Keywords
Nitric oxide supplementation
Nitric oxide synthesis
L-arginine supplementation
L-citrulline supplementation
Dietary supplements
Nitric oxide synthesis
L-arginine supplementation
L-citrulline supplementation
Dietary supplements
Abstract
Nitric oxide (NO) is an essential component of the human body, involved in blood vessel dilation, stimulation of hormone release, signaling and regulation of neurotransmission. Nitric oxide is synthesized by nitric-oxide-synthase-dependent and -independent pathways. Nitric oxide supplementation improves cardiac health, enhances performance during exercise, reduces high blood pressure during pregnancy, reduces erectile dysfunction and improves healing processes and respiratory response. Nitric-oxide-associated benefits are mostly apparent in untrained or moderately trained individuals. L-arginine and L-citrulline supplementation contributes to nitric oxide levels because L-arginine is directly involved in NO synthesis, whereas L-citrulline acts as an L-arginine precursor that is further converted to NO by a reaction catalyzed by NO synthase. L-arginine supplements increase respiratory response and enhance performance during exercise, while L-citrulline with malate and other molecules increase working capacity. Various studies involving beetroot juice have reported a significant increase in plasma nitrite levels, regarded as markers of NO, after intake of beetroot juice. Although NO supplementation may have mild to moderate side-effects, using smaller or divided doses could avoid some of these side-effects. Since nitric oxide supplementation may worsen certain health conditions and may interfere with certain medicines, it should only be taken under medical supervision.
References
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[3] Tipton KD and Ferrando AA. Improving muscle mass: response of muscle metabolism to exercise, nutrition and anabolic agents. Essays Biochem 2008;44:85-98. https://doi.org/10.1042/BSE0440085
[4] Maiorana A, O’Driscoll G, Taylor R, Green D. Exercise and the nitric oxide vasodilator system. Sports Med 2003;33:1013-35. https://doi.org/10.2165/00007256-200333140-00001
[5] Morita M, Hayashi T, Ochiai M, Maeda M, Yamaguchi T, Ina K, Kuzuya M. Oral supplementation with a combination of L-citrulline and L-arginine rapidly increases plasma L-arginine concentration and enhances NO bioavailability. Biochem Biophys Res Commun 2014;454:53-7. https://doi.org/10.1016/j. bbrc.2014.10.029
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[7] Vanhatalo A, Bailey SJ, Blackwell JR, DiMenna FJ, Pavey TG, Wilkerson DP, Benjamin N, Winyard PG, Jones AM. Acute and chronic effects of dietary nitrate supplementation on blood pressure and the physiological responses to moderate-intensity and incremental exercise. Am J Physiol Regul Integr Comp Physiol 2010;299:R1121-31. https://doi/org.10.1152/ajpregu.00206.2010
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[9] Koppo K, Taes YE, Pottier A, Boone J, Bouckaert J, Derave W. Dietary arginine supplementation speeds pulmonary VO2 kinetics during cycle exercise. Med Sci Sports Exerc 2009;41:1626-32. https://doi.org/10.1249/MSS.0b013e31819d81b6
[10] Chen S, Kim W, Henning SM, Carpenter CL, Li Z. Arginine and antioxidant supplement on performance in elderly male cyclists: a randomized controlled trial. J Int Soc Sports Nutr 2010;7:13. https://doi.org/10.1186/1550-2783-7-13
