Nitric oxide: its role in your body and the truth behind its performance enhancing properties

Do nitric oxide supplements improve performance?

At a glance

In recent years, a new type of sports supplement has become popular among strength athletes. But what does the science say about ‘nitric oxide enhancers’, and do they really do what it says on the tin? Andrew Hamilton comes up with some surprising conclusions…

A sports nutritionist colleague once remarked that ‘there are lies, damn lies and sports supplements’. In the light of genuinely performance-enhancing supplements, such as carbohydrate drinks, creatine and caffeine, this seems a little harsh. Yet the fact remains that the scientific evidence for many of the supplements on sale today is either very patchy, purely theoretical or in some cases, non-existent!

What is nitric oxide?

Until fairly recently, the colourless gas nitric oxide (chemical formula NO) was a relatively obscure substance. Environmental scientists were already aware of NO emissions from car exhausts, because as an atmospheric pollutant and a precursor to photochemical smog, it’s very irritating when breathed into the lungs, especially for asthma sufferers. NO is also sometimes found in the chemist’s lab, where it can be employed in a range of exotic reactions.

However, in the late 1970s, researchers who were investigating the dilation mechanisms of the anti-angina drug nitrogylcerine made an important discovery: the drug was being metabolised into nitric oxide, and it was this NO that was producing the potent vasodilation effects. This finding initiated a whole new raft of research into NO, but the real breakthrough came in the late 1980s, when it was discovered that not only does the human body produce its own NO, but that this NO also acts as an important neurotransmitter – a chemical signaller that tells cells in the body how to behave(1). And when NO was then discovered to be the neurotransmitter to erectile tissue, it spawned the development of Viagra – and the rest, as they say, is history!

We now know that nitric oxide is not just an important neurotransmitter, but is in fact the most widespread signalling molecule in the body, helping to control a range of processes in the body, including nerve signalling, immune function, tissue turnover and the dilation of blood vessels (see box 1). In particular, nitric oxide acts as a messenger molecule that acts on a variety of endothelial tissues in the circulatory system (eg blood vessels and capillaries), causing them to ‘relax’. As they relax or deconstrict, they open up, allowing more blood to flow.

Box 1

NO benefits

In theory, any nutritional approach that can enhance tissue turnover and vasodilation is a good thing for an athlete; all the nutrients required for muscle-tissue growth and repair are transported via the circulatory system and delivered by tiny capillaries, and waste products such as lactate are also removed via this route. Encouraging more vasodilation enhances circulation to the working muscles and, as well as producing a better pump during workouts, should theoretically improve nutrient delivery. These vasodilation benefits go a long way to explaining the current popularity of NO-enhancing supplements.

If we accept that boosting NO production in the body is a good thing, the obvious question is whether there are any nutritional strategies that can increase NO generation in the body. The answer to this question is yes; it just so happens that we can synthesise NO in our bodies from the amino acid L-arginine. We obtain L-arginine from dietary protein we eat because L-arginine is one of the basic amino acid building blocks of protein foods.

Because NO has such a short lifetime in the body, it’s synthesised ‘in situ’ from the amino acid L-arginine, which (in the presence of oxygen) is broken down by an enzyme known as ‘nitric oxide synthase’, into nitric oxide and another amino acid called L-citrulline (see figure 1). In other words, L-arginine is a major precursor of NO in the body and numerous studies have shown that increasing arginine intake increases the production of NO(2), which explains why arginine supplementation has found favour among some sportsmen and women as an ‘NO booster’ (see box 2).

Figure 1

Box 2

NO evidence

So far, so good, but what’s the evidence that using NO boosters confers scientifically proven benefits to sportsmen and women? There are two main claims made for L-arginine-based NO boosters:

The NO-mediated increased vasodilation enhances blood flow, ensuring a better delivery of blood and nutrients to working muscles and more efficient removal of by-products such as lactate, all of which lead to better performance;
 L-arginine supplementation also stimulates the body’s natural production of growth hormone, which in turns helps recovery and particularly muscle/strength gains.

