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No effect of acute l-arginine supplementation on O2 cost or exercise tolerance

Abstract

The extent to which dietary supplementation with the nitric oxide synthase (NOS) substrate, l-arginine (ARG), impacts on NO production and NO-mediated physiological responses is controversial. This randomised, double blinded, cross-over study investigated the effects of acute ARG supplementation on NO biomarkers, O2 cost of exercise and exercise tolerance in humans. In one experiment, 15 subjects completed moderate- and severe-intensity running bouts after acute supplementation with 6 g ARG or placebo (PLA). In another experiment, eight subjects completed moderate- and severe-intensity cycling bouts after acute supplementation with 6 g ARG plus 25 g of carbohydrate (ARG + CHO) or an energy-matched dose of carbohydrate alone (CHO). The plasma nitrite concentration was not different after ARG (Pre: 204 ± 79; Post: 241 ± 114 nM; P > 0.05) or ARG + CHO consumption (Pre: 304 ± 57; Post: 335 ± 116 nM; P > 0.05). During moderate-intensity exercise, the steady-state pulmonary \( \dot{V}{\text{O}}_{2} \) was not different, relative to the respective placebo conditions, after ARG (PLA: 2,407 ± 318, ARG: 2,422 ± 333 mL min−1) or ARG + CHO (CHO: 1,695 ± 304, ARG + CHO: 1,712 ± 312 mL min−1) ingestion (P > 0.05). The tolerable duration of severe exercise was also not significantly different (P > 0.05) after ingesting ARG (PLA: 551 ± 140, ARG: 552 ± 150 s) or ARG + CHO (CHO: 457 ± 182, ARG + CHO: 441 ± 221 s). In conclusion, acute dietary supplementation with ARG or ARG + CHO did not alter biomarkers of NO synthesis, O2 cost of exercise or exercise tolerance in healthy subjects.

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References

  1. Abel T, Knechtle B, Perret C, Eser P, von Arx P, Knecht H (2005) Influence of chronic supplementation of arginine aspartate in endurance athletes on performance and substrate metabolism—a randomized, double-blind, placebo-controlled study. Int J Sports Med 26:344–349

    Article  CAS  PubMed  Google Scholar 

  2. Allen JD, Stabler T, Kenjale A, Ham KL, Robbins JL, Duscha BD, Dobrosielski DA, Annex BH (2010) Plasma nitrite flux predicts exercise performance in peripheral arterial disease after 3 months of exercise training. Free Radic Biol Med 49:1138–1144

    Article  CAS  PubMed  Google Scholar 

  3. Álvares TS, Meirelles CM, Bhambhani YN, Paschoalin VM, Gomes PS (2011) l-arginine as a potential ergogenic aid in healthy subjects. Sports Med 41:233–248

    Article  PubMed  Google Scholar 

  4. Bailey SJ, Winyard P, Vanhatalo A, Blackwell JR, DiMenna FJ, Wilkerson DP, Tarr J, Benjamin N, Jones AM (2009) Dietary nitrate supplementation reduces the O2 cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans. J Appl Physiol 107:1144–1155

    Article  CAS  PubMed  Google Scholar 

  5. Bailey SJ, Winyard PG, Vanhatalo A, Blackwell JR, DiMenna FJ, Wilkerson DP, Jones AM (2010) Acute l-arginine supplementation reduces the O2 cost of moderate-intensity exercise and enhances high-intensity exercise tolerance. J Appl Physiol 109:1394–1403

    Article  CAS  PubMed  Google Scholar 

  6. Bednarz B, Jaxa-Chamiec T, Gebalska J, Herbaczyńska-Cedro K, Ceremuzyński L (2004) l-arginine supplementation prolongs exercise capacity in congestive heart failure. Kardiol Pol 60:348–353

    PubMed  Google Scholar 

  7. Beis L, Mohammad Y, Easton C, Pitsiladis YP (2011) Failure of glycine-arginine-α-ketoisocaproic acid to improve high-intensity exercise performance in trained cyclists. Int J Sport Nutr Exerc Metab 21:33–39

    PubMed  Google Scholar 

  8. Bescós R, Gonzalez-Haro C, Pujol P, Drobnic F, Alonso E, Santolaria ML, Ruiz O, Esteve M, Galilea P (2009) Effects of dietary l-arginine intake on cardiorespiratory and metabolic adaptation in athletes. Int J Sport Nutr Exerc Metab 19:355–365

