Effect of NO Precursors on Physiological Responses to Exercise

Physiology Clinical Trial

— NO-SUP  

Official title:

The Effect of NO Precursors on Physiological Responses to Exercise

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02850367
• Other study ID #: 38RC14.430
• Status: Completed
• Phase: N/A
• Start date: May 9, 2016
• Est. completion date: September 2021

Study information

• Verified date: January 2020
• Source: University Hospital, Grenoble
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

NO is an ubiquitous molecule contributing to many physiological functions such as vasodilation, immune and oxidative stress responses. NO production can be supplemented either by providing substrate to the NO-synthase (L-Arginine and L-Citruline) or by providing nitrate which can lead to NO. In the present project the investigators evaluate the effect of various acute and chronic oral NO precursors supplementation on exercise performance and responses in healthy young and older subjects.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 63
• Est. completion date: September 2021
• Est. primary completion date: September 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

• Sedentary subjects
• No cardiovascular, respiratory, metabolic and neurological disorders

Exclusion Criteria:

• Body mass index > 28 kg.m-2
• Smoker
• Alcool intake > 10g/day
• Psychiatric diseases
• Subjects under treatment able to interfere with their cardiovascular, metabolic and neurological status

Related Conditions & MeSH terms

• Physiology

Intervention

Dietary Supplement:
• Nitrate
Subjects will be supplemented orally either acutely or chronically (4-8 weeks) with NO precursors.
• Nitrate and L-Arginine
Subjects will be supplemented orally either acutely or chronically (4-8 weeks) with NO precursors.
• Nitrate and L-Citrulline
Subjects will be supplemented orally either acutely or chronically (4-8 weeks) with NO precursors.
• Placebo
Subjects will be supplemented orally either acutely or chronically (4-8 weeks) with a placebo.

Biological:
• Evaluation of post-ischemic vascular reactivity
After the intake of the supplement. Concentration of hemoglobin (g/mL) in the quadriceps with the device : NIRS system Oxymon, ARTINIS.
• Neuromuscular evaluations
After the intake of the supplement. Measure the stretching force in the ankle (N)

Locations

Country	Name	City	State
France	Grenoble University Hospital	Grenoble	Rhone Alpes

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Grenoble

Country where clinical trial is conducted

France, 

References & Publications (60)

Alvares TS, Conte CA, Paschoalin VM, Silva JT, Meirelles Cde M, Bhambhani YN, Gomes PS. Acute l-arginine supplementation increases muscle blood volume but not strength performance. Appl Physiol Nutr Metab. 2012 Feb;37(1):115-26. doi: 10.1139/h11-144. Epub 2012 Jan 17. — View Citation

Alvares TS, Conte-Junior CA, Silva JT, Paschoalin VM. Acute L-Arginine supplementation does not increase nitric oxide production in healthy subjects. Nutr Metab (Lond). 2012 Jun 12;9(1):54. doi: 10.1186/1743-7075-9-54. — View Citation

Bachasson D, Guinot M, Wuyam B, Favre-Juvin A, Millet GY, Levy P, Verges S. Neuromuscular fatigue and exercise capacity in fibromyalgia syndrome. Arthritis Care Res (Hoboken). 2013 Mar;65(3):432-40. doi: 10.1002/acr.21845. — View Citation

Bachasson D, Temesi J, Bankole C, Lagrange E, Boutte C, Millet GY, Verges S, Levy P, Feasson L, Wuyam B. Assessement of quadriceps strength, endurance and fatigue in FSHD and CMT: benefits and limits of femoral nerve magnetic stimulation. Clin Neurophysiol. 2014 Feb;125(2):396-405. doi: 10.1016/j.clinph.2013.08.001. Epub 2013 Aug 31. — View Citation

Bachasson D, Wuyam B, Pepin JL, Tamisier R, Levy P, Verges S. Quadriceps and respiratory muscle fatigue following high-intensity cycling in COPD patients. PLoS One. 2013 Dec 6;8(12):e83432. doi: 10.1371/journal.pone.0083432. eCollection 2013. — View Citation

Bailey JC, Feelisch M, Horowitz JD, Frenneaux MP, Madhani M. Pharmacology and therapeutic role of inorganic nitrite and nitrate in vasodilatation. Pharmacol Ther. 2014 Dec;144(3):303-20. doi: 10.1016/j.pharmthera.2014.06.009. Epub 2014 Jun 30. Review. — View Citation

