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The Science of Perfect Pumps and Peak Performance

Let’s face it, few things feel as good as having a tremendous nitric-oxide-facilitated muscle pump peaking just as you step out onto that gym floor for your first set of reps. Your veins are bulging, vascularity is surging, muscle tissue is suffused with oxygen and fuel, waste is being shuttled away from muscle tissue efficiently, and you’re ready to embark on a truly productive workout. But how does nitric oxide (NO) work? How does the potentiation of nitric oxide translate into enhanced performance? Do pre-workout nitric oxide potentiators work? Do nitric oxide supplements have their drawbacks? Let’s take a closer look.

How Is Nitric Oxide Produced In The Body?

Joseph Priestly first identified nitric oxide as a gas in 1772, when it was described as a pollutant found in air. Over 200 years later, in the 1980s, the bulk of the scientific work investigating nitric oxide as one of the most important biological molecules occurred and led to a Nobel Prize by 1998. Since then, the research devoted to understanding mechanisms behind nitric oxide signaling and their physiological consequences has exploded.

Nitric oxide is a highly reactive and diffusible free radical that is produced by many cells throughout the body. Studies have shown that nitric oxide production depends on physical stimuli that activate specific nitric oxide synthases (enzymes which catalyze nitric oxide production). These enzymes come in a few ‘flavors’, endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and neuronal nitric oxide synthase (nNOS); where eNOS is associated with endothelial cells that line our blood vessels, iNOS is most associated with macrophages and the immune system, and nNOS is most associated with the body’s nervous systems.

When we think of exercise and nitric oxide, eNOS is considered the major player in its production. However, at the end of the day, all NOS catalyzes the following reaction:


Production of Nitric Oxide


FIGURE 1: Production of nitric oxide from arginine via nitric oxide synthase (NOS).


As you can see in FIGURE 1, arginine is a precursor to nitric oxide production and citrulline is a byproduct. Research has shown that the body’s arginine levels can limit this reaction (especially under exercise conditions, where nitric oxide production is heightened). We discuss arginine and citrulline as nitric oxide boosting supplements in subsequent sections of this article.
 
Nitric oxide can also be produced via reduction of circulating nitrates (NO3-) and nitrites (NO2-). Nitrates and nitrites are produced by the degradation of excess nitric oxide (like nitric oxide recycling system) and/or taken in via diet (green leafy vegetables and some fruits) (FIGURE 2).

Biological Roles of Nitric Oxide (In the Context of Exercise)

Vasodilation and increased blood flow.
Nitric oxide plays a variety of roles in the body, including modulating many aspects of cardiovascular homeostasis and health. In the context of exercise, one of the most important roles of nitric oxide is to produce robust and global vasodilation. Overall, this decreases the amount of pressure (energy) needed to circulate the blood and increases blood flow. The net result is greater efficiency in delivery of nutrients and removal of waste products in active muscle. This vasodilation helps maintain healthy blood pressure levels and is the primary mechanism responsible behind the increased ‘pump’ you feel when using nitric oxide potentiating supplements.

Angiogenesis
Angiogenesis is the process of forming new blood vessels from existing vasculature. This vascularization process is essential for the body to maintain and/or augment the blood supply to tissues. Nitric oxide is an important signaling molecule for angiogenesis and keeping this system optimized and primed will ensure that vascular adaptation is supported and optimal blood flow to working muscle is maintained.  

Mitochondrial Adaptations
Mitochondria are specialized organelles that reside in nearly every cell. They are classically described as the ‘powerhouse’ of the cell, due to the fact that they produce most of the cell’s ATP for energy. Mitochondria are also involved in cellular signaling processes, and maintenance of the cell cycle (i.e., cellular growth, differentiation, and apoptosis).  

Nitric oxide potentiation and its increased bioavailability during heavy exercise increases mitochondrial efficiency and boosts mitochondrial density. As such, your body produces ATP more efficiently and it has more ‘powerhouses’ to do so, resulting in increased energy production for better performance.   