    PubMed  Google Scholar 

  9. Bescós R, Rodríguez FA, Iglesias X, Ferrer MD, Iborra E, Pons A (2011) Acute administration of inorganic nitrate reduces VO2peak in endurance athletes. Med Sci Sports Exerc 43:1979–1986

    Article  PubMed  Google Scholar 

  10. Bescós R, Ferrer-Roca V, Galilea PA, Roig A, Drobnic F, Sureda A, Martorell M, Cordova A, Tur JA, Pons A (2012) Sodium nitrate supplementation does not enhance performance of endurance athletes. Med Sci Sports Exerc 44:2400–2409

    Article  PubMed  Google Scholar 

  11. Bloomer RJ, Farney TM, Trepanowski JF, McCarthy CG, Canale RE (2011) Effect of betaine supplementation on plasma nitrate/nitrite in exercise-trained men. J Int Soc Sports Nutr 8:5

    Article  CAS  PubMed  Google Scholar 

  12. Bode-Böger SM, Böger RH, Galland A, Tsikas D, Frölich JC (1998) l-arginine-induced vasodilation in healthy humans: pharmacokinetic-pharmacodynamic relationship. Br J Clin Pharmacol 46:489–497

    Article  PubMed  Google Scholar 

  13. Böger RH, Tsikas D, Bode-Böger SM, Phivthong-Ngam L, Schwedhelm E, Frölich JC (2004) Hypercholesterolemia impairs basal nitric oxide synthase turnover rate: a study investigating the conversion of l-[guanidino-(15)N(2)]-arginine to (15)N-labeled nitrate by gas chromatography–mass spectrometry. Nitric Oxide 11:1–8

    Article  PubMed  Google Scholar 

  14. Boucher JL, Moali C, Tenu JP (1999) Nitric oxide biosynthesis, nitric oxide synthase inhibitors and arginase competition for l-arginine utilization. Cell Mol Life Sci 55(8–9):1015–1028

    Article  CAS  PubMed  Google Scholar 

  15. Broglio F, Gottero C, Benso A, Prodam F, Destefanis S, Gauna C, Maccario M, Deghenghi R, van der Lely AJ, Ghigo E (2003) Effects of ghrelin on the insulin and glycemic responses to glucose, arginine, or free fatty acids load in humans. J Clin Endocrinol Metab 88:4268–4272

    Article  CAS  PubMed  Google Scholar 

  16. Buford BN, Koch AJ (2004) Glycine-arginine-alpha-ketoisocaproic acid improves performance of repeated cycling sprints. Med Sci Sports Exerc 36:583–587

    Article  CAS  PubMed  Google Scholar 

  17. Burtscher M, Brunner F, Faulhaber M, Hotter B, Likar R (2005) The prolonged intake of l-arginine-l-aspartate reduces blood lactate accumulation and oxygen consumption during submaximal exercise. J Sports Sci Med 4:314–322

    Google Scholar 

  18. Camic CL, Housh TJ, Mielke M, Zuniga JM, Hendrix CR, Johnson GO, Schmidt RJ, Housh DJ (2010a) The effects of 4 weeks of an arginine-based supplement on the gas exchange threshold and peak oxygen uptake. Appl Physiol Nutr Metab 35:286–293

    Article  CAS  PubMed  Google Scholar 

  19. Camic CL, Housh TJ, Zuniga JM, Hendrix RC, Mielke M, Johnson GO, Schmidt RJ (2010b) Effects of arginine-based supplements on the physical working capacity at the fatigue threshold. J Strength Cond Res 24:1306–1312

    Article  PubMed  Google Scholar 

  20. Campbell B, Roberts M, Kerksick C, Wilborn C, Marcello B, Taylor L, Nassar E, Leutholtz B, Bowden R, Rasmussen C, Greenwood M, Kreider R (2006) Pharmacokinetics, safety, and effects on exercise performance of l-arginine alpha-ketoglutarate in trained adult men. Nutrition 22:872–881

    Article  CAS  PubMed  Google Scholar 

  21. Cannon RO 3rd, Schechter AN, Panza JA, Ognibene FP, Pease-Fye ME, Waclawiw MA, Shelhamer JH, Gladwin MT (2001) Effects of inhaled nitric oxide on regional blood flow are consistent with intravascular nitric oxide delivery. J Clin Invest 108:279–287

    CAS  PubMed  Google Scholar 

  22. Castillo L, deRojas TC, Chapman TE, Vogt J, Burke JF, Tannenbaum SR, Young VR (1993) Splanchnic metabolism of dietary arginine in relation to nitric oxide synthesis in normal adult man. Proc Natl Acad Sci USA 90:193–197

