Some of the most popular supplements today are the so called pre-workout nitric oxide (NO) boosters 1, 2. These contain a panoply of ingredients, but the main one is arginine. The rationale goes that arginine is a nitric oxide (NO) precursor and NO is a potent vasodilator 3, 4, which in turn supposedly will boost blood flow to exercising muscles, performance and recovery. And while arginine supplementation is beneficial for various clinical populations (see below), studies in healthy adults have not unequivocally supported the marketing hype surrounding arginine supplementation and nitric oxide boosters 1, 5, 6. Why? Let’s take a look under the hood…
Some reasons explaining the inefficacy of arginine supplementation and nitric oxide boosters
The popular pre-workout NO boosting supplements rely on the arginine-NO pathway and a lot of theoretical assumptions. Some reason for the conflicting findings on arginine supplementation are that studies have used different routes of administration (oral vs. intravenous), various forms of L-arginine, varying exercise testing protocols, different test subjects (trained vs. untrained, young vs. elderly), and supplement cocktails containing other substances (eg. creatine, beta-alanine, caffeine, carbs etc) that indeed do have performance enhancing effects.
The rationale for L-arginine supplementation is based largely on research using intravenous L-arginine, often at dosage of 30 g. This has no practical relevance since most, if not all, supplements are taken orally. In a direct head-to-head comparison of oral and intravenous L-arginine administration, no effect on vasodilatation was found after oral L-arginine supplementation 7. One reason for this could be the extensive elimination of orally ingested L-arginine due to intestinal arginase activity and low bioavailability 8. This would require intake of very large amounts of L-arginine, which not only has an unpleasant taste, but also can cause gastric problems 9.
The Arginine Paradox
The backbone running the arginine-NO pathway is an enzyme called eNOS (endothelial nitric oxide synthase) 10. One factor that affects the velocity of an enzyme catalyzed reaction is the concentration of the substance the enzyme uses (a.k.a substrate). L-arginine is a substrate for the NOS, which converts L-arginine into NO 11. For eNOS, the Michaelis-Menten (Km) constant (which is nerd speak denoting the substrate concentration with which half the enzyme reaction velocity maximum rate is attained) is about 3 mmol/L 12, whereas the blood L-arginine concentrations in both healthy and diseased individuals ranges from 40 to 100 mmol/L 11. This means that the typical non-supplemented blood level of is high enough to saturate endothelial NOS. And when an enzyme is saturated with substrate (in this case L-arginine) more substrate won’t have an effect on a reaction. Therefore, if you’re healthy, when you supplement L-arginine (even in large dosages) you won’t get more NO from the arginine-NO pathway, because L-arginine is not rate-limiting for eNOS.
However, the story is different in clinical conditions like e.g. high blood pressure 13, 14, elevated cholesterol levels 15, 16, heart disease 17, insulin resistance 18, diabetes 19, 20 and in the elderly population 14, 21, in whom L-arginine supplementation has beneficial effects, possibly due to increased NO production 14. Thus, it appears that L-arginine is a limiting factor for NO synthesis in clinical conditions, but not for healthy individuals.
The term ‘L-arginine paradox’ refers to specific situations in which L-arginine supplementation indeed does stimulate NOS activity and NO production, even when blood arginine levels are within the normal range. One explanation for the L-arginine paradox is the presence of high levels of ADMA (asymmetric dimethylarginine), which is an inhibitor of eNOS 10, 22-24. ADMA is produced as part of the body’s normal metabolism 25-27, but in clinical conditions the ADMA levels are elevated several fold 24. In the presence of elevated blood levels of ADMA, eNOS activity diminishes, resulting in a reduced NO production.
How L-arginine supplementation works in the context of elevated ADMA levels
Because ADMA “displaces” L-arginine and thereby reduces the L-arginine availability for eNOS, the ratio of L-arginine to ADMA determines how much of the L-arginine that is floating around in the blood that will be available for eNOS to use for NO production 28, 29. In conditions with elevated ADMA levels, L-arginine supplementation will antagonize ADMA by re-establishing the L-arginine/ADMA ratio and thereby “re-activating” eNOS and increasing NO production 30. This is supported by studies showing that L-arginine supplementation reverses endothelial dysfunction attributable to high ADMA levels in clinical populations 21, 31-33, and that there exist a direct correlation between the change in L-arginine/ADMA ratio and the change in blood flow mediated dilation (vasodilatation) 8.
How to combat elevated ADMA levels
The importance of ADMA is underscored by the fact that it is considered a novel cardiovascular risk factor 22, 33, 34. ADMA seems to mediate the effect of many risk factors on the NOS pathway. Therefore, blood ADMA levels have been suggested to be an “Über marker”, or an overall risk factor that reflects the summative effect of all risk factors on endothelial and cardiovascular health 26.
Because of this, drug companies are currently fervently trying to develop drugs that lower ADMA levels. As of this writing there is no ADMA specific drug available. The strongest candidate as an ADMA specific drug is DDAH, the enzyme that naturally breaks down ADMA 27, 35, 36, and whose activity is also impaired in the above mentioned clinical conditions. DDAH boosting drugs are still in the research phase of development, and it will likely take many years before they, or any other ADMA lowering drugs hit the market. However, several well known drugs used for diabetes (metformin, rosiglitazone) and high blood pressure (ACE inhibitors, angiotensin receptor antagonists) have been shown to lower ADMA levels 37-40. Today, the only dietary option is L-arginine supplementation for those in need.