Glucose uptake
During exercise, how well your body clears the blood of sugar, stores it as glycogen in skeletal muscle, and uses it for energy (for movement) is directly related to performance and recovery.  We tend to only associate insulin with glucose uptake, but, during exercise, nitric oxide has been shown to be a key player in glucose homeostasis (independent of increases in blood flow). In this case, potentiating nitric oxide production and/or bioavailability during exercise may provide greater/rapid glycogen storage for increased energy production, and faster recovery between performances.  



Nitric Oxide and Increased Performance

FIGURE 2

Does Using Nitric Oxide Boosters Increase Exercise Performance?

Numerous peer reviewed studies support the use of nitric oxide boosting supplements on exercise and sports performance. As shown in FIGURE 2, there are two direct means to increasing nitric oxide production:

1) increased dietary nitrates
2) increased blood arginine   

In terms of nitrate supplementation, a randomized control trial published this year in the Journal of Science and Medicine investigated the effects of ingesting dietary nitrate 2-hours prior to training sessions (∼8 mmol), during a 3-week sprint interval training program. With nitrate supplementation, compared to placebo, subjects had an 85% increase in work rate and reduced fatigue during repeated supramaximal sprints.  

Along similar lines, an earlier study published in Nitric Oxide (2015) concluded that nitrate supplementation (beetroot juice) promoted increased blood flow (red blood cell flux) to working muscle, greater exercise tolerance, and greater number of work periods completed before exhaustion, compared to placebo.

Finally, a recent study published in the Journal of Strength & Conditioning Research provides support for the use of beetroot extract prior to resistance training. In this randomized, double blinded, and placebo-controlled study, the effects of a beetroot nitrate supplement on bench press performance were evaluated in physically active resistance-trained males. The researchers reported that, compared to placebo, nitrate supplementation resulted in 23% more repetitions completed to failure and a 19% increase in total weight lifted per 3 set bench press session.

Studies aimed at increasing nitric oxide bioavailability through the arginine pathway have shown that one of the best supplements for this is L-citrulline, a by-product of nitric oxide production. This is mainly because oral L-citrulline converts back to L-arginine in the body, which elevates blood arginine even better than arginine itself. A recent study carried out by researchers in Japan reported that cyclists who took L-citrulline (2.4 g/day) for 8 days reduced time to completion of a 4 km cycling exercise test and significantly improved feelings of fatigue and concentration immediately post-exercise.

In a study of advanced weightlifters, it was found that citrulline malate supplementation (8 g, 1-hour preworkout) led to significantly reduced fatigue to working muscles during repeated bouts of lower-body weight training, allowing subjects to perform more repetitions within a given workout.

Finally, in a most recent study, published in the European Journal of Sports Science, it was reported that (in masters level tennis athletes) an acute dose of citrulline malate (8 g) taken 1-hour before strength testing resulted in significant improvements in maximal and average grip strength, as well as relative and explosive peak power versus placebo.   


Nitric Oxide Boosting Supplements

L-Arginine
For several years, strength athletes have taken advantage of L-arginine supplements to increase nutrient delivery and metabolite washout in working muscles, leading to greater strength, endurance, harder pumps, and decreased recovery time. The body uses L-arginine in a reaction with the enzyme eNOS endothelial nitric oxide synthase) to produce the potent vasodilator nitric oxide. However, contrary to what was reported in the past, the most recent evidence suggests that taking arginine on its own does not significantly increase nitric oxide production or exercise blood flow in healthy subjects. Nevertheless, this does not mean that you should not be using it! In fact, supplements (like those described below) that increase nitric oxide production are more effective with supplemental L-arginine on board. This is due to the fact that L-arginine, if it is not supplied in abundance, may be rate limiting under conditions of augmented nitric oxide production.

L-Citrulline/Citrulline Malate
L-citrulline in any form helps prevent muscle fatigue, as it assists in production of energy by increasing the rate of phosphocreatine and ATP production. Citrulline, converts to arginine (the precursor to nitric oxide) in the body and optimizes blood and nutrient delivery to working muscles. Recent research indicates that citrulline supplements can actually increase blood levels of arginine and nitric oxide more effectively than arginine ingestion. Beyond creating incredible pumps, a single pre-workout dose of citrulline was recently shown to combat exercise-induced fatigue, increase time to exhaustion, and substantially decrease muscle soreness.

