How Are Nitric Oxide Stimulators Supposed to Help Me and Why is Arginine Involved?

As best as I can remember these types of supplements really became popular around 2002–2004. In my opinion the product that really made this category popular was NO2, which was manufactured by Medical Research Institute. Whether that’s important or not remains to be determined, but for the most part this category of supplements exploded in popularity and continues to be popular. Nitric oxide is a substance that when produced results in vasodilation of the vascular beds. Vasodilation means the blood vessels expand. Think of the blood vessel as a garden hose or a tube. The larger the hose, the less resistance which will be felt by whatever is going through the hose (blood in this instance). With less resistance, an increased ability to delivery blood to working tissues occurs. Additionally, because the size of your blood vessels increases, the extent to which the volume of blood occupies the vessels (or pressure, specifically blood pressure) goes down. Of course, you remember that physics relationship from high school, don’t you? In summary and from a bodybuilding perspective, increasing the amount of nitric oxide in the blood or stimulating increases in nitric oxide leads to increased blood flow. With greater blood flow, the delivery of valuable nutrients such as carbohydrate, proteins, amino acids, etc. goes up and with a greater supply of nutrients the muscle should be able to adapt more effective to the exercise demands placed upon it. At least that’s how it is supposed to work in theory.

How does arginine find itself in the middle of all this? Arginine is a conditionally essential amino acid, which means the body produces it on its own, but during times of stress (exercise or disease) or increased demand, it requires that additional arginine comes from dietary sources [1]. Furthermore, arginine is a substrate for nitric oxide synthase (NOS), the key rate-limiting enzyme responsible for the body’s production of nitric oxide. In other words without adequate levels of arginine your cells will be unable to optimally produce nitric oxide. If you’re following along, this adds another step to the theoretical train associated with how arginine supplementation and nitric oxide stimulation may be effective.

Step #1 – Increased arginine levels in the blood (through supplementation or dietary sources, but that’s not typical) should lead to increased nitric oxide levels.
Step #2 – Increased nitric oxide causes vasodilation in our blood vessels.
Step #3 – Vasodilation goes on to increase the blood flow of nutrients to the working muscles.
Step #4 – Greater blood flow will deliver more nutrients throughout your body, specifically to the muscles you just targeted at the gym.
Step #5 – A greater delivery of nutrients to these muscles will result in greater adaptations to exercise training such as improved strength, muscle mass and body composition.

In a nutshell that is the basis behind arginine supplementation and nitric oxide modulators. All of the theoretical support in the world is great, but what scientific support is available to support the idea of supplementing with arginine?

The most troubling part starts at the beginning. Many factors are responsible for increasing blood flow and a recent study suggested that of the viable mechanisms to stimulate an increase in blood flow, nitric oxide played a minor role [2], and that’s assuming the dosage and oral delivery of arginine did increase nitric oxide. Which brings me to another key point, a large part of the basis for including arginine is because of two studies which found that infusing 20–30 grams of arginine increases nitric oxide and blood flow [3, 4]. Upon considering most supplements use a much lower dosage of 3–5 grams per serving and a good portion of the available arginine is removed in the intestines (meaning it’s never absorbed into the blood), it’s possible that oral ingestion of arginine may have minimal impact. In fact, this was supported by studies that provided oral doses of 10–20 grams (3-7x the amount provided in supplements) and found it to have no positive effect over increasing circulating nitric oxide or blood flow [5-7]. All this being said, extremely high doses (100–250 mg/pound of body or 15–62 grams for 150–250 pound men) of arginine have been shown to help increase collagen growth, immune responses and facilitate growth hormone and insulin-like growth factor-1 (IGF-1) release [8, 9]. However, when 5 grams was ingested orally 30 min before exercise, no impact on growth hormone was found. This is likely due to the tremendous difference in dosage provided and again the route of administrate (oral vs. infusion). Lastly and in clinical populations, arginine administration does improve various performance parameters and continues to be used as an alternative form of treatment with heart disease, although its efficacy has been questioned in these areas as well [10].

