they still count towards the label total. That means even a product with a high standardization may have limited benefits if the OPCs are not small enough to be absorbed and utilized. It may be wise to buy grape seed that is tannin free or at least standardizes its OPCs to only small particles so they can be properly absorbed.

Garlic

Garlic is one of the best known herbal interventions for improving cardiovascular function. One of the mechanisms behind garlic’s therapeutic actions may be the enhancement of NO production (Das 1995). In fact, many of garlic’s protective effects within the cardiovascular system overlap with NO’s activity. Even more impressive may be the combination of garlic with other antioxidants, like vitamin C, for even more powerful heart benefits. In a pilot human study, subjects were given vitamin C, garlic or a combination of the two. Vitamin C showed no anti-hypertensive effects by itself, whereas garlic showed significant lowering of the average systolic blood pressure. The combination of vitamin C and garlic significantly lowered both average systolic and diastolic blood pressures. When exploring the mechanism by which these changes occurred, it was found that endothelial cell NO synthesis increased 200 percent with garlic treatment alone and about 300 percent when combined with vitamin C (Mousa 2007).

Two Kinds of NO

Increasing NO production using amino acids, botanicals, and antioxidant vitamins is almost universally a good thing. NO production decreases with disease and age. However, there is another system in the body that, when triggered, releases massive amounts of NO that can be dangerous. This is only triggered by severe trauma or septicemia (massive infection in the bloodstream) that results in shock. Using healthy supplements that boost NO does not create these dangerous conditions.

While the majority of NO’s activities are beneficial for the body, there is also another side to the NO story. In instances of severe stress or trauma to the body, like septic shock, a reactive NO response is triggered that can be life threatening. In septic shock, the cardiovascular system becomes compromised by low blood pressure and blood vessel collapse, and subsequent organ failure or shutdown may follow. An influx of cytokines, which are certain inflammatory molecules, can trigger iNOS production, which plays a direct role in the immune system. This increase of iNOS results in a surge of NO, which can drop blood pressure even further and lead to perfusion issues and hypoxia. It is important not to confuse these two physiological processes that involve nitric oxide.

The Future

Almost two decades have passed since three pharmacologists discovered the secret power of NO and were awarded the Nobel prize. Since that time, thousands of research papers have been published on nitric oxide. Scientists are still investigating the many ways NO influences our health, but one thing is certain: dietary supplements eliciting NO production can have tremendous health benefits! VR

Resources:

Altman, Lawrence K. Three Americans Awarded Nobel for Discoveries of How a Gas Affects the Body. The New York Times. Published: October 13, 1998 Available at: http://www.nytimes.com/1998/10/13/us/three-americans-awarded-nobel-for-discoveries-of-how-a-gas-affects-the-body.html?pagewanted=1. Accessed 7-16-15

Das I, Khan NS, Sooranna SR. Potent activation of nitric oxide synthase by garlic: a basis for its therapeutic applications. Curr Med Res Opin. 1995;13(5):257-263.

Feng Z, Wei RB, Hong Q, Cui SY, Chen XM. Grape seed extract enhances eNOS expression and NO production through regulating calcium-mediated AKT phosphorylation in H2O2-treated endothelium. Cell Biol Int. 2010 Oct;34(10):1055-1061.

Lerman A, Burnett JC, Higano ST, McKinley LJ, Holmes DR. Long-term L-Arginine Supplementation Improves Small-Vessel Coronary Endothelial Function in Humans. Circulation. 1998;97:2123-2128.

McKinley-Barnard S, Andre T, Morita M, Willoughby DS. Combined L-citrulline and glutathione supplementation increases the concentration of markers indicative of nitric oxide synthesis. J Int Soc Sports Nutr. 2015 Jun 10;12:27.

Morita M, Hayashi T, Ochiai M, Maeda M, Yamaguchi T, Ina K, Kuzuya M. Oral supplementation with a combination of L-citrulline and L-arginine rapidly increases plasma L-arginine concentration and enhances NO bioavailability. Biochem Biophys Res Commun. 2014 Nov 7;454(1):53-57.

Mousa AS, Mousa SA. Cellular effects of garlic supplements and antioxidant vitamins in lowering marginally high blood pressure in humans: pilot study. Nutrition Research. 2007;27:119-123.

Pons Z, Margalef M, Bravo FI, Arola-Arnal A, Muguerza B. Acute administration of single oral dose of grape seed polyphenols restores blood pressure in a rat model of metabolic syndrome: role of nitric oxide and prostacyclin. Eur J Nutr. 2015 April 11 (Epub ahead of print).

Titheradge MA. Nitric oxide in septic shock. Bioenergetics. May 1999;1411(2-3):437-455.

Zheng L, Pan Y, Feng Y, Cui L, Cao Y. L-Arginine supplementation in mice enhances NO production in spleen cells and inhibits Plasmodium yoelii transmission in mosquitoes.

Cheryl Myers is an integrative health practitioner, author and an expert on natural medicine. Additionally, she has a degree in psychology and worked for several years in psychiatric care. She is a nationally recognized speaker who has been interviewed by the New York Times, Wall Street Journal and Prevention Magazine. Myers is the head of Scientific Affairs and Education for EuroPharma, Inc. (www.europharmausa.com).