[11] Camic CL, Housh TJ, Mielke M, Zuniga JM, Hendrix CR, Johnson GO, Schmidt RJ, Housh DJ. The effects of 4 weeks of an arginine-based supplement on the gas exchange threshold and peak oxygen uptake. Appl Physiol Nutr Metab 2010;35:286-93. https://doi.org/10.1139/H10-019
[12] Campbell B, Roberts M, Kerksick C, Wilborn C, Marcello B, Taylor L, Nassar E, Leutholtz B, Bowden R, Rasmussen C, Greenwood M, Kreider R. Pharmacokinetics, safety, and effects on exercise performance of L-arginine alpha-ketoglutarate in trained adult men. Nutrition 2006;22:872-81. https://doi.org/10.1016/j.nut.2006.06.003
[13] Buford BN, Koch AJ. Glycine-arginine-alpha-ketoisocaproic acid improves performance of repeated cycling sprints. Med Sci Sports Exerc 2004;36:583-7. https://doi.org/10.1249/01. mss.0000122075.14060.c4
[14] Stevens BR, Godfrey MD, Kaminski TW, Braith RW. High-intensity dynamic human muscle performance enhanced by a metabolic intervention. Med Sci Sports Exerc 2000;32:2102-8. https://doi.org/10.1097/00005768-200012000-00021
[15] Bailey SJ, Blackwell JR, Lord T, Vanhatalo A, Winyard PG, Jones AM. l-Citrulline supplementation improves O2 uptake kinetics and high-intensity exercise performance in humans. J Appl Physiol 2015;119:385-95. https://doi.org/10.1152/japplphysiol.00192.2014
[16] Sureda A, Cordova A, Ferrer MD, Tauler P, Perez G, Tur JA,Pons A. Effects of L-citrulline oral supplementation on polymorphonuclear neutrophils oxidative burst and nitric oxide production after exercise. Free Radic Res 2009;43:828-35. https://doi.org/10.1080/10715760903071664
[17] Mehta S, Stewart DJ, Levy RD. The hypotensive effect of L-arginine is associated with increased expired nitric oxide in humans. Chest 1996;109:1550-5. https://doi.org/10.1378/chest.109.6.1550
[18] Romero MJ, Platt DH, Caldwell RB,Caldwell RW. Therapeutic use of citrulline in cardiovascular disease. Cardiovasc Drug Rev 2006;24:275-90. https://doi.org/10.1111/j.1527-3466.2006.00275.x
[19] Rouge C, Des Robert C, Robins A, Le Bacquer O, Volteau C, De La Cochetiere MF,Darmaun D. Manipulation of citrulline availability in humans. Am J Physiol Gastrointest Liver Physiol 2007;293:G1061-7. https://doi.org/10.1152/ajpgi.00289.2007
[20] van de Poll MC, Soeters PB, Deutz NE, Fearon KC, Dejong CH. Renal metabolism of amino acids: its role in interorgan amino acid exchange. Am J Clin Nutr 2004;79:185-97. https://doi.org/10.1093/ajcn/79.2.185
[21] Bendahan D, Mattei JP, Ghattas B, Confort-Gouny S, Le Guern ME,Cozzone PJ. Citrulline/malate promotes aerobic energy production in human exercising muscle. Br J Sports Med 2002;282-9. https://doi.org/10.1136/bjsm.36.4.282
[22] Perez-Guisado J, Jakeman PM. Citrulline malate enhances athletic anaerobic performance and relieves muscle soreness. J Strength Cond Res 2010;24:1215-22. https://doi.org/10.1519/JSC.0b013e3181cb28e0
[23] Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993;329:2002-12. https://doi.org/10.1056/NEJM199312303292706
[24] Balon TW, Nadler JL. Evidence that nitric oxide increases glucose transport in skeletal muscle. J Appl Physiol 1997;82:359-63. https://doi.org/10.1152/jappl.1997.82.1.359
[25] Capanni C, Squarzoni S, Petrini S, Villanova M, Muscari C, Maraldi NM, Guarnieri C, Caldarera CM. Increase of neuronal nitric oxide synthase in rat skeletal muscle during ageing. Biochem Biophys Res Commun 1998;245:216-9. https://doi.org/10.1006/bbrc.1998.8404
[26] Shen W, Zhang X, Zhao G, Wolin MS, Sessa W, Hintze TH. Nitric oxide production and NO synthase gene expression contribute to vascular regulation during exercise. Med Sci Sports Exerc 1995;27:1125-34.