Arginine and growth hormone

Let’s start with the second claim, which is based on evidence derived mainly from animal studies and from sedentary human subjects. In recent years, trials with arginine supplementation or infusions in rats have shown that it can increase the activity of genes known to be responsible for the synthesis of growth hormone(3,4). Moreover, a study carried out by Danish scientists showed that healthy young men who had an infusion of arginine demonstrated an increase in release rates of growth hormone, compared to those who didn’t(5). This seemed to confirm the work of British scientists three years earlier, who also found that, compared to a placebo, an arginine infusion boosted growth hormone release in 18 young healthy males. Another study demonstrated that arginine was able to boost growth hormone production in children aged 5-14(6), a finding mirrored in a study of healthy elderly people who took either oral arginine supplements or who had an infusion(7).

The problem with the arginine-growth hormone claim, however, comes when you look at studies carried out on physically active subjects, where the evidence is not just weak but actually suggests that arginine supplementation may be counter-productive! For example, Californian scientists looked at the combined effects of both arginine and resistance training in both young and old adults(8). Exercise, particularly resistance training, is known to produce a natural release of growth hormone, and the researchers wanted to see whether giving extra arginine augmented the growth hormone boost provided by training.

The subjects (20 with average age 22 and eight with average age 68) had growth hormone levels measured under three conditions:

  1. At rest after 5g of arginine;
  2. Following three sets or 8-10 reps at 85% of 1 rep max on 12 separate resistance exercises;
  3. After 5g of arginine plus the same exercise protocol above.

The results showed that not only did the arginine infusion at rest fail to produce a significant increase in growth hormone release, it also failed to augment growth hormone release when exercise was performed. Even worse, in the young subjects, arginine seemed to blunt the release of growth hormone compared to exercise only.

A very recent scientific review paper published earlier this year by US scientists supports the findings above(9). In the paper, researchers looked carefully at the evidence for the effects or otherwise of L-arginine supplementation on growth hormone response when combined with exercise. The key finding was that most studies using oral arginine have shown that 5-9g of arginine alone increases the resting growth hormone levels at least 100%, while exercise
can increase growth hormone levels by 300-500% over resting levels. Worryingly, however, the combination of oral arginine plus exercise attenuates the exercise-only growth hormone response, and increases growth hormone levels by only around 200% compared to resting levels.

The reasons why extra arginine may diminish exercise-induced growth hormone release are unclear, but what is clear from the available evidence is that the effects of exercise on growth hormone release dramatically outweigh any produced by arginine, so those seeking to maximise the muscle-building effects of a workout have
little to gain by taking arginine and possibly something to lose!

Arginine as an NO booster

Given that the evidence for arginine as an effective growth hormone booster is patchy to say the least, what about its other claim – as an NO enhancer? There are two issues here: firstly, does taking extra arginine significantly boost NO production in the body and if so, does this produce any real benefits for sportsmen and women?

As far as extra arginine goes, studies have shown that both diabetic rats(10,11) and human patients(12,13) have markedly decreased concentrations of arginine in the blood, and clinical and experimental studies have shown beneficial effects of arginine administration in improving vascular function (via vasodilation) in diabetic subjects(14,15). Moreover, studies in rats have shown that extra dietary arginine boosts NO synthesis in diabetic rats(16). But what’s the evidence that the same is true in exercising humans?

Results from studies are far from conclusive. For example, a double-blind, placebo-controlled US study showed that 8.4g of arginine a day for two weeks significantly reduced platelet aggregation (blood cell stickiness) in patients suffering from high blood cholesterol(17). The researchers surmised that this effect occurred as a result of increased NO production because their previous studies had shown that reduced vascular activity of nitric oxide in rabbits suffering from this condition was restored by arginine supplementation.

However, another US study carried out just last year produced very different results. In the study, scientists set out to determine the effects of long-term administration of 3g of arginine for six months on vascular reactivity and functional capacity in 133 patients with peripheral arterial disease(18). Importantly, the researchers not only looked at the effects of arginine on symptoms of this condition (such as calf pain during exercise), they also directly measured NO availability to the tissues using a number of different techniques. They found that arginine supplementation did not increase nitric oxide synthesis or improve measures of vascular health; indeed, when they looked at the symptoms of this condition, those who had taken a placebo (ie no arginine) actually fared better than those who took the arginine!

Arginine as a performance enhancer

The evidence in favour of using arginine as an NO booster is far from convincing – but surely, if it helps you deliver the goods performance-wise, that’s what matters, isn’t it? Unfortunately for devotees of NO enhancers, the scientific evidence for this is even less convincing!