Bailey SJ, Winyard PG, Vanhatalo A, Blackwell JR, DiMenna FJ, Wilkerson DP, Jones AM. Acute L-arginine supplementation reduces the O2 cost of moderate-intensity exercise and enhances high-intensity exercise tolerance. J Appl Physiol (1985). 2010 Nov;109(5):1394-403. doi: 10.1152/japplphysiol.00503.2010. Epub 2010 Aug 19. — View Citation

Beloucif S, Beloucif L, Payen D. [Nitrate derivatives and anesthesia-resuscitation: physiopathologic bases and therapeutic indications]. Cah Anesthesiol. 1991;39(4):261-74. Review. French. — View Citation

Bescós R, Sureda A, Tur JA, Pons A. The effect of nitric-oxide-related supplements on human performance. Sports Med. 2012 Feb 1;42(2):99-117. doi: 10.2165/11596860-000000000-00000. Review. — View Citation

Bezemer R, Lima A, Myers D, Klijn E, Heger M, Goedhart PT, Bakker J, Ince C. Assessment of tissue oxygen saturation during a vascular occlusion test using near-infrared spectroscopy: the role of probe spacing and measurement site studied in healthy volunteers. Crit Care. 2009;13 Suppl 5:S4. doi: 10.1186/cc8002. Epub 2009 Nov 30. — View Citation

Bryan NS, Alexander DD, Coughlin JR, Milkowski AL, Boffetta P. Ingested nitrate and nitrite and stomach cancer risk: an updated review. Food Chem Toxicol. 2012 Oct;50(10):3646-65. doi: 10.1016/j.fct.2012.07.062. Epub 2012 Aug 4. Review. — View Citation

Burnett AL. The role of nitric oxide in erectile dysfunction: implications for medical therapy. J Clin Hypertens (Greenwich). 2006 Dec;8(12 Suppl 4):53-62. Review. — View Citation

Chan TY. Vegetable-borne nitrate and nitrite and the risk of methaemoglobinaemia. Toxicol Lett. 2011 Jan 15;200(1-2):107-8. doi: 10.1016/j.toxlet.2010.11.002. Epub 2010 Nov 12. — View Citation

Collins JK, Wu G, Perkins-Veazie P, Spears K, Claypool PL, Baker RA, Clevidence BA. Watermelon consumption increases plasma arginine concentrations in adults. Nutrition. 2007 Mar;23(3):261-6. — View Citation

Delp MD, Behnke BJ, Spier SA, Wu G, Muller-Delp JM. Ageing diminishes endothelium-dependent vasodilatation and tetrahydrobiopterin content in rat skeletal muscle arterioles. J Physiol. 2008 Feb 15;586(4):1161-8. Epub 2007 Dec 6. — View Citation

Dong JY, Qin LQ, Zhang Z, Zhao Y, Wang J, Arigoni F, Zhang W. Effect of oral L-arginine supplementation on blood pressure: a meta-analysis of randomized, double-blind, placebo-controlled trials. Am Heart J. 2011 Dec;162(6):959-65. doi: 10.1016/j.ahj.2011.09.012. Epub 2011 Nov 8. Review. — View Citation

Doutreleau S, Rouyer O, Di Marco P, Lonsdorfer E, Richard R, Piquard F, Geny B. L-arginine supplementation improves exercise capacity after a heart transplant. Am J Clin Nutr. 2010 May;91(5):1261-7. doi: 10.3945/ajcn.2009.27881. Epub 2010 Mar 3. — View Citation

Figueroa A, Trivino JA, Sanchez-Gonzalez MA, Vicil F. Oral L-citrulline supplementation attenuates blood pressure response to cold pressor test in young men. Am J Hypertens. 2010 Jan;23(1):12-6. doi: 10.1038/ajh.2009.195. Epub 2009 Oct 22. — View Citation

Gómez H, Torres A, Polanco P, Kim HK, Zenker S, Puyana JC, Pinsky MR. Use of non-invasive NIRS during a vascular occlusion test to assess dynamic tissue O(2) saturation response. Intensive Care Med. 2008 Sep;34(9):1600-7. doi: 10.1007/s00134-008-1145-1. Epub 2008 Jun 4. — View Citation

