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In the NO

The Science of Nitric Oxide and Outrageous Muscle Pumps

It’s the latest rage in body’building supplements: nitric oxide boosters, food supplements that supply the amino acid L-arginine. Since L-arginine is the substance from which the body synthesizes nitric oxide, taking NO boosters promotes increased blood flow to muscle due to a rapid dilation of blood vessels. The result is a pronounced muscle pump. While you’re probably aware of the psychological benefits of getting a pump’like the impetus to train harder’you may not know about the physical benefits. The increased blood flow provides a greater delivery of oxygen and nutrients to muscle, which may have anabolic, a.k.a. muscle-building, effects.

What isn’t revealed in the many ads that tout the benefits of nitric oxide supplements are the myriad ways that NO affects health and fitness. While nitric oxide is unequivocally involved in blood vessel dilation, that’s just a small part of its role in the human body. Those who know nothing about nitric oxide supplements likely have heard of the drug Viagra, which is prescribed mainly to treat impotence. It does that by enhancing nitric oxide release in the penis, which in turn promotes a blood flow so powerful that it can overcome defects in the blood flow system caused by disease.

NO Comes to the Fore

Until about 20 years ago NO was dismissed as a junk substance that had few, if any, redeeming qualities. After all, how could something that’s a component of smog and acid rain have any health benefits? Indeed, since nitric oxide is a gas that dissipates in six to 10 seconds, how could it have time to accomplish anything important?

Another key point: Not only is NO a gas, but it’s a free radical as well. Free radicals are unpaired electrons that are usually created as by-products of normal oxygen metabolism. They can adversely affect health in a number of ways, mainly by attaching themselves to other electrons, such as those found in various fats, creating metabolic havoc that’s been linked to everything from cancer to cardiovascular disease to premature aging.

Less well known are the vital roles that free radicals play in helping to destroy invading pathogenic organisms, such as bacteria, as part of the immune response and in the production of thyroid hormone. Although it’s a free radical, NO is a relatively stable substance.

Nitric oxide was first isolated in 1772 by Joseph Priestley, who also discovered oxygen and is considered the father of chemistry. As noted, however, no particular significance was attached to it until 1987, when scientists were looking to find the true identity of a mysterious substance that potently dilated blood vessels. They referred to it as ‘endothelial relaxation factor.’ The endothelium is the lining of blood vessels, which are composed of smooth muscle. The unknown substance appeared to relax such muscle upon contact, leading to a dilating effect.

In various experiments scientists found that touching the surface of any blood vessel with acetylcholine led to a rapid dilation. Eventually, they discovered that the effect occurred because the acetylcholine promoted the release of nitric oxide. That led to an explosion of studies looking at the effects of nitric oxide in the body. Thanks to the work that followed, we now know that NO has both good and bad effects, depending on when, where and how much is released.

In the brain it acts as a neurotransmitter. In smooth muscle it has a relaxing effect that can lower blood pressure. Under pathological conditions, however, the intense release of NO is involved in septic shock, in which the blood pressure drops too low, too fast, resulting in the failure of multiple organs and death. In fact, the effects of NO in the body are so diverse that one noted researcher, Dr. Solomon Snyder, declared, ‘In my 25 years of research I have never seen a molecule that so pervasively affects normal and abnormal body functions.’ In 1998 three scientists shared the Nobel Prize in medicine for their research into the effects of nitric oxide.

NO Power: How It Works

NO is synthesized in the body from the amino acid L-arginine through the action of the enzyme nitric oxide synthase. NOS exists in three forms, or isoforms: neuronal NOS (NOS-1), inducible NOS (NOS-2) and endothelial NOS (NOS-3). Depending on where they are, they produce various effects. For example, NOS-1 acts as a neurotransmitter in the gastrointestinal tract, and animal studies show that it’s involved in appetite regulation. It’s also the isoform that’s involved in penile erection. ALL NOS-2 is particularly active in immune reactions and is part of the inflammatory response. It also tends to be the bad guy of the three enzymes, producing too much NO at the wrong time, leading to serious health problems. NOS-3 governs blood flow and pressure, as well as inhibiting blood platelets, which are involved in the clotting process.