    Article  CAS  PubMed  Google Scholar 

  23. Cermak NM, Gibala MJ, van Loon LJC (2012a) Nitrate supplementation’s improvement of 10-km time-trial performance in trained cyclists. Int J Sport Nutr Exerc Metab 22:64–71

    CAS  PubMed  Google Scholar 

  24. Cermak NM, Res P, Stinkens R, Lundberg JO, Gibala MJ, van Loon LJC (2012b) No improvement in endurance performance after a single dose of beetroot juice. Int J Sport Nutr Exerc Metab 22:470–478

    CAS  Google Scholar 

  25. Christensen PM, Nyberg M, Bangsbo J (2012) Influence of nitrate supplementation on VO2 kinetics and endurance of elite cyclists. Scand J Med Sci Sports. doi:10.1111/sms.12005

  26. Closs EI, Basha FZ, Habermeier A, Förstermann U (1997) Interference of l-arginine analogues with l-arginine transport mediated by the y+ carrier hCAT-2B. Nitric Oxide 1:65–73

    Article  CAS  PubMed  Google Scholar 

  27. Colombani PC, Bitzi R, Frey-Rindova P, Frey W, Arnold M, Langhans W, Wenk C (1999) Chronic arginine aspartate supplementation in runners reduces total plasma amino acid level at rest and during a marathon run. Eur J Nutr 38:263–270

    Article  CAS  PubMed  Google Scholar 

  28. Dong JY, Qin LQ, Zhang Z, Zhao Y, Wang J, Arigoni F, Zhang W (2011) Effect of oral l-arginine supplementation on blood pressure: a meta-analysis of randomized, double-blind, placebo-controlled trials. Am Heart J 162:959–965

    Article  CAS  PubMed  Google Scholar 

  29. Dreissigacker U, Wendt M, Wittke T, Tsikas D, Maassen N (2010) Positive correlation between plasma nitrite and performance during high-intensive exercise but not oxidative stress in healthy men. Nitric Oxide 23:128–135

    Article  CAS  PubMed  Google Scholar 

  30. Forbes SC, Bell GJ (2011) The acute effects of a low and high dose of oral l-arginine supplementation in young active males at rest. Appl Physiol Nutr Metab 36:405–411

    Article  CAS  PubMed  Google Scholar 

  31. Gladwin MT, Shelhamer JH, Schechter AN, Pease-Fye ME, Waclawiw MA, Panza JA, Ognibene FP, Cannon RO 3rd (2000) Role of circulating nitrite and S-nitrosohemoglobin in the regulation of regional blood flow in humans. Proc Natl Acad Sci USA 97:11482–11487

    Article  CAS  PubMed  Google Scholar 

  32. Greer BK, Jones BT (2011) Acute arginine supplementation fails to improve muscle endurance or affect blood pressure responses to resistance training. J Strength Cond Res 25:1789–1794

    Article  PubMed  Google Scholar 

  33. Hoffman JR, Ratamess NA, Kang J, Rashti SL, Faigenbaum AD (2009) Effect of betaine supplementation on power performance and fatigue. J Int Soc Sports Nutr 6:7

    Article  PubMed  Google Scholar 

  34. Jones AM, Doust JH (1996) A 1 % treadmill grade most accurately reflects the energetic cost of outdoor running. J Sports Sci 14:321–327

    Article  CAS  PubMed  Google Scholar 

  35. Kapil V, Milsom AB, Okorie M, Maleki-Toyserkani S, Akram F, Rehman F, Arghandawi S, Pearl V, Benjamin N, Loukogeorgakis S, Macallister R, Hobbs AJ, Webb AJ, Ahluwalia A (2010) Inorganic nitrate supplementation lowers blood pressure in humans: role for nitrite-derived NO. Hypertension 56:274–281

    Article  CAS  PubMed  Google Scholar 

  36. Kleinbongard P, Dejam A, Lauer T, Rassaf T, Schindler A, Picker O, Scheeren T, Gödecke A, Schrader J, Schulz R, Heusch G, Schaub GA, Bryan NS, Feelisch M, Kelm M (2003) Plasma nitrite reflects constitutive nitric oxide synthase activity in mammals. Free Radic Biol Med 35:790–796

    Article  CAS  PubMed  Google Scholar 

  37. Koppo K, Taes YE, Pottier A, Boone J, Bouckaert J, Derave W (2009) Dietary arginine supplementation speeds pulmonary VO2 kinetics during cycle exercise. Med Sci Sports Exerc 41:1626–1632

