Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Contribution of nitric oxide to the blood pressure and arterial responses to exercise in humans

Journal of Human Hypertension volume 25, pages 262–270 (2011)Cite this article

Subjects

Abstract

An exaggerated blood pressure (BP) response to exercise predicts future cardiovascular risk. The mechanisms underlying exercise-induced hypertension remain unclear, although endothelial dysfunction and elevated arterial stiffness may contribute. Given the association between reductions in nitric oxide (NO) and vascular dysfunction, we sought to determine whether acute inhibition of NO synthase with NG-monomethyl-L-arginine (L-NMMA) would lead to exaggerated BP responses to maximal exercise and attenuate exercise-induced reductions in arterial stiffness. In 10 healthy subjects (31±5 years), BP and heart rate (HR) were measured before, during and after an incremental cycling exercise test to determine maximal oxygen consumption (VO2max). Trials were performed with placebo (saline) or intravenous infusion of L-NMMA on separate days in a randomized, double-blind, crossover design. Central (aortic) and peripheral (femoral) arterial stiffness were assessed using pulse wave velocity (PWV). BP was increased with L-NMMA at rest and during sub-maximal exercise, but not at maximal exercise (mean BP 117±5 vs 118±8 mm Hg, saline vs L-NMMA, P>0.05). Furthermore, L-NMMA had no influence on exercising HR or VO2max (P<0.05). Notably, aortic PWV was similarly increased after exercise with either saline or L-NMMA (P<0.05), whereas postexercise decreases in femoral PWV were attenuated with L-NMMA (P<0.05). Our findings suggest that NO is an important contributor to reductions in femoral artery stiffness after maximal exercise in healthy individuals. Furthermore, acute pharmacological inhibition of NO synthase causes augmented BP responses to sub-maximal exercise, but does not lead to exaggerated BP responses to maximal exercise or reduce maximal oxygen consumption.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Le VV, Mitiku T, Sungar G, Myers J, Froelicher V . The blood pressure response to dynamic exercise testing: a systematic review. Prog Cardiovasc Dis 2008; 51 (2): 135–160.

    Article  Google Scholar 

  2. Miyai N, Arita M, Morioka I, Miyashita K, Nishio I, Takeda S . Exercise BP response in subjects with high-normal BP: exaggerated blood pressure response to exercise and risk of future hypertension in subjects with high-normal blood pressure. J Am Coll Cardiol 2000; 36 (5): 1626–1631.

    Article  CAS  Google Scholar 

  3. Singh JP, Larson MG, Manolio TA, O’Donnell CJ, Lauer M, Evans JC et al. Blood pressure response during treadmill testing as a risk factor for new-onset hypertension. The Framingham heart study. Circulation 1999; 99 (14): 1831–1836.

    Article  CAS  Google Scholar 

  4. Kurl S, Laukkanen JA, Rauramaa R, Lakka TA, Sivenius J, Salonen JT . Systolic blood pressure response to exercise stress test and risk of stroke. Stroke 2001; 32 (9): 2036–2041.

    Article  CAS  Google Scholar 

  5. Filipovsky J, Ducimetiere P, Safar ME . Prognostic significance of exercise blood pressure and heart rate in middle-aged men. Hypertension 1992; 20 (3): 333–339.

    Article  CAS  Google Scholar 

  6. Mundal R, Kjeldsen SE, Sandvik L, Erikssen G, Thaulow E, Erikssen J . Exercise blood pressure predicts mortality from myocardial infarction. Hypertension 1996; 27 (3 Part 1): 324–329.

    Article  CAS  Google Scholar 

  7. Kannel WB, McGee D, Gordon T . A general cardiovascular risk profile: the Framingham Study. Am J Cardiol 1976; 38 (1): 46–51.

    Article  CAS  Google Scholar 

  8. Nashar K, Nguyen JP, Jesri A, Morrow JD, Egan BM . Angiotensin receptor blockade improves arterial distensibility and reduces exercise-induced pressor responses in obese hypertensive patients with the metabolic syndrome. Am J Hypertens 2004; 17 (6): 477–482.

    Article  CAS  Google Scholar 

  9. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J 2006; 27 (21): 2588–2605.

    Article  Google Scholar 

  10. Naka KK, Tweddel AC, Parthimos D, Henderson A, Goodfellow J, Frenneaux MP . Arterial distensibility: acute changes following dynamic exercise in normal subjects. Am J Physiol Heart Circ Physiol 2003; 284 (3): H970–H978.