[27] Benjamin N, O’Driscoll F, Dougall H, Duncan C, Smith L, Golden M, McKenzie H. Stomach NO synthesis. Nature 1994;368:502. https://doi.org/10.1038/368502a0
[28] Lundberg JO, Weitzberg E, Lundberg JM, Alving K. Intragastric nitric oxide production in humans: measurements in expelled air. Gut 1994;35:1543-6. https://doi.org/10.1136/gut.35.11.1543
[29] Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov 2008;7:156-67. https://doi.org/10.1038/nrd2466
[30] Tannenbaum SR, Weisman M, Fett D. The effect of nitrate intake on nitrite formation in human saliva. Food Cosmet Toxicol 1976;14:549-52. https://doi.org/10.1016/s0015-6264(76)80006-5
[31] Lundberg JO, Govoni M. Inorganic nitrate is a possible source for systemic generation of nitric oxide. Free Radic Biol Med 2004;37:395-400. https://doi.org/10.1016/j.freeradbiomed.2004.04.027
[32] Larsen FJ, Weitzberg E, Lundberg JO, Ekblom B. Effects of dietary nitrate on oxygen cost during exercise. Acta Physiol 2007;191:59-66. https://doi.org/10.1111/j.1748-1716.2007.01713.x
[33] Larsen FJ, Weitzberg E, Lundberg JO, Ekblom B. Dietary nitrate reduces maximal oxygen consumption while maintaining work performance in maximal exercise. Free Radic Biol Med 2010;48:342-7. https://doi.org/10.1016/j.freeradbiomed.2009.11.006
[34] Larsen FJ, Schiffer TA, Borniquel S, Sahlin K, Ekblom B, Lundberg JO, Weitzberg E. Dietary inorganic nitrate improves mitochondrial efficiency in humans. Cell Metab 2011;13:149-59. https://doi.org/10.1016/j.cmet.2011.01.004
[35] Bailey SJ, Fulford J, Vanhatalo A, Winyard PG, Blackwell JR, DiMenna FJ, Wilkerson DP, Benjamin N, Jones AM. Dietary nitrate supplementation enhances muscle contractile efficiency during knee-extensor exercise in humans. J Appl Physiol 2010;109:135-48. https://doi.org/10.1152/japplphysiol.00046.2010
[36] Webb AJ, Patel N, Loukogeorgakis S, Okorie M, Aboud Z, Misra S, Rashid R, Miall P, Deanfield J, Benjamin N, MacAllister R, Hobbs AJ, Ahluwalia A. Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite. Hypertension 2008;51:784-90. https://doi.org/10.1161/HYPERTENSIONAHA.107.103523
[37] Lansley KE, Winyard PG, Bailey SJ, Vanhatalo A, Wilkerson DP, Blackwell JR, Gilchrist M, Benjamin N, Jones AM. Acute dietary nitrate supplementation improves cycling time trial performance. Med Sci Sports Exerc 2011;43:1125-31. https://doi.org/10.1249/MSS.0b013e31821597b4
[38] Bloomer RJ, Fisher-Wellman KH, Tucker PS. Effect of oral acetyl L-carnitine arginate on resting and postprandial blood biomarkers in pre-diabetics. Nutr Metab 2009;6:25. https://doi.org/10.1186/1743-7075-6-25
[39] Calo LA, Pagnin E, Davis PA, Semplicini A, Nicolai R, Calvani M, Pessina AC. Antioxidant effect of L-carnitine and its short chain esters: relevance for the protection from oxidative stress related cardiovascular damage. Int J Cardiol 2006;107:54-60. https://doi.org/10.1016/j.ijcard.2005.02.053
[40] Bueno R, Alvarez de Sotomayor M, Perez-Guerrero C, Gomez-Amores L, Vazquez CM, Herrera MD. L-carnitine and propionyl-L-carnitine improve endothelial dysfunction in spontaneously hypertensive rats: different participation of NO and COX-products. Life Sci 2005;77:2082-97. https://doi.org/10.1016/j.lfs.2005.01.035
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