Will L-arginine supplementation benefit me?
If you are insulin resistant (have elevated levels of insulin and/or blood glucose), have high blood pressure, elevated blood cholesterol, high homocysteine levels 32, diabetes or cardiovascular disease, and/or passed your middle-age a while ago, L-arginine supplementation will work for you in restoring subpar NO production.
In contrast, if you don’t have any risk factors and, save your money. In the next article I will cover a less well known NO producing pathway, that can benefit both healthy and risk factor affected folks.
About Monica Mollica - www.trainergize.com
Trainergize is an informational and motivational resource, presenting the latest health related research findings to fitness geeks and health conscious people in an easy to understand way.
While still under development, trainergize.com is committed to providing credible, objective, and reliable health information on a wide range of topics that impact your health and wellness and that of your family. The information is derived from medical news and studies published in top tier medical journals or presented at professional medical meetings.
Trainergize was developed and is run and maintained by Monica Mollica. Monica has a Bachelor and Master degree in Nutrition from the University of Stockholm, Sweden, and is an ISSA Certified Personal Trainer. She works as diet/nutrition counselor, medical writer/health journalist, and is also a fitness model. On trainergize.com Monica offers online personalized diet/nutrition and exercise consultations.
As a young athlete, Monica realized the importance of nutrition for maximal performance at an early, and went for a major in Nutrition at the University of Stockholm. During her years at the University she was a regular contributor to the Swedish fitness and bodybuilding magazine BODY, and she has written the book (in Swedish) “Functional Foods for Health and Energy Balance”, and authored several book chapters in Swedish publications.
After having earned her Bachelor and Master degree in Nutrition, she completed one semester at the PhD-program “Exercise, Nutrition and Preventive Health” at Baylor University Texas, department of Health Human Performance and Recreation.
Having lost her father in an heart attack at an age of 49, she is specializing in cardiovascular health, and primordial and primary prevention. She is a strong advocate of early risk factor detection and intervention, and of the importance of lifestyle habits for health promotion at all ages.
Today, Monica is sharing her solid academic and real-life experience by offering nutrition/diet and exercise program services and working as a health journalist and medical writer on topics related to fitness, health and anti-aging. She is currently in the process of writing a book “Successful Aging – it’s your choice”, and developing the related website www.SuccessfulAging.me
1. Bloomer RJ. Nitric oxide supplements for sports. Strength and Conditioning Journal. 2010;32(2):14-20.
2. Bloomer RJ, Farney TM, Trepanowski JF, 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 the International Society of Sports Nutrition. 2010;7:16.
3. Bode-Boger SM, Boger RH, Creutzig A, et al. L-arginine infusion decreases peripheral arterial resistance and inhibits platelet aggregation in healthy subjects. Clin Sci (Lond). 1994;87(3):303-310.
4. Giugliano D, Marfella R, Verrazzo G, et al. The vascular effects of L-Arginine in humans. The role of endogenous insulin. The Journal of clinical investigation. 1997;99(3):433-438.
5. Alvares TS, Meirelles CM, Bhambhani YN, et al. L-Arginine as a potential ergogenic aid in healthy subjects. Sports Med. 2011;41(3):233-248.
6. Wax B, Kavazis AN, Webb HE, et al. Acute L-arginine alpha ketoglutarate supplementation fails to improve muscular performance in resistance trained and untrained men. Journal of the International Society of Sports Nutrition. 2012;9(1):17.
7. Bode-Boger SM, Boger RH, Galland A, et al. L-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship. British journal of clinical pharmacology. 1998;46(5):489-497.
8. Schwedhelm E, Maas R, Freese R, et al. Pharmacokinetic and pharmacodynamic properties of oral L-citrulline and L-arginine: impact on nitric oxide metabolism. British journal of clinical pharmacology. 2008;65(1):51-59.
9. Robinson TM, Sewell DA, Greenhaff PL. L-arginine ingestion after rest and exercise: effects on glucose disposal. Medicine and science in sports and exercise. 2003;35(8):1309-1315.
10. Vallance P, Chan N. Endothelial function and nitric oxide: clinical relevance. Heart. 2001;85(3):342-350.
11. Boger RH, Bode-Boger SM. The clinical pharmacology of L-arginine. Annual review of pharmacology and toxicology. 2001;41:79-99.
12. Pollock JS, Forstermann U, Mitchell JA, et al. Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells. Proceedings of the National Academy of Sciences of the United States of America. 1991;88(23):10480-10484.
13. Gokce N. L-arginine and hypertension. The Journal of nutrition. 2004;134(10 Suppl):2807S-2811S; discussion 2818S-2819S.
14. Higashi Y, Oshima T, Ozono R, et al. Aging and severity of hypertension attenuate endothelium-dependent renal vascular relaxation in humans. Hypertension. 1997;30(2 Pt 1):252-258.