    Article  CAS  PubMed  Google Scholar 

  38. Lansley KE, Winyard PG, Fulford J, Vanhatalo A, Bailey SJ, Blackwell JR, DiMenna FJ, Gilchrist M, Benjamin N, Jones AM (2011) Dietary nitrate supplementation reduces the O2 cost of walking and running: a placebo-controlled study. J Appl Physiol 110:591–600

    Article  CAS  PubMed  Google Scholar 

  39. Larsen FJ, Weitzberg E, Lundberg JO, Ekblom B (2007) Effects of dietary nitrate on oxygen cost during exercise. Acta Physiol 191:59–66

    Article  CAS  Google Scholar 

  40. Larsen FJ, Weitzberg E, Lundberg JO, Ekblom B (2010) Dietary nitrate reduces maximal oxygen consumption while maintaining work performance in maximal exercise. Free Radic Biol Med 48:342–347

    Article  CAS  PubMed  Google Scholar 

  41. Lauer T, Preik M, Rassaf T, Strauer BE, Deussen A, Feelisch M, Kelm M (2001) Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action. Proc Natl Acad Sci USA 2001(98):12814–12819

    Article  Google Scholar 

  42. Lin KY, Ito A, Asagami T, Tsao PS, Adimoolam S, Kimoto M, Tsuji H, Reaven GM, Cooke JP (2002) Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase. Circulation 106:987–992

    Article  CAS  PubMed  Google Scholar 

  43. Linden KC, Wadley GD, Garnham AP, McConell GK (2011) Effects of l-arginine infusion on glucose disposal during exercise in humans. Med Sci Sports Exerc 43:1626–1634

    Article  CAS  PubMed  Google Scholar 

  44. Liu TH, Wu CL, Chiang CW, Lo YW, Tseng HF, Chang CK (2009) No effect of short-term arginine supplementation on nitric oxide production, metabolism and performance in intermittent exercise in athletes. J Nutr Biochem 20:462–468

    Article  CAS  PubMed  Google Scholar 

  45. Lundberg JO, Weitzberg E (2010) NO-synthase independent NO generation in mammals. Biochem Biophys Res Commu 396:39–45

    Article  CAS  Google Scholar 

  46. MacAllister RJ, Parry H, Kimoto MT, Russell RJ, Hodson H, Whitley GS, Vallance P (1996) Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br J Pharmacol 119:1533–1540

    Article  CAS  PubMed  Google Scholar 

  47. McConell GK, Huynh NN, Lee-Young RS, Canny BJ, Wadley GD (2006) l-Arginine infusion increases glucose clearance during prolonged exercise in humans. Am J Physiol Endocrinol Metab 290:E60–E66

    Article  CAS  PubMed  Google Scholar 

  48. Morris SM Jr (2002) Regulation of enzymes of the urea cycle and arginine metabolism. Annu Rev Nutr 22:87–105

    Article  CAS  PubMed  Google Scholar 

  49. Pollock JS, Förstermann U, Mitchell JA, Warner TD, Schmidt HH, Nakane M, Murad F (1991) Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells. Proc Natl Acad Sci USA 88:10480–10484

    Article  CAS  PubMed  Google Scholar 

  50. Powers SK, Jackson MJ (2008) Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production. Physiol Rev 88:1243–1276

    Article  CAS  PubMed  Google Scholar 

  51. Rassaf T, Lauer T, Heiss C, Balzer J, Mangold S, Leyendecker T, Rottler J, Drexhage C, Meyer C, Kelm M (2007) Nitric oxide synthase-derived plasma nitrite predicts exercise capacity. Br J Sports Med 41:669–673

    Article  PubMed  Google Scholar 

  52. Rizza S, Muniyappa R, Iantorno M, Kim JA, Chen H, Pullikotil P, Senese N, Tesauro M, Lauro D, Cardillo C, Quon MJ (2011) Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome. J Clin Endocrinol Metab 96:E782–E792

    Article  CAS  PubMed  Google Scholar 

  53. Schaefer A, Piquard F, Geny B, Doutreleau S, Lampert E, Mettauer B, Lonsdorfer J (2002) l-arginine reduces exercise-induced increase in plasma lactate and ammonia. Int J Sports Med 23:403–407