Nitric oxide works with hemoglobin to deliver oxygen to cells. Perhaps its most familiar function relates to nitroglycerin, which is given to people who suffer from a narrowing of coronary arteries, the blood vessels that feed the heart muscle. When the heart doesn’t get enough oxygen as a result of occlusion of the coronary arteries, taking nitroglycerin will rapidly relieve pain because it’s converted into NO. The NO immediately relaxes the smooth muscle in the tightened arteries, leading to increased blood flow and a relief of pain. It does that by stimulating an enzyme called guanylate cyclase, which leads to an increase of cyclic GMP, the substance that relaxes smooth muscle.

Nitric oxide helps prevent cardiovascular disease in several ways. It prevents the blood platelet adhesion that creates internal blood clots, which can impede blood circulation to the heart, leading to a heart attack or stroke. Animal-based studies show that taking supplemental arginine can both prevent and reverse atherosclerosis, the buildup of plaque in arteries that is the underlying cause of most heart attacks and strokes.

The brain needs NO for memory formation, but released at the wrong time and in too high a quantity, NO can also promote brain pathology. An example of that occurs during a stroke, when an excess amount of glutamate, an amino acid that stimulates neuron activity, is released, leading to overstimulation of brain neurons. The glutamate surge creates an increased calcium flux into the brain, where the calcium, in turn, activates NOS, causing NO to be released at the wrong time and in too great a quantity. Under those conditions NO acts like a typical free radical, destroying vital brain neurons.

Scientists know that the primary cholesterol carrier in the blood, low-density lipoprotein, is dangerous only when oxidized. It turns out that oxidized LDL inhibits the activity of local NOS in blood vessels, leading to elevated blood pressure and further damage. Studies published a few years ago found that after people eat a high-fat meal, their arteries contract and blood pressure can soar. But the same studies show that taking vitamins C and E after the meal prevents the effect. Basically, the free radicals produced from the high-fat meal interfere with NOS function, lowering NO in the blood vessels, but antioxidants such as vitamins C and E prevent that and also prevent the clamping of the blood vessels.

NO and Exercise

All three isoforms of NOS are found in skeletal muscle, principally neuronal NOS. NO not only increases blood flow in muscle but is actively involved in muscle contraction and force production as well. That implies that a lack of NO would lead to muscular weakness. NO in muscle is also involved in respiration through increased oxygen delivery and in promoting glucose uptake into muscle. Just contracting a muscle increases NO because the contraction elevates intracellular calcium, which activates NOS and, consequently, NO.

Studies have shown some interesting relationships between exercise and NO release. The increase in blood flow that occurs with aerobic exercise produces a shearing effect inside blood vessels that is a known impetus of upgraded NO production and may explain the often noted blood pressure’lowering effects linked to aerobics.

Training small muscle groups, such as the forearms, leads to an upgrading of NO release in that area but doesn’t affect NO release elsewhere in the body. On the other hand, training larger muscle groups, such as the legs, results in upgraded NO release not only in the trained muscles but also throughout the body. Studies show that in those who exercise regularly, resting levels of NO are higher, leading to, among other things, lower blood pressure at rest and a lower heart rate. The increased cholesterol metabolism that results from both weight training and aerobics leads to more efficient NO release, since unclogged blood vessels are far more efficient at synthesizing and releasing NO.