A glimmer of hope for NO-enhancers’ fans came from a Polish study that looked at the exercise capacity of 21 patients with congestive heart failure who took 9g of arginine a day for a week(19). The researchers found that, compared to a placebo, arginine supplementation did enhance exercise duration time. However, the researchers were not able to ascertain the cause of this increase in performance because there were no signs of changes in NO production in the patients.

By contrast, studies of arginine supplementation and subsequent performance using trained athletes are very thin on the ground, and those that have been conducted have drawn a blank. In one such example, Swiss scientists investigated whether daily intake of two different dosages of arginine aspartate (AA, a type of arginine supplement purported to be readily absorbed and utilised) over a four-week period would affect selected parameters of overtraining syndrome, such as performance and metabolic parameters, in 30 male endurance-trained athletes(20).

The athletes were split into three groups and ingested either a high dose of AA (containing 5.7g arginine and 8.7g aspartate), a low dose of AA (2.8g arginine and 4.2g aspartate) or a placebo. Maximal oxygen uptake and time to exhaustion were determined on a cycling ergometer in an incremental exercise test before and after supplementation. The researchers found that regardless of dose, the arginine aspartate had absolutely no influence on performance or any of the metabolic parameters measured. Indeed, they went on to comment: ‘There seems to be no apparent reason why the supplementation of arginine aspartate should be an effective ergogenic aid and the practice of using arginine aspartate as potential ergogenic aid should be critically re-evaluated.’

Taiwanese scientists drew another blank in a study using well-trained male athletes, the report of which was published just a few months ago. It investigated the effect of short-term arginine supplementation on performance in intermittent anaerobic exercise(21). Ten elite male college judo athletes participated and consumed 6g per day of arginine or a placebo for three days and then performed an intermittent anaerobic exercise test on a cycle ergometer. The researchers found that there was no significant differences between the two trials in blood nitrate and nitrite concentrations, suggesting an absence of increased NO production. Moreover, there was no difference in peak and average power during exercise.

Fruit and vegetables as NO boosters

Swedish scientists have carried out a fascinating study indicating that rather than using NO-boosters, simply eating more fruit and vegetables may be a route to enhanced NO activity and performance(22). Fruit and vegetables are naturally rich in nitrate and nitrite, both of which can be metabolised into NO in the body. The researchers investigated the effects of a simulated high fruit and vegetable intake by giving nine healthy, young, well-trained men a nitrate supplement and compared its effects on submaximal and maximal work tests on a cycle ergometer, to a placebo. They discovered that the nitrate supplementation resulted in a lower oxygen demand during sub-maximal work and that this effect occurred without an accompanying increase in blood lactate concentration, indicating that the energy production had become more efficient. If this effect is subsequently confirmed, it could be yet another reason to eat those greens!

Andrew Hamilton BSc Hons, MRSC, ACSM is a member of the Royal Society of Chemistry, the American College of Sports Medicine and a consultant to the fitness industry, specialising in sport and performance nutrition

References

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5. J Endocrinol Invest. 1999;22(5 Suppl):89-93
6. J Endocrinol Invest 1993 Jul-Aug;16(7):521-5
7. J Endocrinol Invest1994 Feb;17(2):113-7
8. J Gerontol A Biol Sci Med Sci. 1999 Aug;54(8):M395-9
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10. Am. J Physiol. Endocrinol. Metab. 1983, 244:E151-E158
11. J Pharmacol. Exp. Ther. 1997, 283:684-691
12. Metabolism 1992, 41:28-32
13. Amino Acid Metabolism and Therapy in Health and Nutritional Disease, 1995:287-298 CRC Press New York, NY
14. Clin. Sci. 1994, 87:37-43
15. J Am. Coll. Nutr. 2002, 21:422-427
16. J Nutr. 2004 Mar;134(3):600-8
17. J Am Coll Cardiol. 1997 Mar 1;29(3):479-85
18. Circulation. 2007 Jul 10;116(2):188-95
19. Kardiol Pol. 2004 Apr;60(4):348-53
20. Int J Sports Med. 2005 Jun;26(5):344-9
21. J Nutr Biochem. 2008 Aug 15. [Epub ahead of print]
22. Acta Physiol (Oxf). 2007 Sep;191(1):59-66

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