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:

Salt-sensitive men show reduced heart rate variability, lower norepinephrine and enhanced cortisol during mental stress

Journal of Human Hypertension volume 22, pages 423–431 (2008)Cite this article

Abstract

Salt sensitivity (SS) represents a risk factor for essential hypertension, which has been related to enhanced cardiovascular stress reactivity possibly mediated by increased noradrenergic susceptibility. We investigated biophysiological responses to mental stress in salt-sensitive (ss) and salt-resistant (sr) subjects, hypothesizing lower heart rate variability (HRV) and higher cortisol in the ss. A total of 48 healthy normotensive Caucasian men (age 25.6±2.6, body mass index 22.9±2.3) were phenotyped for SS (defined as significant drop in mean arterial pressure>3 mm Hg under the low-salt diet) by a 2-week high- versus low-salt diet. Subjects underwent a standardized mental stress task with continuous cardiovascular monitoring before, during and after the test (Finapres; Ohmeda, Louisville, CO, USA). Blood samples were drawn to examine cortisol and catecholamines before, after and 20 min after stress. The task elicited significant increases of systolic blood pressure (SBP), diastolic BP (DBP) and heart rate (HR) and a significant decrease of HRV (all time effects P<0.0001). The ss subjects showed lower norepinephrine (NE) and higher cortisol, indicated by significant group effects (P=0.009 and 0.025, respectively). HR increased and HRV decreased more in the ss under the stress, shown by significant time by group interactions (P=0.045 and 0.003, respectively). The observation of a more pronounced HR rise coupled with a greater decrease of HRV in healthy ss men under the influence of brief mental stress confirms their enhanced physiological stress reactivity. The lower peripheral NE may represent an effort to compensate for increased noradrenergic receptor sensitivity. The enhanced cortisol levels are backed by recent genetic findings on HSD11B2 polymorphisms and may promote hypertension.

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
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Weinberger MH . Pathogenesis of salt sensitivity of blood pressure. Curr Hypertens Rep 2006; 8 (2): 166–170.

    Article  CAS  PubMed  Google Scholar 

  2. Weinberger MH, Fineberg NS, Fineberg SE, Weinberger M . Salt sensitivity, pulse pressure, and death in normal and hypertensive humans. Hypertension 2001; 37: 429–432.

    Article  CAS  PubMed  Google Scholar 

  3. Morimoto A, Uzu T, Fujii T, Nishimura M, Kuroda S, Nakamura S et al. Sodium sensitivity and cardiovascular events in patients with essential hypertension. Lancet 1997; 13: 1734–1737.

    Article  Google Scholar 

  4. Capasso G, Cantone A, Evangelista C, Zacchia M, Trepiccione F, Acone D et al. Channels, carriers, and pumps in the pathogenesis of sodium-sensitive hypertension. Semin Nephrol 2005; 25: 419–424.

    Article  CAS  PubMed  Google Scholar 

  5. Sharma AM, Cetto C, Schorr U, Spies KP, Distler A . Renal acid-base excretion in normotensive salt-sensitive humans. Hypertension 1993; 6: 884–890.

    Article  Google Scholar 

  6. Sharma AM, Schorr U, Distler A . Insulin resistance in young salt-sensitive normotensive subjects. Hypertension 1993; 3: 273–279.

    Article  Google Scholar 

  7. The GenSalt Collaborative Research Group. GenSalt: rationale, design, methods and baseline characteristics of study participants. J Hum Hypertens 2007; 8: 639–646.

    Article  Google Scholar 

  8. Alikhani-Koupaei R, Fouladkou F, Fustier P, Cenni B, Sharma AM, Deter HC et al. Identification of polymorphisms in the human 11beta-hydroxysteroid dehydrogenase type 2 gene promoter: functional characterization and relevance for salt sensitivity. FASEB J 2007; 21 (13): 3618–3628.

    Article  CAS  PubMed  Google Scholar 

  9. Mariniello B, Ronconi V, Sardu C, Pagliericcio A, Galletti F, Strazzullo P et al. Analysis of the 11beta-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) in human essential hypertension. Am J Hypertens 2005; 18: 1091–1098.

    Article  CAS  PubMed  Google Scholar 

  10. Lovati E, Ferrari P, Dick B, Jostarndt K, Frey BM, Frey FJ et al. Molecular basis of human salt sensitivity: the role of the 11beta-hydroxysteroid dehydrogenase type 2. J Clin Endocrinol Metab 1999; 84 (10): 3745–3749.