    Article  CAS  Google Scholar 

  11. Kingwell BA, Berry KL, Cameron JD, Jennings GL, Dart AM . Arterial compliance increases after moderate-intensity cycling. Am J Physiol 1997; 273 (5 Part 2): H2186–H2191.

    CAS  PubMed  Google Scholar 

  12. Sugawara J, Otsuki T, Tanabe T, Maeda S, Kuno S, Ajisaka R et al. The effects of low-intensity single-leg exercise on regional arterial stiffness. Jpn J Physiol 2003; 53 (3): 239–241.

    Article  Google Scholar 

  13. Kinlay S, Creager MA, Fukumoto M, Hikita H, Fang JC, Selwyn AP et al. Endothelium-derived nitric oxide regulates arterial elasticity in human arteries in vivo. Hypertension 2001; 38 (5): 1049–1053.

    Article  CAS  Google Scholar 

  14. Chang HJ, Chung J, Choi SY, Yoon MH, Hwang GS, Shin JH et al. Endothelial dysfunction in patients with exaggerated blood pressure response during treadmill test. Clin Cardiol 2004; 27 (7): 421–425.

    Article  Google Scholar 

  15. Stewart KJ, Sung J, Silber HA, Fleg JL, Kelemen MD, Turner KL et al. Exaggerated exercise blood pressure is related to impaired endothelial vasodilator function. Am J Hypertens 2004; 17 (4): 314–320.

    Article  Google Scholar 

  16. Tzemos N, Lim PO, Farquharson CAJ, Struthers, MacDonald TM . Dundee step test predicts vascular endothelial dysfunction in subjects with mild to moderate essential hypertension. Circulation 2004; 102 (Supp II): 606.

    Google Scholar 

  17. Wilson MF, Sung BH, Pincomb GA, Lovallo WR . Exaggerated pressure response to exercise in men at risk for systemic hypertension. Am J Cardiol 1990; 66 (7): 731–736.

    Article  CAS  Google Scholar 

  18. Kelly RP, Tunin R, Kass DA . Effect of reduced aortic compliance on cardiac efficiency and contractile function of in situ canine left ventricle. Circ Res 1992; 71 (3): 490–502.

    Article  CAS  Google Scholar 

  19. Little WC, Cheng CP . Effect of exercise on left ventricular-arterial coupling assessed in the pressure-volume plane. Am J Physiol 1993; 264 (5 Part 2): H1629–H1633.

    CAS  PubMed  Google Scholar 

  20. Casadei B . The emerging role of neuronal nitric oxide synthase in the regulation of myocardial function. Exp Physiol 2006; 91 (6): 943–955.

    Article  CAS  Google Scholar 

  21. Paulus WJ, Shah AM . NO and cardiac diastolic function. Cardiovasc Res 1999; 43 (3): 595–606.

    Article  CAS  Google Scholar 

  22. Sagach VF, Shimanskaya TV, Sagach VV, Bogomolets AA . Coronary endothelium dysfunction and heart failure. J Heart Fail 1998; 5: 79.

    Google Scholar 

  23. Fortin J, Habenbacher W, Heller A, Hacker A, Grullenberger R, Innerhofer J et al. Non-invasive beat-to-beat cardiac output monitoring by an improved method of transthoracic bioimpedance measurement. Comput Biol Med 2006; 36 (11): 1185–1203.

    Article  CAS  Google Scholar 

  24. McEniery CM, Yasmin, Hall IR, Qasem A, Wilkinson IB, Cockcroft JR . Normal vascular aging: differential effects on wave reflection and aortic pulse wave velocity: the Anglo-Cardiff Collaborative Trial (ACCT). J Am Coll Cardiol 2005; 46 (9): 1753–1760.

    Article  Google Scholar 

  25. Lehmann ED, Gosling RG, Parker JR, deSilva T, Taylor MG . A blood pressure independent index of aortic distensibility. Br J Radiol 1993; 66 (782): 126–131.

    Article  CAS  Google Scholar 

  26. Safar ME, London GM . Therapeutic studies and arterial stiffness in hypertension: recommendations of the European Society of Hypertension. The Clinical Committee of Arterial Structure and Function. Working Group on Vascular Structure and Function of the European Society of Hypertension. J Hypertens 2000; 18 (11): 1527–1535.

    Article  CAS  Google Scholar 

  27. Chen CH, Nevo E, Fetics B, Pak PH, Yin FC, Maughan WL et al. Estimation of central aortic pressure waveform by mathematical transformation of radial tonometry pressure. Validation of generalized transfer function. Circulation 1997; 95 (7): 1827–1836.