Gruet M, Temesi J, Rupp T, Levy P, Millet GY, Verges S. Stimulation of the motor cortex and corticospinal tract to assess human muscle fatigue. Neuroscience. 2013 Feb 12;231:384-99. doi: 10.1016/j.neuroscience.2012.10.058. Epub 2012 Nov 3. Review. — View Citation

Gruet M, Temesi J, Rupp T, Levy P, Verges S, Millet GY. Dynamics of corticospinal changes during and after high-intensity quadriceps exercise. Exp Physiol. 2014 Aug;99(8):1053-64. doi: 10.1113/expphysiol.2014.078840. Epub 2014 Jun 6. — View Citation

Gruet M, Temesi J, Rupp T, Millet GY, Verges S. Effect of different approaches to target force on transcranial magnetic stimulation responses. Muscle Nerve. 2013 Sep;48(3):430-2. doi: 10.1002/mus.23786. Epub 2013 Jul 15. — View Citation

Hermens HJ, Freriks B, Disselhorst-Klug C, Rau G. Development of recommendations for SEMG sensors and sensor placement procedures. J Electromyogr Kinesiol. 2000 Oct;10(5):361-74. — View Citation

Hickner RC, Tanner CJ, Evans CA, Clark PD, Haddock A, Fortune C, Geddis H, Waugh W, McCammon M. L-citrulline reduces time to exhaustion and insulin response to a graded exercise test. Med Sci Sports Exerc. 2006 Apr;38(4):660-6. — View Citation

Jones AM. Dietary nitrate supplementation and exercise performance. Sports Med. 2014 May;44 Suppl 1:S35-45. doi: 10.1007/s40279-014-0149-y. Review. — View Citation

Kapil V, Weitzberg E, Lundberg JO, Ahluwalia A. Clinical evidence demonstrating the utility of inorganic nitrate in cardiovascular health. Nitric Oxide. 2014 Apr 30;38:45-57. doi: 10.1016/j.niox.2014.03.162. Epub 2014 Mar 18. Review. — View Citation

Kelly J, Vanhatalo A, Wilkerson DP, Wylie LJ, Jones AM. Effects of nitrate on the power-duration relationship for severe-intensity exercise. Med Sci Sports Exerc. 2013 Sep;45(9):1798-806. doi: 10.1249/MSS.0b013e31828e885c. — View Citation

Lasker GF, Matt CJ, Badejo AM Jr, Casey DB, Dhaliwal JS, Murthy SN, Kadowitz PJ. Intracavernosal administration of sodium nitrite as an erectile pharmacotherapy. Can J Physiol Pharmacol. 2010 Jul;88(7):770-6. doi: 10.1139/y10-032. — View Citation

Lee M, Gandevia SC, Carroll TJ. Cortical voluntary activation can be reliably measured in human wrist extensors using transcranial magnetic stimulation. Clin Neurophysiol. 2008 May;119(5):1130-8. doi: 10.1016/j.clinph.2007.12.018. Epub 2008 Mar 4. — View Citation

Liu TH, Wu CL, Chiang CW, Lo YW, Tseng HF, Chang CK. No effect of short-term arginine supplementation on nitric oxide production, metabolism and performance in intermittent exercise in athletes. J Nutr Biochem. 2009 Jun;20(6):462-8. doi: 10.1016/j.jnutbio.2008.05.005. Epub 2008 Aug 15. — View Citation

Martín MJ, Jiménez MD, Motilva V. New issues about nitric oxide and its effects on the gastrointestinal tract. Curr Pharm Des. 2001 Jul;7(10):881-908. Review. — View Citation

Moinard C, Nicolis I, Neveux N, Darquy S, Bénazeth S, Cynober L. Dose-ranging effects of citrulline administration on plasma amino acids and hormonal patterns in healthy subjects: the Citrudose pharmacokinetic study. Br J Nutr. 2008 Apr;99(4):855-62. Epub 2007 Oct 22. — View Citation

Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. 1993 Dec 30;329(27):2002-12. Review. — View Citation

Moncada S. The L-arginine: nitric oxide pathway, cellular transduction and immunological roles. Adv Second Messenger Phosphoprotein Res. 1993;28:97-9. Review. — View Citation

Morris CR, Morris SM Jr, Hagar W, Van Warmerdam J, Claster S, Kepka-Lenhart D, Machado L, Kuypers FA, Vichinsky EP. Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? Am J Respir Crit Care Med. 2003 Jul 1;168(1):63-9. Epub 2003 Mar 5. — View Citation