    CAS  PubMed  Google Scholar 

  11. Agarwal AK, Giacchetti G, Lavery G, Nikkila H, Palermo M, Ricketts M et al. CA-repeat polymorphism in intron 1 of HSD11B2: effects on gene expression and salt sensitivity. Hypertension 2000; 36 (2): 187–194.

    Article  CAS  PubMed  Google Scholar 

  12. Ferrari P, Lovati E, Frey FJ . The role of the 11beta-hydroxysteroid dehydrogenase type 2 in human hypertension. J Hypertens 2000; 18 (3): 241–248.

    Article  CAS  PubMed  Google Scholar 

  13. Brand E, Kato N, Chatelain N, Krozowski ZS, Jeunemaitre X, Corvol P et al. Structural analysis and evaluation of the 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) gene in human essential hypertension. J Hypertens 1998; 16 (11): 1627–1633.

    Article  CAS  PubMed  Google Scholar 

  14. Watson Jr B, Bergman SM, Myracle A, Callen DF, Acton RT, Warnock DG . Genetic association of 11 beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) flanking microsatellites with essential hypertension in blacks. Hypertension 1996; 28 (3): 478–482.

    Article  CAS  PubMed  Google Scholar 

  15. Williams TA, Mulatero P, Filigheddu F, Troffa C, Milan A, Argiolas G et al. Role of HSD11B2 polymorphisms in essential hypertension and the diuretic response to thiazides. Kidney Int 2005; 67 (2): 631–637.

    Article  CAS  PubMed  Google Scholar 

  16. Miyoshi A, Suzuki H, Fujiwara M, Masai M, Iwasaki T . Impairment of endothelial function in salt-sensitive hypertension in humans. Am J Hypertens 1997; 10: 1083–1090.

    Article  CAS  PubMed  Google Scholar 

  17. Simon G . Experimental evidence for blood pressure-independent vascular effects of high sodium diet. Am J Hypertens 2003; 16: 1074–1078.

    Article  CAS  PubMed  Google Scholar 

  18. Skrabal F, Herholz H, Neumayr M, Hamberger L, Ledochowski M, Sporer H et al. Salt sensitivity in humans is linked to enhanced sympathetic responsiveness and to enhanced proximal tubular reabsorption. Hypertension 1984; 6: 152–158.

    Article  CAS  PubMed  Google Scholar 

  19. Mu J, Liu Z, Yang J . Blood pressure responses to cold pressor stress and its relation to sodium metabolism in salt-sensitive children. Chin Med J 1997; 77 (8): 583–585.

    CAS  Google Scholar 

  20. Deter HC, Buchholz K, Schorr U, Schachinger H, Turan S, Sharma AM . Psychophysiological reactivity of salt-sensitive normotensive subjects. J Hypertens 1997; 15: 839–844.

    Article  CAS  PubMed  Google Scholar 

  21. Buchholz K, Schachinger H, Wagner M, Sharma AM, Deter HC . Reduced vagal activity in salt-sensitive subjects during mental challenge. Am J Hypertens 2003; 16: 531–536.

    Article  PubMed  Google Scholar 

  22. Akselrod S, Gordon D, Ubel FA, Shannon DC, Berger AC, Cohen RJ . Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science 1981; 213: 220–222.

    Article  CAS  PubMed  Google Scholar 

  23. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology: Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Eur Heart J 1996; 17: 354–381.

    Article  Google Scholar 

  24. Liao D, Cai J, Barnes RW, Tyroler HA, Rautaharju P, Holme I et al. Association of cardiac autonomic function and the development of hypertension: the ARIC study. Am J Hypertens 1996; 9: 1147–1156.

    Article  CAS  PubMed  Google Scholar 

  25. Schachinger H, Weinbacher M, Kiss A, Ritz R, Langewitz W . Cardiovascular indices of peripheral and central sympathetic activation. Psychosom Med 2001; 63: 788–796.

    Article  CAS  PubMed  Google Scholar 

  26. Piccirillo G, Fimognari FL, Munizzi MR, Bucca C, Cacciafesta M, Marigliano V . Age-dependent influence on heart rate variability in salt-sensitive hypertensive subjects. J Am Geriatr Soc 1996; 44: 530–538.

    Article  CAS  PubMed  Google Scholar 

  27. Yo Y, Nagano M, Moriguchi A, Nakamura F, Kobayashi R, Okuda N et al. Predominance of nocturnal sympathetic nervous activity in salt-sensitive normotensive subjects. Am J Hypertens 1996; 9: 726–731.