    Article  CAS  Google Scholar 

  28. Sharman JE, Lim R, Qasem AM, Coombes JS, Burgess MI, Franco J et al. Validation of a generalized transfer function to noninvasively derive central blood pressure during exercise. Hypertension 2006; 47 (6): 1203–1208.

    Article  CAS  Google Scholar 

  29. Chemla D, Hebert JL, Coirault C, Zamani K, Suard I, Colin P et al. Total arterial compliance estimated by stroke volume-to-aortic pulse pressure ratio in humans. Am J Physiol 1998; 274 (2 Part 2): H500–H505.

    CAS  Google Scholar 

  30. Kelly RP, Ting CT, Yang TM, Liu CP, Maughan WL, Chang MS et al. Effective arterial elastance as index of arterial vascular load in humans. Circulation 1992; 86 (2): 513–521.

    Article  CAS  Google Scholar 

  31. Sharman JE, McEniery CM, Campbell R, Pusalkar P, Wilkinson IB, Coombes JS et al. Nitric oxide does not significantly contribute to changes in pulse pressure amplification during light aerobic exercise. Hypertension 2008; 51 (4): 856–861.

    Article  CAS  Google Scholar 

  32. Kleber FX, Vietzke G, Wernecke KD, Bauer U, Opitz C, Wensel R et al. Impairment of ventilatory efficiency in heart failure: prognostic impact. Circulation 2000; 101 (24): 2803–2809.

    Article  CAS  Google Scholar 

  33. Beaver WL, Wasserman K, Whipp BJ . A new method for detecting anaerobic threshold by gas exchange. J Appl Physiol 1986; 60 (6): 2020–2027.

    Article  CAS  Google Scholar 

  34. Howley ET, Bassett Jr DR, Welch HG . Criteria for maximal oxygen uptake: review and commentary. Med Sci Sports Exerc 1995; 27 (9): 1292–1301.

    Article  CAS  Google Scholar 

  35. Chang HJ, Chung JH, Choi BJ, Choi TY, Choi SY, Yoon MH et al. Endothelial dysfunction and alteration of nitric oxide/cyclic GMP pathway in patients with exercise-induced hypertension. Yonsei Med J 2003; 44 (6): 1014–1020.

    Article  CAS  Google Scholar 

  36. Doshi SN, Naka KK, Payne N, Jones CJ, Ashton M, Lewis MJ et al. Flow-mediated dilatation following wrist and upper arm occlusion in humans: the contribution of nitric oxide. Clin Sci (Lond) 2001; 101 (6): 629–635.

    Article  CAS  Google Scholar 

  37. Bech JN, Nielsen CB, Pedersen EB . Effects of systemic NO synthesis inhibition on RPF, GFR, UNa, and vasoactive hormones in healthy humans. Am J Physiol 1996; 270 (5 Part 2): F845–F851.

    CAS  PubMed  Google Scholar 

  38. Liang YL, Gatzka CD, Du XJ, Cameron JD, Kingwell BA, Dart AM . Effects of heart rate on arterial compliance in men. Clin Exp Pharm Physiol 1999; 26 (4): 342–346.

    Article  CAS  Google Scholar 

  39. O’Dochartaigh C, Ong H, Lovell S, Donnelly R, Hanratty C, Riley M et al. Changes in pulmonary vascular function after acute methionine loading in normal men. Clin Sci (Lond) 2004; 106 (4): 413–419.

    Article  Google Scholar 

  40. Kruger M, Kotter S, Grutzner A, Lang P, Andresen C, Redfield MM et al. Protein kinase G modulates human myocardial passive stiffness by phosphorylation of the titin springs. Circ Res 2009; 104 (1): 87–94.

    Article  Google Scholar 

  41. Harrison RW, Thakkar RN, Senzaki H, Ekelund UE, Cho E, Kass DA et al. Relative contribution of preload and afterload to the reduction in cardiac output caused by nitric oxide synthase inhibition with L-N(G)-methylarginine hydrochloride. Crit Care Med 2000; 28 (5): 1263–1268.

    Article  CAS  Google Scholar 

  42. Prendergast BD, Sagach VF, Shah AM . Basal release of nitric oxide augments the Frank-Starling response in the isolated heart. Circulation 1997; 96 (4): 1320–1329.

    Article  CAS  Google Scholar 

  43. Imai K, Sato H, Hori M, Kusuoka H, Ozaki H, Yokoyama H et al. Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure. J Am Coll Cardiol 1994; 24 (6): 1529–1535.

