By: Layne Norton

Those of you who are supplement-savvy have undoubtedly heard of the products that claim to increase nitric oxide production, as they have been quite the rage of the supplement industry over the past year. Products that increase nitric oxide claim to have positive influences on body composition and recovery by increasing blood flow to skeletal muscle.

At First...

When I first heard these claims I was very skeptical. It is all well and good to increase blood flow to skeletal muscle, but I had my doubts as to whether or not that would actually increase muscle cell uptake of the nutrients being delivered in the blood.

In fact, for the past year I actually advised many people against spending money on NO products. Well new research from researchers at the University of Texas has made me eat my words.

These researchers collected data on amino acid uptake kinetics and concluded that the rate limiting step of amino acid uptake into muscle tissue is NOT transport across the cellular membrane, but rather the transport of the amino acids through the blood and interstitial fluid ¹.

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That means it is likely an increase in blood flow to skeletal muscle, coupled with an increase in blood amino acid concentrations may lead to an increase in amino acid uptake by the muscle cells.

How Does It Increase Nitric Oxide Output?

So the next series of questions I'm sure many of you are asking is; how exactly do these supplements increase nitric oxide output, how does nitric oxide increase blood flow to skeletal muscles, and how do I maximize the effectiveness of these supplements? Well don't worry... I got ya covered.

Nitric oxide(NO) is synthesized from the amino acid l-arginine in the endothelium of blood vessels by an enzyme called Nitric Oxide Synthase (eNOS) which catalyzes the conversion of l-arginine to NO and Citrulline.

Citrulline can be recycled to arginine by combining with aspartate and thus become an available substrate for eNOS again. Once produced, NO is a potent vasodilator, meaning that it acts to relax the smooth muscle cells of the blood vessels, which increases the diameter of the blood vessel and allows more blood to flow through that area. Imagine gripping a water hose tightly and turning water on.

The flow of water would decrease through that area. If you relax your hands, the water flows through the hose faster. Think of the hose as your blood vessels, your hands as the smooth muscle, and the water as your blood (carrying nutrients in it).

By relaxing the smooth muscle cells of the blood vessels, more nutrients (including amino acids) will be allowed to pass through that area and be made available for uptake by the skeletal muscle. In addition to being a potent vasodilator itself, NO also stimulates production of cyclic GMP (cGMP), another potent vasodilator.

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It has been known for some time that exercise increases nitric oxide output and blood flow to the area exercised, but the significance of this increase in NO output has just begun to be unraveled ^2,3. Some researchers believe that increased blood flow to skeletal muscles may be one of the means by which protein synthesis is increased post workout ⁴.

They cite that the increased blood flow only occurs in the area that is exercised, and that area is also the only place that protein synthesis increases after a workout. For example, if you workout quads, you feel a pump in your quads, not your hamstrings.

Likewise the increase in protein synthesis occurs in your quads and not your hamstrings. If indeed vasodilatation of the blood vessels via NO output is an important mechanism by which protein synthesis increases post workout, then perhaps increasing nitric oxide output will have favorable results on recovery and body composition.

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It is well established that arginine ingestion will increase NO output as will exercise ⁴. However the body is quite efficient at producing NO during exercise, it falls short of optimal NO levels by shooting itself in the foot so to speak.

Allow me to elaborate on this statement; in addition to increasing NO output, exercise also increases the production of reactive oxygen species (ROS) also known as free radicals ^5,6,7. Free radicals reduce NO levels by "quenching" NO production. This means that ROS, such as superoxide, react with NO to form peroxynitrite species (PNS) ⁸.

In addition to not promoting vasodilation, and reducing the effectiveness of nitric oxide, ROS and PNS can inhibit protein synthesis, and are potentially damaging to cells and also impair the effectiveness of insulin by disrupting insulin signaling ^9,10,11. To combat ROS, one can ingest compounds that scavenge these species called anti-oxidants.

Anti-oxidants that have been shown to reduce NO degredation include lipoic acid, vitamin E, vitamin C, grape seed polyphenols, selenium, and quercetin ^12-20.

In addition to lipoic acid being a free radical scavenger, it also increases the activity of eNOS ¹⁵! Similarly, vitamin C not only acts to increase NO output by scavenging ROS and stabilizing nitric oxide, it is also important in stabilizing and maintaining intracellular levels of tetrahydrobiopterin (BH4), a cofactor of eNOS ¹², ¹³.

Folic acid will further increase the stabilization of BH4 ²¹. Stabilizing BH4 assures that eNOS can convert arginine to NO at an optimal rate.

Reactive oxygen species also reduce NO bioavailability by stimulating the synthesis of asymmetric dimethylarginine (ADMA), a competitive inhibitor of eNOS ²¹.

If ADMA levels are high, it can occupy the active site of the eNOS enzyme and prevent arginine from occupying that site, thus preventing NO synthesis. Therefore, it is important to make sure the ratio of arginine to ADMA is high, this can be achieved by supplementing with the aforementioned anti-oxidants along with arginine ²².

Other compounds that may increase NO production or reduce NO degradation include vitamin B2, B3, omega-3's (fish oil), coenzyme Q10, acetylcholine, and insulin ^21-25.

OK, enough with the science? how should I use this stuff!

Since there hasn't been a direct study examining what combination of these nutrients is optimal, I can only provide my educated guess. So here is what I recommend to maximize your NO levels.