Ochiai M, Hayashi T, Morita M, Ina K, Maeda M, Watanabe F, Morishita K. Short-term effects of L-citrulline supplementation on arterial stiffness in middle-aged men. Int J Cardiol. 2012 Mar 8;155(2):257-61. doi: 10.1016/j.ijcard.2010.10.004. Epub 2010 Nov 9. — View Citation

Park JW, Piknova B, Kurtz J, Seetharaman S, Wagner SJ, Schechter AN. Effect of storage on levels of nitric oxide metabolites in platelet preparations. Transfusion. 2013 Mar;53(3):637-44. doi: 10.1111/j.1537-2995.2012.03777.x. Epub 2012 Jul 15. — View Citation

Pavy B, Iliou MC, Meurin P, Tabet JY, Corone S; Functional Evaluation and Cardiac Rehabilitation Working Group of the French Society of Cardiology. Safety of exercise training for cardiac patients: results of the French registry of complications during cardiac rehabilitation. Arch Intern Med. 2006 Nov 27;166(21):2329-34. — View Citation

Peacock O, Tjønna AE, James P, Wisløff U, Welde B, Böhlke N, Smith A, Stokes K, Cook C, Sandbakk O. Dietary nitrate does not enhance running performance in elite cross-country skiers. Med Sci Sports Exerc. 2012 Nov;44(11):2213-9. doi: 10.1249/MSS.0b013e3182640f48. — View Citation

Perrey S. Non-invasive NIR spectroscopy of human brain function during exercise. Methods. 2008 Aug;45(4):289-99. doi: 10.1016/j.ymeth.2008.04.005. Epub 2008 Jun 6. Review. — View Citation

Preli RB, Klein KP, Herrington DM. Vascular effects of dietary L-arginine supplementation. Atherosclerosis. 2002 May;162(1):1-15. Review. — View Citation

Rupp T, Esteve F, Bouzat P, Lundby C, Perrey S, Levy P, Robach P, Verges S. Cerebral hemodynamic and ventilatory responses to hypoxia, hypercapnia, and hypocapnia during 5 days at 4,350 m. J Cereb Blood Flow Metab. 2014 Jan;34(1):52-60. doi: 10.1038/jcbfm.2013.167. Epub 2013 Sep 25. — View Citation

Rupp T, Jubeau M, Millet GY, Wuyam B, Levy P, Verges S, Perrey S. Muscle, prefrontal, and motor cortex oxygenation profiles during prolonged fatiguing exercise. Adv Exp Med Biol. 2013;789:149-155. doi: 10.1007/978-1-4614-7411-1_21. — View Citation

Rupp T, Jubeau M, Wuyam B, Perrey S, Levy P, Millet GY, Verges S. Time-dependent effect of acute hypoxia on corticospinal excitability in healthy humans. J Neurophysiol. 2012 Sep;108(5):1270-7. doi: 10.1152/jn.01162.2011. Epub 2012 Jun 13. — View Citation

Rupp T, Leti T, Jubeau M, Millet GY, Bricout VA, Levy P, Wuyam B, Perrey S, Verges S. Tissue deoxygenation kinetics induced by prolonged hypoxic exposure in healthy humans at rest. J Biomed Opt. 2013 Sep;18(9):095002. doi: 10.1117/1.JBO.18.9.095002. — View Citation

Rupp T, Perrey S. Effect of severe hypoxia on prefrontal cortex and muscle oxygenation responses at rest and during exhaustive exercise. Adv Exp Med Biol. 2009;645:329-34. doi: 10.1007/978-0-387-85998-9_49. — View Citation

Sidhu SK, Bentley DJ, Carroll TJ. Locomotor exercise induces long-lasting impairments in the capacity of the human motor cortex to voluntarily activate knee extensor muscles. J Appl Physiol (1985). 2009 Feb;106(2):556-65. doi: 10.1152/japplphysiol.90911.2008. Epub 2008 Dec 4. — View Citation

Siervo M, Lara J, Ogbonmwan I, Mathers JC. Inorganic nitrate and beetroot juice supplementation reduces blood pressure in adults: a systematic review and meta-analysis. J Nutr. 2013 Jun;143(6):818-26. doi: 10.3945/jn.112.170233. Epub 2013 Apr 17. Review. — View Citation