Beetroot Extract
Beetroot provides a very rich source of nitrates. Research studies have noted the benefit beetroot extract can have on exercise and performance, as athletes who consume it before training experience increased endurance and time to exhaustion. Most recent research illustrates that taking beetroot extract (for even less than a week) significantly enhances muscle contractile efficiency, meaning you can push more weight with less energy cost.

Vitamin C
Ascorbic acid is certainly a well-known supplement with a plethora of health benefits including extraordinary antioxidant properties. It’s been known for years that vitamin C is a potent free radical scavenger and recent research has shown that because of this characteristic, vitamin C ingestion bolsters nitric oxide bioavailability by preventing its breakdown by free radicals. Scientists in Greece have reported that taking vitamin C with L-arginine significantly boosts nitric oxide over ingesting arginine on its own.

Pycogenol
This trademarked substance is extracted from the bark of the French maritime pine. The extract has several effects on the body, as it’s a potent antioxidant. However, most relevant to this article is its ability to augment the activity of nitric oxide synthase and aid in the production of nitric oxide. According to the literature, Pycogenol works synergistically with arginine.

Cnidium Monnier
This extract from the fruit of the Chinese plant Cnidium monnieri is also known as She chuang zi in traditional Chinese medicine, where it was used as a libido booster for men. Cnidium monnier works by enhancing the action of nitric oxide by stopping the enzyme, known as phosphodiesterase-5 (PDE-5), that shuts down nitric oxide’s vasodilating effects.

Cocoa Extract
The two main flavonoids in cocoa that are responsible for the health benefits are epicatechin and catechin. A study from the University of California, Davis, has found that cocoa can actually boost nitric oxide levels. When subjects drank a cocoa drink with high concentrations of epicatechin, they had enhanced blood vessel dilation as compared to subjects who drank a cocoa drink with low concentrations of epicatechin. They concluded that the increased blood vessel dilation was due to increased nitric oxide production from the epicatechin in the cocoa.

Jiaogulan (Gynostemma pentaphyllum)
This herb is often referred to as southern ginseng because it grows mainly in south central China and its chemical composition and function is similar to Asian ginseng. The active ingredients in Jiaogulan are called gypenosides. Gypenosides are triterpenoid saponins contained in an extract from Gynostemma pentaphyllum and are reported to directly increase nitric oxide release from endothelial cells in blood vessels. Gypenosides also possess strong antioxidant properties that protect nitric oxide from free radicals, much like vitamin C.

Rutaecarpine
Although it does not increase nitric oxide levels, this extract from the herb Evodia rutaecarpa promotes robust blood vessel dilation. Research shows that this alkaloid increases blood flow by altering calcium levels in the smooth muscle that lines blood vessels, causing them to relax. Taking rutaecarpine with arginine and other nitric oxide boosters can have an additive effect on muscle blood flow and muscle pump.

Agmatine Sulfate
Well, simply put, agmatine is synthesized in the body from arginine and plays a role in regulating nitric oxide synthase (NOS)---the enzyme responsible for nitric oxide production. Several studies illustrate that agmatine supplementation protects neurons in the brain during ischemia (i.e., low blood flow to the brain) by boosting endothelial NOS (eNOS) in microvessels. As you likely know, nitric oxide from eNOS produces potent vasodilation in skeletal muscle, however the effects of agmatine on nitric oxide in skeletal muscle are yet to be shown scientifically.

Conclusion

As we can see, there is considerable evidence to suggest that nitric-oxide potentiation vasodilation can have positive effects on performance, which in turn paves the way for more productive workouts. In addition, nitric-oxide facilitation, in the form of supplementation with one or more of the agents cited above, would seem to be recommended for athletes looking to attain a performance edge. When choosing a pre-workout supplement, you'd be well-advised to check the ingredients label for a powerful nitric-oxide complex.
 