I Would Consume A Post Workout Shake Consisting Of The Following:

• 20-30g whey protein
• 30-50g dextrose
• 6-12g arginine

I Would Also Consume A Post Workout Anti-Oxidant/Vitamin Cocktail Consisting Of The Following:

• Lipoic acid, quercetin, vitamin C, and vitamin E.
• B vitamin complex
• Folic acid
• 3g fish oil

You may also add in any of the aforementioned anti-oxidants if you wish. I wouldn't supplement with more than 300mg of any one anti-oxidant and I wouldn't consume more than 1200mg of total anti-oxidants as this will just be overkill.

Note that the shake contains whey and dextrose as this will illicit an insulin spike, and insulin will increase NO effectiveness.

Begin by dosing your arginine at 6g and increase it slowly until you can feel a better than normal pump consistently from this cocktail.

Now go get your PUMP on!

	Do You Think Nitric Oxide Products Live Up To Their Claims? Yes. No.

References

1. Wolfe, et. al., "In vivo muscle amino acid transport involves two distinct processes." Am J Physiol Endocrinol Metab. 2004 Jul;287(1):E136-41.
2. Bisquolo, et. al., "Previous Exercise Attenuates Muscle Sympathetic Activity and Increases Blood Flow During Acute Euglycemic Hyperinsulinemia." J Appl Physiol. 2004 Nov 12.
3. Green, et. al., "Effects of exercise training on endothelium-derived nitric oxide function." J. Physiology. 2004; 561(1): 1-25.
4. Douglas, Borsheim, and Wolfe. "Potential Ergogenic Effects of Arginine and Creatine Supplementation" J Nutr. 2004 Oct;134(10 Suppl):2888S-2894S.
5. Palazzetti et al., "Overloaded training increases exercise-induced oxidative stress and damage." Canadian Journal of Applied Physiology. 2003, Aug. 28th (4): 588-604.
6. Young et al., "Exercise-induced endotoxemia: the effect of absorbic acid supplementation." Free Radical Biological Medicine. 35(3): 284-91.
7. Sen, CK., "Antioxidants in exercise nutrition." Sports Medicine. 31(13): 891-908.
8. Berges A. et al., "Role of nitric oxide and oxidative stress in ischaemic myocardial injury and preconditioning., Acta Cardiol. 2003;58:119-132.
9. Hanson et al., "Insulin signaling is inhibited by micromolar concentrations of peroxide. Evidence for a role of peroxide in tumor necrosis factor alpha-mediated insulin resistance." Journal of Biological Chemistry. 274(35): 25078-84.
10. Gardner et al., "Hydrogen peroxide inhibits insulin signaling in vascular smooth muscle cells." Experimental Biological Medicine. 228(7): 836-42.
11. Patel, J. et al., "Cellular stresses profoundly inhibit protein synthesis and modulate the states of phosphorylation of multiple translation factors." Eur. J. Biochem. 269, 3076-3085 (2002).
12. Heller, R. et al., "L-ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. J. Biol. Chem. 2001; 276:40-47.
13. d'Uscio, LV. et al., "Long-term vitamin C treatment increases vascular tetrahydrobiopterin levels and nitric oxide synthase activity. Circ. Res. 2003;92:88-95.
14. Trujillo, M. et al., "Peroxynitrite reaction with the reduced and the oxidized forms of lipoic acid: new insights into the reaction of peroxynitrite with thiols. Arch. Biochem. Biophys. 2002397:91-98.
15. Smith, AR and Hagen, TM. "Vascular endothelial dysfunction in aging: loss of Akt-dependant endothelial nitric oxide synthase Phosphorylation and partial restoration by R-alpha-lipoic acid." Biochem Soc. Trans. 2003 Dec;31(Pt 6):1447-9.
16. Visioli, F. et al., "Lipoic acid and vitamin C potentiate nitric oxide synthesis in human aortic endothelial cells independently of cellular glutathione status." Redox Rep. 2002;7(4):223-7.
17. Freedman, JE. et al., "alpha-Tocopherol and protein kinase C inhibition enhance platelet-derived nitric oxide release. FASEB J. 2000;14:2377-2379.
18. Clifton, PM. "Effect of Grape Seed Extract and Quercetin on Cardiovascular and Endothelial Parameters in High-Risk Subjects." J. Biomed. Biotechnol. 2004;2004(5):272-278.
19. Arthur JR, McKenzie RC, Beckett GJ. "Selenium in the immune system." J Nutr. 2003 May;133(5 Suppl 1):1457S-9S.
20. Haenen GR, et al., "Peroxynitrite scavenging by flavenoids. Biochem. Biophys. Res. Commun. 1997;236:591-593.
21. Das UN. "Folic Acid says NO to vascular diseases." Nutrition. 2003;19:686-692.
22. Sydow K. et al., "ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of L-arginine and B vitamins. Cardiovasc. Res. 2003;57:244-252.
23. Osiecki H. "The role of chronic inflammation in cardiovascular disease and its regulation by nutrients." Altern. Med. Rev. 2004 Mar;9(1):32-53.
24. Zhang WJ and Frei B. "Alpha-lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion molecule expression in human aortic endothelial cells. FASEB J. 2001;15:2423-2432.
25. de Jongh RT et al., "Physiological hyperinsulinaemia increases intramuscular microvascular reactive hyperaemia and vasomotion in healthy volunteers." Diabetologia. 2004 Jun;47(6):978-86. Epub 2004 May 28.

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