Sunderland KL, Greer F, Morales J. VO2max and ventilatory threshold of trained cyclists are not affected by 28-day L-arginine supplementation. J Strength Cond Res. 2011 Mar;25(3):833-7. doi: 10.1519/JSC.0b013e3181c6a14d. — View Citation

Takeda K, Machida M, Kohara A, Omi N, Takemasa T. Effects of citrulline supplementation on fatigue and exercise performance in mice. J Nutr Sci Vitaminol (Tokyo). 2011;57(3):246-50. — View Citation

Tang JE, Lysecki PJ, Manolakos JJ, MacDonald MJ, Tarnopolsky MA, Phillips SM. Bolus arginine supplementation affects neither muscle blood flow nor muscle protein synthesis in young men at rest or after resistance exercise. J Nutr. 2011 Feb;141(2):195-200. doi: 10.3945/jn.110.130138. Epub 2010 Dec 29. — View Citation

Vanhatalo A, Bailey SJ, DiMenna FJ, Blackwell JR, Wallis GA, Jones AM. No effect of acute L-arginine supplementation on O2 cost or exercise tolerance. Eur J Appl Physiol. 2013 Jul;113(7):1805-19. doi: 10.1007/s00421-013-2593-z. Epub 2013 Feb 20. — View Citation

Vega-Villa K, Pluta R, Lonser R, Woo S. Quantitative Systems Pharmacology Model of NO Metabolome and Methemoglobin Following Long-Term Infusion of Sodium Nitrite in Humans. CPT Pharmacometrics Syst Pharmacol. 2013 Jul 31;2:e60. doi: 10.1038/psp.2013.35. — View Citation

Verges S, Maffiuletti NA, Kerherve H, Decorte N, Wuyam B, Millet GY. Comparison of electrical and magnetic stimulations to assess quadriceps muscle function. J Appl Physiol (1985). 2009 Feb;106(2):701-10. doi: 10.1152/japplphysiol.01051.2007. Epub 2008 Aug 28. — View Citation

Villanueva C, Giulivi C. Subcellular and cellular locations of nitric oxide synthase isoforms as determinants of health and disease. Free Radic Biol Med. 2010 Aug 1;49(3):307-16. doi: 10.1016/j.freeradbiomed.2010.04.004. Epub 2010 Apr 11. Review. — View Citation

Vuillemin A, Oppert JM, Guillemin F, Essermeant L, Fontvieille AM, Galan P, Kriska AM, Hercberg S. Self-administered questionnaire compared with interview to assess past-year physical activity. Med Sci Sports Exerc. 2000 Jun;32(6):1119-24. — View Citation

Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992 Jun;30(6):473-83. — View Citation

Wylie LJ, Kelly J, Bailey SJ, Blackwell JR, Skiba PF, Winyard PG, Jeukendrup AE, Vanhatalo A, Jones AM. Beetroot juice and exercise: pharmacodynamic and dose-response relationships. J Appl Physiol (1985). 2013 Aug 1;115(3):325-36. doi: 10.1152/japplphysiol.00372.2013. Epub 2013 May 2. — View Citation

Wylie LJ, Mohr M, Krustrup P, Jackman SR, Erm?dis G, Kelly J, Black MI, Bailey SJ, Vanhatalo A, Jones AM. Dietary nitrate supplementation improves team sport-specific intense intermittent exercise performance. Eur J Appl Physiol. 2013 Jul;113(7):1673-84. doi: 10.1007/s00421-013-2589-8. Epub 2013 Feb 1. — View Citation

Zhu Q, Yue X, Tian QY, Saren G, Wu MH, Zhang Y, Liu TT. Effect of L-arginine supplementation on blood pressure in pregnant women: a meta-analysis of placebo-controlled trials. Hypertens Pregnancy. 2013;32(1):32-41. doi: 10.3109/10641955.2012.697952. Epub 2012 Sep 7. — View Citation

* Note: There are 60 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Neuromuscular evaluations	After the intake of the supplement. Measure the stretching force in the ankle (N)	3 half days
Primary	Evaluation of post-ischemic vascular reactivity	After the intake of the supplement. Concentration of hemoglobin (g/mL) in the quadriceps with the device : NIRS system Oxymon, ARTINIS.	3 half days