    Article  CAS  Google Scholar 

  44. Cole CR, Blackstone EH, Pashkow FJ, Snader CE, Lauer MS . Heart-rate recovery immediately after exercise as a predictor of mortality. N Engl J Med 1999; 341 (18): 1351–1357.

    Article  CAS  Google Scholar 

  45. Herring N, Paterson DJ . Neuromodulators of peripheral cardiac sympatho-vagal balance. Exp Physiol 2009; 94 (1): 46–53.

    Article  CAS  Google Scholar 

  46. Stamler JS, Loh E, Roddy MA, Currie KE, Creager MA . Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans. Circulation 1994; 89 (5): 2035–2040.

    Article  CAS  Google Scholar 

  47. Mayer BX, Mensik C, Krishnaswami S, Derendorf H, Eichler HG, Schmetterer L et al. Pharmacokinetic-pharmacodynamic profile of systemic nitric oxide-synthase inhibition with L-NMMA in humans. Br J Clin Pharmacol 1999; 47 (5): 539–544.

    Article  CAS  Google Scholar 

  48. Haynes WG, Noon JP, Walker BR, Webb DJ . L-NMMA increases blood pressure in man. Lancet 1993; 342 (8876): 931–932.

    Article  CAS  Google Scholar 

  49. Sugawara J, Maeda S, Otsuki T, Tanabe T, Ajisaka R, Matsuda M . Effects of nitric oxide synthase inhibitor on decrease in peripheral arterial stiffness with acute low-intensity aerobic exercise. Am J Physiol Heart Circ Physiol 2004; 287 (6): H2666–H2669.

    Article  CAS  Google Scholar 

  50. Brett SE, Cockcroft JR, Mant TG, Ritter JM, Chowienczyk PJ . Haemodynamic effects of inhibition of nitric oxide synthase and of L-arginine at rest and during exercise. J Hypertens 1998; 16 (4): 429–435.

    Article  CAS  Google Scholar 

  51. Dyke CK, Proctor DN, Dietz NM, Joyner MJ . Role of nitric oxide in exercise hyperaemia during prolonged rhythmic handgripping in humans. J Physiol 1995; 488 (Part 1): 259–265.

    Article  CAS  Google Scholar 

  52. Sander M, Chavoshan B, Victor RG . A large blood pressure-raising effect of nitric oxide synthase inhibition in humans. Hypertension 1999; 33 (4): 937–942.

    Article  CAS  Google Scholar 

  53. Casino PR, Kilcoyne CM, Quyyumi AA, Hoeg JM, Panza JA . The role of nitric oxide in endothelium-dependent vasodilation of hypercholesterolemic patients. Circulation 1993; 88 (6): 2541–2547.

    Article  CAS  Google Scholar 

  54. Fisher JP, Young CN, Fadel PJ . Central sympathetic overactivity: maladies and mechanisms. Auton Neurosci 2009; 148 (1-2): 5–15.

    Article  Google Scholar 

  55. Osanai T, Fujita N, Fujiwara N, Nakano T, Takahashi K, Guan W et al. Cross talk of shear-induced production of prostacyclin and nitric oxide in endothelial cells. Am J Physiol Heart Circ Physiol 2000; 278 (1): H233–H238.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The time and effort expended by all the volunteer subjects is greatly appreciated. The invaluable clinical support of Drs Leong Lee, Matthias Schmidt, Abdul Maher and Khalid Abozguia is gratefully acknowledged. This research was supported by the British Heart Foundation (to MPF) and the Royal Society (to JPF).

Author information

Authors and Affiliations

  1. Department of Cardiovascular Medicine, University of Birmingham, Edgbaston, Birmingham, UK

    R Campbell

  2. School of Sport and Exercise Sciences, University of Birmingham, Edgbaston, Birmingham, UK

    J P Fisher

  3. Menzies Research Institute, University of Tasmania, Hobart, Tasmania, Australia

    J E Sharman

  4. School of Health Sciences, University of Wales Institute Cardiff, Cardiff, UK

    B J McDonnell

  5. School of Medicine, University of Aberdeen, Foresterhill, Aberdeen, UK

    M P Frenneaux

Authors
  1. R Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J P Fisher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J E Sharman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B J McDonnell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M P Frenneaux
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M P Frenneaux.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Campbell, R., Fisher, J., Sharman, J. et al. Contribution of nitric oxide to the blood pressure and arterial responses to exercise in humans. J Hum Hypertens 25, 262–270 (2011). https://doi.org/10.1038/jhh.2010.53

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jhh.2010.53

Keywords

This article is cited by

Search

Advanced search

Quick links