    Article  CAS  PubMed  Google Scholar 

  54. Simmons WW, Closs EI, Cunningham JM, Smith TW, Kelly RA (1996) Cytokines and insulin induce cationic amino acid transporter (CAT) expression in cardiac myocytes. Regulation of l-arginine transport and no production by CAT-1, CAT-2A, and CAT-2B. J Biol Chem 271:11694–11702

    Article  CAS  PubMed  Google Scholar 

  55. Stamler JS, Meissner G (2001) Physiology of nitric oxide in skeletal muscle. Physiol Rev 81:209–237

    CAS  PubMed  Google Scholar 

  56. Stevens BR, Godfrey MD, Kaminski TW, Braith RW (2000) High-intensity dynamic human muscle performance enhanced by a metabolic intervention. Med Sci Sports Exerc 32:2102–2108

    Article  CAS  PubMed  Google Scholar 

  57. Stühlinger MC, Tsao PS, Her JH, Kimoto M, Balint RF, Cooke JP (2001) Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation 104:2569–2575

    Article  PubMed  Google Scholar 

  58. Tang JE, Lysecki PJ, Manolakos JJ, MacDonald MJ, Tarnopolsky MA, Phillips SM (2011) Bolus arginine supplementation affects neither muscle blood flow nor muscle protein synthesis in young men at rest or after resistance exercise. J Nutr 141:195–200

    Article  CAS  PubMed  Google Scholar 

  59. Thams P, Capito K (1999) l-arginine stimulation of glucose-induced insulin secretion through membrane depolarization and independent of nitric oxide. Eur J Endocrinol 140:87–93

    Article  CAS  PubMed  Google Scholar 

  60. Totzeck M, Hendgen-Cotta UB, Rammos C, Frommke LM, Knackstedt C, Predel HG, Kelm M, Rassaf T (2012) Higher endogenous nitrite levels are associated with superior exercise capacity in highly trained athletes. Nitric Oxide 2012(27):75–81

    Article  Google Scholar 

  61. van de Poll MC, Siroen MP, van Leeuwen PA, Soeters PB, Melis GC, Boelens PG, Deutz NE, Dejong CH (2007) Interorgan amino acid exchange in humans: consequences for arginine and citrulline metabolism. Am J Clin Nutr 85:167–172

    PubMed  Google Scholar 

  62. Wascher TC, Posch K, Wallner S, Hermetter A, Kostner GM, Graier WF (1997) Vascular effects of l-arginine: anything beyond a substrate for the NO-synthase? Biochem Biophys Res Commun 234:35–38

    Article  CAS  PubMed  Google Scholar 

  63. Wilkerson DP, Hayward GM, Bailey SJ, Vanhatalo A, Blackwell JR, Jones AM (2012) Influence of acute dietary nitrate supplementation on 50 mile time trial performance in well-trained cyclists. Eur J Appl Physiol 112:4127–4134

    Article  CAS  PubMed  Google Scholar 

  64. Willoughby DS, Boucher T, Reid J, Skelton G, Clark M (2011) Effects of 7 days of arginine-alpha-ketoglutarate supplementation on blood flow, plasma l-arginine, nitric oxide metabolites, and asymmetric dimethyl arginine after resistance exercise. Int J Sport Nutr Exerc Metab 21:291–299

    CAS  PubMed  Google Scholar 

  65. Wu G (1998) Intestinal mucosal amino acid catabolism. J Nutr 128:1249–1252

    CAS  PubMed  Google Scholar 

  66. Wu G, Meininger CJ (2009) Nitric oxide and vascular insulin resistance. BioFactors 35:21–27

    Article  PubMed  Google Scholar 

  67. Wu G, Morris SM Jr (1998) Arginine metabolism: nitric oxide and beyond. Biochem J 336:1–17

    CAS  PubMed  Google Scholar 

  68. Yu YM, Burke JF, Tompkins RG, Martin R, Young VR (1996) Quantitative aspects of interorgan relationships among arginine and citrulline metabolism. Am J Physiol 271:E1098–E1109

    CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by a Grant from GlaxoSmithKline Nutrition, UK.

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Authors report no conflict of interest.

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Correspondence to Andrew M. Jones.

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Communicated by Carsten Lundby.

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Vanhatalo, A., Bailey, S.J., DiMenna, F.J. et al. No effect of acute l-arginine supplementation on O2 cost or exercise tolerance. Eur J Appl Physiol 113, 1805–1819 (2013). https://doi.org/10.1007/s00421-013-2593-z

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Keywords

  • Nitric oxide
  • Dietary supplementation
  • Exercise efficiency
  • Blood pressure