Say Yes to NO

Based on the sheer numbers of nitric oxide–boosting supplements on the market, bodybuilders must love them. It’s not difficult to see why: NO-boosting supplements increase muscle pump during exercise. They all contain the amino acid L-arginine, which is the main nutritional ingredient in NO production.

Only recently has science recognized the importance of NO in human health. In the past chemists viewed it as a junk product, the main constituent of smog. NO is both a gas and a free radical, used by immune cells to kill bacteria and other disease-causing invaders of the body. Ads for nitric oxide supplements sometimes mention that the product was based on the work of “Nobel Prize–winning scientists.” In reality, those scientists didn’t work on food supplements, but they did discover the precise functions of NO, a feat that earned three of them the Nobel Prize in physiology in 1998.

One of those scientists, Louis J. Ignarro, a professor of pharmacology at UCLA, is the most vociferous proponent of using arginine as a means of increasing NO production in the body. In 2005 he wrote a book for the general public, No More Heart Disease, in which he suggests that increasing NO production through supplemental arginine will prevent heart attacks and strokes. Ignarro generated much criticism from fellow academics when he developed a food supplement called Niteworks, which combined arginine with antioxidants to prevent the premature breakdown of the nitric oxide produced from the arginine.

The research on NO is prodigious, showing that it’s involved in brain neurotransmission, immune response and cardiovascular function. When NO synthesis is reduced, as occurs with several diseases, various pathologies become apparent. They include elevated blood pressure, cardiovascular disease, diabetes and impotence. The discovery of the precise functions of NO led to the development of Viagra, which was initially formulated to treat high blood pressure.

NO is ephemeral, lasting only six to 10 seconds before it’s degraded. That’s the reason it took so long for scientists to recognize its functions: It’s a biochemical phantom. The body synthesizes NO from L-arginine using three different NO synthetase enzymes as well as folic acid and riboflavin. Both nutrients should be included in a properly designed NO supplement, yet for some reason, they rarely are.

Pump It Up

NO production in the endothelium, or lining of blood vessels, is stimulated by rapid blood flow and increased arterial pressure, as occurs during exercise. The familiar muscle pump is, in fact, caused by that uptick in nitric oxide production for the purpose of increasing blood circulation to the working muscles. At a molecular level, NO activates the enzyme that stimulates the synthesis of cyclic GMP, which relaxes smooth muscle, such as that lining the arteries. That causes vasodilation, the expanded-blood-vessel effect.

While the muscle pump derived from using an NO-boosting supplement is great for the psychological effects, such as increasing training drive, if that were all it did, it wouldn’t be too impressive. In fact, recent research shows that NO is involved in bodyfat control and glucose uptake into muscle.

Less Fat, Fuller Muscles

Studies show that NO aids fat oxidation, a.k.a. burning, in muscle, heart, liver and fat tissue. It also inhibits the production of fat in fat cells. A substance called AMPK is known to stimulate fat burning in muscle, and some preliminary evidence shows that it may work by modulating nitric oxide levels. Doing that would increase blood flow and nutrient uptake in muscles while also favoring the burning of fat and glucose in muscle. Giving arginine to obese rats doubled the level of AMPK mRNA levels in their fat tissue.

In the mitochondria of cells, where energy is produced, NO also increases blood flow and regulates the electron transport system that produces ATP, the immediate source of energy.

The mitochondria are also where fat is oxidized, and NO aids the production of additional mitochondria in cells, which means more fat being burned. Rats that were given arginine burned more fat in their abdomens, an effect attributed to higher mitochondria activity. One way that aerobic exercise reduces bodyfat is by increasing the numbers and activity of cellular mitochondria, an effect that is presumably enhanced when arginine enters the equation.

Rat-based studies have also shown that supplemental arginine normalized plasma glucose and prevented elevated glucose, which suggests that it may help prevent diabetes. Diabetics have heightened oxidative activity, which lowers NO production. That may lead to such complications as hypertension and cardiovascular disease. Unfortunately, a form of NO linked to inflammation is overproduced in obese people, adding to the inflammation characteristic of diabetes.