How much NO is released during exercise depends on several factors. Those who have damaged arteries, such as people with atherosclerosis, release more NO during exercise than those who have normal arteries. That’s probably a compensation effect to help the body increase blood circulation during exercise. Another factor is exercise intensity and volume. The harder and longer you train, the more NO your body produces. One study showed that an exhaustive 45-minute workout increased both neuronal and endothelial NOS activity in rats.1

People who have excessive bodyfat levels produce higher levels of NO, but in them the NO produced likely acts to increase overall body inflammation. Many scientists who study the effects of NO believe that the beneficial effects of exercise may be largely due to the interaction between exercise and NO release. All the risk factors linked to cardiovascular disease that are blunted by exercise, such as high blood fats, elevated insulin, high blood pressure and so on, are modified by NO, which is increased by exercise. NO and Nutrition

The key to maximizing the health benefits of NO is to maintain the optimal balance and release of it at the right time. As noted above, excess NO is linked to overall inflammation, which is believed to be the cornerstone of all major degenerative diseases, including cardiovascular disease, cancer, diabetes and Alzheimer’s disease.

Clearly, the nutrient most associated with NO production is the amino acid L-arginine, but many others also affect NO synthesis, release and control. Since out-of-control oxidation induced by free radicals inhibits the enzymes that produce NO, most dietary antioxidants will help preserve optimal NO functions in the body. Studies show that the polyphenol compounds found in red wine and green tea not only protect NO functions but also prevent the out-of-control inflammation that results from excess activity of inducible NOS. Methylated forms of L-arginine have no biological activity but do displace arginine in reactions that involve NO synthesis. Green tea is known to block that inhibiting effect.

Various herbs, including ginseng and Ginkgo biloba, increase the activity of NOS. Other nutrient interactions with NO include the following:

‘ Palmitic acid, a primary fatty acid found in saturated fat, inhibits NO production in blood vessels, which may explain the link between high-saturated-fat intake and CVD. Interestingly, another fatty acid found in meat, stearic acid, doesn’t have any effect on NO production.2

‘Cruciferous vegetables, such as broccoli, put the brakes on inducible NOS, which lowers inflammation.3

‘ The B-complex vitamin folic acid is particularly important for maintaining NO levels in blood vessels because a substance produced from folic acid is required to activate NO synthase enzymes.4

‘A deficiency of the trace mineral selenium leads to excess production of inducible NOS.

‘ Cocoa potently increases NO production, likely because of its rich flavonoid content.5

‘ Conjugated linoleic acid (CLA) lowers NOS in blood vessels but also inhibits inducible NOS.6

‘ N-acetylcysteine (NAC) inhibits inducible NOS, lowering inflammation.7

‘ In low or normal amounts NO promotes testosterone release. In higher amounts it effectively blocks testosterone synthesis and release in the Leydig cells of the testes.

‘Testosterone itself promotes NO release by stimulating the activity of NOS enzymes, as does IGF-1, the primary product of growth hormone.

‘ NO is not directly involved in growth hormone release, but it does play a role in the activity of growth-hormone-releasing hormone, which is released in the brain.

Add it all up, and it makes sense to say yes to NO.


1 Roberts, C.K., et al. (1999). Acute exercise increases nitric oxide synthase activity in skeletal muscles. Am J Physiol. 277:E390-E394.
2 Moers, A., et al. (1997). Palmitic acid but not stearic acid inhibits NO production in endothelial cells. Exp Clin Endocrin Diabetes. 105(Supp):78-80.
3 Chen, Y., et al. (2003). Suppression of inducible nitric oxide production by indole and isothiocyanate derivatives from brassica plants in stimulated macrophages. Planta Med. 69:696-700.
4 Das, U. (2003). Folic acid says NO to vascular diseases. Nutrition. 8:686-92.
5 Fisher, N., et al. (2003). Flavonal-rich cocoa induces nitric acid’dependent vasodilation in healthy humans. J Hypertension. 21:2281-2286.
6 Eder, K., et al. (2003). Conjugated linoleic acid lowers the release of eicosanoids and nitric oxide from human endothelial cells. J Nutr. 133:4083-4089.
7 Bergamini, S., et al. (2001). N-acetulcysteine inhibits in vivo nitric oxide production by inducible nitric oxide synthase. Nitric Oxide. 5:349-60. IM

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