15. Clarkson P, Adams MR, Powe AJ, et al. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. The Journal of clinical investigation. 1996;97(8):1989-1994.
16. Kawano H, Motoyama T, Hirai N, et al. Endothelial dysfunction in hypercholesterolemia is improved by L-arginine administration: possible role of oxidative stress. Atherosclerosis. 2002;161(2):375-380.
17. Adams MR, McCredie R, Jessup W, et al. Oral L-arginine improves endothelium-dependent dilatation and reduces monocyte adhesion to endothelial cells in young men with coronary artery disease. Atherosclerosis. 1997;129(2):261-269.
18. Sydow K, Mondon CE, Cooke JP. Insulin resistance: potential role of the endogenous nitric oxide synthase inhibitor ADMA. Vasc Med. 2005;10 Suppl 1:S35-43.
19. Piatti PM, Monti LD, Valsecchi G, et al. Long-term oral L-arginine administration improves peripheral and hepatic insulin sensitivity in type 2 diabetic patients. Diabetes care. 2001;24(5):875-880.
20. Pieper GM, Siebeneich W, Dondlinger LA. Short-term oral administration of L-arginine reverses defective endothelium-dependent relaxation and cGMP generation in diabetes. European journal of pharmacology. 1996;317(2-3):317-320.
21. Bode-Boger SM, Muke J, Surdacki A, et al. Oral L-arginine improves endothelial function in healthy individuals older than 70 years. Vasc Med. 2003;8(2):77-81.
22. Boger RH, Cooke JP, Vallance P. ADMA: an emerging cardiovascular risk factor. Vasc Med. 2005;10 Suppl 1:S1-2.
23. Cooke JP. ADMA: its role in vascular disease. Vasc Med. 2005;10 Suppl 1:S11-17.
24. Boger RH. Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, explains the “L-arginine paradox” and acts as a novel cardiovascular risk factor. The Journal of nutrition. 2004;134(10 Suppl):2842S-2847S; discussion 2853S.
25. Sibal L, Agarwal SC, Home PD, et al. The Role of Asymmetric Dimethylarginine (ADMA) in Endothelial Dysfunction and Cardiovascular Disease. Current cardiology reviews. 2010;6(2):82-90.
26. Cooke JP. Asymmetrical dimethylarginine: the Uber marker? Circulation. 2004;109(15):1813-1818.
27. Tran CT, Leiper JM, Vallance P. The DDAH/ADMA/NOS pathway. Atherosclerosis Supplements. 2003;4(4):33-40.
28. Tsikas D, Sandmann J, Savva A, et al. Assessment of nitric oxide synthase activity in vitro and in vivo by gas chromatography-mass spectrometry. Journal of chromatography B, Biomedical sciences and applications. 2000;742(1):143-153.
29. Boger RH, Vallance P, Cooke JP. Asymmetric dimethylarginine (ADMA): a key regulator of nitric oxide synthase. Atherosclerosis Supplements. 2003;4(4):1-3.
30. Bode-Boger SM, Scalera F, Ignarro LJ. The L-arginine paradox: Importance of the L-arginine/asymmetrical dimethylarginine ratio. Pharmacology & therapeutics. 2007;114(3):295-306.
31. Boger RH, Bode-Boger SM, Thiele W, et al. Restoring vascular nitric oxide formation by L-arginine improves the symptoms of intermittent claudication in patients with peripheral arterial occlusive disease. Journal of the American College of Cardiology. 1998;32(5):1336-1344.
32. Sydow K, Schwedhelm E, Arakawa N, et al. ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of L-arginine and B vitamins. Cardiovascular research. 2003;57(1):244-252.
33. Boger RH, Bode-Boger SM, Szuba A, et al. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation. 1998;98(18):1842-1847.
34. Boger RH, Zoccali C. ADMA: a novel risk factor that explains excess cardiovascular event rate in patients with end-stage renal disease. Atherosclerosis Supplements. 2003;4(4):23-28.
35. Cooke JP, Ghebremariam YT. DDAH says NO to ADMA. Arteriosclerosis, thrombosis, and vascular biology. 2011;31(7):1462-1464.
36. Cooke JP. DDAH: a target for vascular therapy? Vasc Med. 2010;15(3):235-238.
37. Asagami T, Abbasi F, Stuelinger M, et al. Metformin treatment lowers asymmetric dimethylarginine concentrations in patients with type 2 diabetes. Metabolism: clinical and experimental. 2002;51(7):843-846.
38. Stuhlinger MC, Abbasi F, Chu JW, et al. Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA : the journal of the American Medical Association. 2002;287(11):1420-1426.
39. Ito A, Egashira K, Narishige T, et al. Renin-angiotensin system is involved in the mechanism of increased serum asymmetric dimethylarginine in essential hypertension. Japanese circulation journal. 2001;65(9):775-778.
40. Delles C, Schneider MP, John S, et al. Angiotensin converting enzyme inhibition and angiotensin II AT1-receptor blockade reduce the levels of asymmetrical N(G), N(G)-dimethylarginine in human essential hypertension. American journal of hypertension. 2002;15(7 Pt 1):590-593.