The million dollar question to all of this is, “Does arginine supplementation or using nitric oxide stimulators actually increase muscle mass, improve strength or some other type of adaptation to regular resistance training?” Amazingly, very little research has been done in this area, but of the little bit of research, there might appear to be some bright spots on the horizon (no it’s not all bad). A study published in 2006 had middle-aged men complete an 8-week exercise program consisting of both resistance and cardiovascular training while supplementing daily with 12 grams of L-arginine alpha-ketoglutarate or a placebo [11]. Small, but statistically significant increases in bench press strength and lower-body power production were found, however a deeper look at the data revealed a great bit of variability in the responses, but nonetheless were significant. A second study in 2009 had individuals supplement with NO-Shotgun, a popular product that contains healthy doses of creatine monohydrate along with other amino acids and whey protein or a placebo over a 4-week period while resistance training. Changes in strength, body composition and muscle biopsies were taken before and after the four-week resistance training program. The authors concluded that NO-Shotgun increased fat-free mass, strength and host of intramuscular markers to a greater degree than placebo. While the results of the study did reveal positive results, it’s likely that the findings were attributed more to the 10 grams of creatine found within in it than any effect associated with arginine and nitric oxide [12]. Additionally, a very recent study suggested that three different pre-workout supplements marketed to stimulate nitric oxide production had no measurable impact over total work completed during an intense exercise bout and in increasing blood flow [13].

If you remember back to one of my initial Q/As I included a breakdown of how my colleagues and I go about discerning which supplements may or may be worthwhile considerations. In this article, I mentioned that many supplements exist largely because of good theory, but when put to the rigors of research inquiry they demonstrate no measurable effect. Arginine and nitric oxide stimulators certainly are one of these types of supplements. Fortunately, their ingestion isn’t harmful and in fact is well tolerated, so if you feel like it may in fact be benefiting your progress, then continue, but the research and available data do suggest otherwise.

-Dr. Chad Kerksick is an Assistant Professor of Exercise Science at Lindenwood University with a PhD in Exercise, Nutrition and Preventive Health. His research and expertise center upon study the impact of exercise and nutrition interventions on health and performance. You can follow him on Twitter at @chadkerksick.

References:

Shils, M.E., et al., eds. Modern Nutrition in Health and Disease. 9th ed. 1999, Lippincott Williams & Wilkins: Baltimore, MD.
Wilson, A.M., et al., L-arginine supplementation in peripheral arterial disease: no benefit and possible harm. Circulation, 2007. 116(2): p. 188-95.
Bode-Boger, S.M., et al., L-arginine infusion decreases peripheral arterial resistance and inhibits platelet aggregation in healthy subjects. Clin Sci (Lond), 1994. 87(3): p. 303-10.
Giugliano, D., et al., The vascular effects of L-Arginine in humans. The role of endogenous insulin. J Clin Invest, 1997. 99(3): p. 433-8.
Adams, M.R., et al., Oral L-arginine inhibits platelet aggregation but does not enhance endothelium-dependent dilation in healthy young men. J Am Coll Cardiol, 1995. 26(4): p. 1054-61.
Chin-Dusting, J.P., et al., Effects of in vivo and in vitro L-arginine supplementation on healthy human vessels. J Cardiovasc Pharmacol, 1996. 28(1): p. 158-66.
Robinson, T.M., D.A. Sewell, and P.L. Greenhaff, L-arginine ingestion after rest and exercise: effects on glucose disposal. Med Sci Sports Exerc, 2003. 35(8): p. 1309-15.
Appleton, J., Arginine: Clinical potential of a semi-essential amino. Altern Med Rev, 2002. 7(6): p. 512-22.
Witte, M.B. and A. Barbul, Arginine physiology and its implication for wound healing. Wound Repair Regen, 2003. 11(6): p. 419-23.
Schulman, S.P., et al., L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. JAMA, 2006. 295(1): p. 58-64.
Campbell, B., et al., Pharmacokinetics, safety, and effects on exercise performance of L-arginine alpha-ketoglutarate in trained adult men. Nutrition, 2006. 22(9): p. 872-81.
Shelmadine, B., et al., Effects of 28 days of resistance exercise and consuming a commercially available pre-workout supplement, NO-Shotgun(R), on body composition, muscle strength and mass, markers of satellite cell activation, and clinical safety markers in males. J Int Soc Sports Nutr, 2009. 6: p. 16.
Bloomer, R.J., et al., Comparison of pre-workout nitric oxide stimulating dietary supplements on skeletal muscle oxygen saturation, blood nitrate/nitrite, lipid peroxidation, and upper body exercise performance in resistance trained men. Journal of International Society of Sports Nutrition, 2010. 7: p. 16.

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