    Article  CAS  PubMed  Google Scholar 

  28. Minami J, Kawano Y, Ishimitsu T, Takishita S . Blunted parasympathetic modulation in salt-sensitive patients with essential hypertension: evaluation by power-spectral analysis of heart-rate variability. J Hypertens 1997; 15 (7): 727–735.

    Article  CAS  PubMed  Google Scholar 

  29. Campese VM, Romoff MS, Levitan D, Saglikes Y, Friedler RM, Massry SG . Abnormal relationship between sodium intake and sympathetic nervous system activity in salt-sensitive patients with essential hypertension. Kidney Int 1982; 21 (2): 371–378.

    Article  CAS  PubMed  Google Scholar 

  30. Gill Jr JR, Gullner G, Lake CR, Lakatua DJ, Lan G . Plasma and urinary catecholamines in salt-sensitive idiopathic hypertension. Hypertension 1988; 11 (4): 312–319.

    Article  PubMed  Google Scholar 

  31. Kawano Y, Yoshida K, Kawamura M, Yoshimi H, Ashida T, Abe H et al. Sodium and noradrenaline in cerebrospinal fluid and blood in salt-sensitive and non-salt-sensitive essential hypertension. Clin Exp Pharmacol Physiol 1992; 19 (4): 235–241.

    Article  CAS  PubMed  Google Scholar 

  32. Kerstens MN, van der Kleij FG, Boonstra AH, Sluiter WJ, Koerts J, Navis G et al. Salt loading affects cortisol metabolism in normotensive subjects: relationships with salt sensitivity. J Clin Endocrinol Metab 2003; 88: 4180–4185.

    Article  CAS  PubMed  Google Scholar 

  33. Lewicka S, Nowicki M, Vecsei P . Effect of sodium restriction on urinary excretion of cortisol and its metabolites in humans. Steroids 1998; 63: 401–405.

    Article  CAS  PubMed  Google Scholar 

  34. Litchfield WR, Hunt SC, Jeunemaitre X, Fisher ND, Hopkins PN, Williams RR et al. Increased urinary free cortisol: a potential intermediate phenotype of essential hypertension. Hypertension 1998; 31: 569–574.

    Article  CAS  PubMed  Google Scholar 

  35. Steptoe A, Marmot M . Impaired cardiovascular recovery following stress predicts 3-year increases in blood pressure. J Hypertens 2005; 23: 529–536.

    Article  CAS  PubMed  Google Scholar 

  36. Deter HC, Buchholz K, Schorr U, Mathiak K, Sharma AM . Salt-sensitivity and other predictors of stress-related cardiovascular reactivity in healthy young males. Clin Exp Hypertens 2001; 23: 213–225.

    Article  CAS  PubMed  Google Scholar 

  37. Johannes B, Eichhorn C, Fischer F . A complex experimental assessment for objective description of hierarchical psychophysiological behavior as human regulatory phenotype. J Gravit Physiol 1994; 1: 73–74.

    Google Scholar 

  38. Vasey MW, Thayer JF . The continuing problem of false positives in repeated measures ANOVA in psychophysiology: a multivariate solution. Psychophysiololgy 1987; 24: 479–486.

    Article  CAS  Google Scholar 

  39. Julius S, Nesbitt S . Sympathetic overactivity in hypertension. A moving target. Am J Hypertens 1996; 9: 113S–120S.

    Article  CAS  PubMed  Google Scholar 

  40. Brook RD, Julius S . Autonomic imbalance, hypertension, and cardiovascular risk. Am J Hypertens 2000; 13: 112S–122S.

    Article  CAS  PubMed  Google Scholar 

  41. Noll G, Wenzel RR, Schneider M, Oesch V, Binggeli C, Shaw S et al. Increased activation of sympathetic nervous system and endothelin by mental stress in normotensive offspring of hypertensive parents. Circulation 1996; 93 (5): 866–869.

    Article  CAS  PubMed  Google Scholar 

  42. Overlack A, Ruppert M, Kolloch R, Gobel B, Kraft K, Diehl J et al. Divergent hemodynamic and hormonal responses to varying salt intake in normotensive subjects. Hypertension 1993; 22: 331–338.

    Article  CAS  PubMed  Google Scholar 

  43. Skrabal F, Aubock J, Hortnagl H . Low sodium/high potassium diet for prevention of hypertension: probable mechanisms of action. Lancet 1981; 2: 895–900.