 
Scientific References

Nosarev AV, Smagliy LV, Anfinogenova Y, Popov SV, Kapilevich LV. Exercise and NO production: relevance and implications in the cardiopulmonary system. Front Cell Dev Biol. 2015 Jan 7;2:73.

SJ. Bailey, JR Blackwell, T Lord, A Vanhatalo, PG Winyard and AM Jones L-citrulline supplementation improves O2 uptake kinetics and high-intensity exercise performance in humans J Appl Physiol (1985). 2015 Aug 15;119(4):385-95.

Khatri J, Mills CE, Maskell P, Odongerel C, Webb AJ. It is Rocket Science - Why dietary nitrate is hard to beet! Part I: Twists and turns in the realisation of the nitrate-nitrite-NO pathway.  Br J Clin Pharmacol. 2016 Feb 20.

Rammos C, Luedike P, Hendgen-Cotta U, Rassaf T. Potential of dietary nitrate in angiogenesis. World J Cardiol. 2015 Oct 26;7(10):652-7.

Park SY, Rossman MJ, Gifford JR, Bharath LP, Bauersachs J, Richardson RS, Abel ED, Symons JD, Riehle C. Exercise training improves vascular mitochondrial function. Am J Physiol Heart Circ Physiol. 2016 Apr 1;310(7):H821-9.

Hong YH, Betik AC, McConell GK. Role of nitric oxide in skeletal muscle glucose uptake during exercise. Exp Physiol. 2014 Dec 1;99(12):1569-73.

Muggeridge DJ, Sculthorpe N, James PE, Easton C. The effects of dietary nitrate supplementation on the adaptations to sprint interval training in previously untrained males. J Sci Med Sport. 2016 May 21. pii: S1440-2440(16)30063-9.

Aucouturier J, Boissière J, Pawlak-Chaouch M, Cuvelier G, Gamelin FX. Effect of dietary nitrate supplementation on tolerance to supramaximal intensity intermittent exercise. Nitric Oxide. 2015 Sep 15;49:16-25.

Mosher S, Sparks SA, Williams E, Bentley DJ, Mc Naughton LR. Ingestion of a nitric oxide enhancing supplement improves resistance exercise performance. J Strength Cond Res. 2016 Apr 2.  

Suzuki T, Morita M, Kobayashi Y, Kamimura A. Oral L-citrulline supplementation enhances cycling time trial performance in healthy trained men: Double-blind randomized placebo-controlled 2-way crossover study. J Int Soc Sports Nutr. 2016 Feb 19;13:6.

Rimer EG, Peterson LR, Coggan AR, Martin JC. Acute Dietary Nitrate Supplementation Increases Maximal Cycling Power in Athletes. Int J Sports Physiol Perform. 2015 Dec 2. [Epub ahead of print]

Glenn JM, Gray M, Jensen A, Stone MS, Vincenzo JL. Acute citrulline-malate supplementation improves maximal strength and anaerobic power in female, masters athletes tennis players. Eur J Sport Sci. 2016 Mar 28:1-9.

Wax B, Kavazis AN, Weldon K, Sperlak J. Effects of supplemental citrulline malate ingestion during repeated bouts of lower-body exercise in advanced weightlifters. J Strength Cond Res. 2015 Mar;29(3):786-92.

Suzuki T, Morita M, Kobayashi Y, Kamimura A. Oral L-citrulline supplementation enhances cycling time trial performance in healthy trained men: Double-blind randomized placebo-controlled 2-way crossover study. J Int Soc Sports Nutr. 2016 Feb 19;13:6.

Clements WT, Lee SR, Bloomer RJ. Nitrate ingestion: a review of the health and physical performance effects. Nutrients. 2014 Nov 18;6(11):5224-64.

Trinity JD, Wray DW, Witman MA, Layec G, Barrett-O'Keefe Z, Ives SJ, Conklin JD, Reese V, Zhao J, Richardson RS. Ascorbic acid improves brachial artery vasodilation during progressive handgrip exercise in the elderly through a nitric oxide-mediated mechanism. Am J Physiol Heart Circ Physiol. 2016 Mar 15;310(6):H765-74.

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.



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