You wouldn’t want your body to overproduce NO—for various reasons. Having higher-than-normal amounts of NO inactivates the catecholamines, such as epinephrine and norepinephrine, which are required for fat mobilization and oxidation. Normal levels of NO, however, increase the rate of fat burning. Having high levels of nitric oxide also triggers protein breakdown while inhibiting muscle protein synthesis. Those who have normal levels of NO, though, benefit from its anabolic effects of stimulating the release of insulin and growth hormone.

Heart Health

Animal-based studies show that interfering with NO synthesis leads to cardiovascular disease. NO inhibits the enzyme that blocks carnitine activity, which results in more fat being burned, particularly in the liver. Obese diabetic rats that got arginine at a level of 2 percent of the total content of their diets had a 20 percent reduction in low-density lipoprotein, a.k.a. the bad cholesterol, and triglyceride. In humans increasing dietary arginine from 2.5 to 7.5 grams a day resulted in a rise of protective high-density lipoprotein with a drop in blood pressure.

NO to Grow?

Do nitric oxide supplements work? Anecdotal evidence reported by many consumers shows a clear increase in muscle pump, pointing to more NO being produced. Several studies that have examined the use of specific NO supplements have shown no changes in muscle mass or fat loss. On the other hand, the studies do show increased maximum strength over what happened with the subjects who got placebos. Some scientists suggest that arginine may be of more use to those with pathological conditions that cause a decline in normal NO synthesis.

Still other studies show that nitric oxide is indeed involved in muscle growth, as well as in contractile gene expression during overload—as occurs during weight training. NO is also a primary signal for the activation of muscle satellite cells, the main process involved in muscle repair and growth following exercise.

Although arginine is the primary nutrient in NO production, a number of others aid in the process, including folic acid, riboflavin, omega-3 fatty acids, antioxidants (not green tea, which blunts NO synthesis) and phytonutrients, which are found in fruits and vegetables. One study found that the polyphenol antioxidants in apples boost NO production.

Moderate consumption of alcohol increases NO production, which may be linked to the cardiovascular-protection effect of alcohol taken in small amounts. Aged garlic also raised NO levels in the laboratory, an effect found to be independent of its arginine content. A recent study found that habitual intake of dark chocolate lowered blood pressure while increasing NO, which was likely due to the polyphenol antioxidant content of cocoa.

While no toxic effects are linked to NO supplements, taking large doses of arginine, more than nine grams at a time, is linked to gastrointestinal stress. That has to do with water and mineral secretion induced by a high level of NO being produced in the gut that leads to diarrhea.

A dose of three to six grams of arginine is considered safe and free of side effects. One case history involved a person who used an NO supplement and had hemorrhages in his eyes. The problem was traced to vasodilation and a decreased blood-clotting effect brought on by increased NO levels. That’s likely an idiosyncratic event, not common to most users of NO supplements. If nothing else, it clearly shows that NO-boosting supplements do boost NO production.

References

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Wu, G., et al. (2000). Arginine nutrition and cardiovascular function. J Nutr. 130:2626-29.
Sellman, J.E., et al. (2006). In vivo inhibition of nitric oxide synthase impairs up-regulation of contractile protein mRNA in overloaded plantaris muscle. J Appl Physiol. 100:258-65.
Peri, L., et al. (2005). Apples increase nitric oxide production by human saliva at the acidic pH of the stomach: a new biological function for polyphenols with a catechol group? Free Rad Biol Med. 39(5):668-81.
Abou-agag, L.H., et al. (2005). Evidence of cardiovascular protection by moderate alcohol: role of nitric oxide. Free Rad Biol Med. 39: 540-548.
Morihara, N., et al. (2002). Aged garlic enhances production of nitric oxide. Life Sci. 71:509-517.
Taubert, D., et al. (2007). Effects of low habitual cocoa intake on blood pressure and bioactive nitric oxide. JAMA. 298;49-60.
Grimble, G.K. (2007). Adverse gastrointestinal effects of arginine and related amino acids. J Nutr. 137(suppl):693S-1701S.
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