    Article  CAS  PubMed  Google Scholar 

  44. Brown MD, Hogikyan RV, Dengel DR, Supiano MA . Sodium-sensitive hypertension is not associated with higher sympathetic nervous system activity in older hypertensive humans. Am J Hypertens 2000; 13: 873–883.

    Article  CAS  PubMed  Google Scholar 

  45. Kong JQ, Taylor DA, Fleming WW . Antagonism of norepinephrine by clonidine in the isolated rat mesenteric vascular bed. J Pharmacol Exp Ther 1991; 259: 653–658.

    CAS  PubMed  Google Scholar 

  46. Ekas Jr RD, Lokhandwala MF . Sympathetic nerve function and vascular reactivity in Doca-salt hypertensive rats. Am J Physiol 1980; 239: R303–R308.

    PubMed  Google Scholar 

  47. Skrabal F, Kotanko P, Luft FC . Inverse regulation of alpha-2 and beta-2 adrenoceptors in salt-sensitive hypertension: an hypothesis. Life Sci 1989; 45: 2061–2076.

    Article  CAS  PubMed  Google Scholar 

  48. Sharma AM, Schorr U, Oelkers W, Distler A . Effects of sodium salts on plasma renin activity and norepinephrine response to orthostasis in salt-sensitive normotensive subjects. Am J Hypertens 1993; 6 (9): 780–785.

    Article  CAS  PubMed  Google Scholar 

  49. Spieker LE, Hürlimann D, Ruschitzka F, Corti R, Enseleit F, Shaw S et al. Mental stress induces prolonged endothelial dysfunction via endothelin-A receptors. Circulation 2002; 105 (24): 2817–2820.

    Article  CAS  PubMed  Google Scholar 

  50. al'Absi M, Lovallo WR, McKey BS, Pincomb GA . Borderline hypertensives produce exaggerated adrenocortical responses to mental stress. Psychosom Med 1994; 56: 245–250.

    Article  CAS  PubMed  Google Scholar 

  51. al'Absi M, Arnett DK . Adrenocortical responses to psychological stress and risk for hypertension. Biomed Pharmacother 2000; 54: 234–244.

    Article  CAS  PubMed  Google Scholar 

  52. Watt GC, Harrap SB, Foy CJ, Holton DW, Edwards HV, Davidson HR et al. Abnormalities of glucocorticoid metabolism and the renin-angiotensin system: a four-corners approach to the identification of genetic determinants of blood pressure. J Hypertens 1992; 10: 473–482.

    Article  CAS  PubMed  Google Scholar 

  53. Yang S, Zhang L . Glucocorticoids and vascular reactivity. Curr Vasc Pharmacol 2004; 2: 1–12.

    Article  PubMed  Google Scholar 

  54. Sudhir K, Jennings GL, Esler MD, Korner PI, Blombery PA, Lambert GW et al. Hydrocortisone-induced hypertension in humans: pressor responsiveness and sympathetic function. Hypertension 1989; 13: 416–421.

    Article  CAS  PubMed  Google Scholar 

  55. Burns VE, Ring C, Drayson M, Carroll D . Cortisol and cardiovascular reactions to mental stress and antibody status following hepatitis B vaccination: a preliminary study. Psychophysiology 2002; 39: 361–368.

    Article  PubMed  Google Scholar 

  56. Isowa T, Ohira H, Murashima S . Immune, endocrine and cardiovascular responses to controllable and uncontrollable acute stress. Biol Psychol 2006; 71: 202–213.

    Article  PubMed  Google Scholar 

  57. Larson MR, Ader R, Moynihan JA . Heart rate, neuroendocrine, and immunological reactivity in response to an acute laboratory stressor. Psychosom Med 2001; 63: 493–501.

    Article  CAS  PubMed  Google Scholar 

  58. DeQuattro V, Feng M . The sympathetic nervous system: the muse of primary hypertension. J Hum Hypertens 2002; 16: S64–S69.

    Article  PubMed  Google Scholar 

  59. Diorio D, Viau V, Meaney MJ . The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic-pituitary-adrenal responses to stress. JNeurosci 1993; 13: 3839–3847.

    Article  CAS  Google Scholar 

  60. Thayer JF, Lane RD . The role of vagal function in the risk for cardiovascular disease and mortality. Biol Psychology 2007; 74: 224–242.

    Article  Google Scholar 

Download references

Acknowledgements

The study was part of an ongoing project on salt sensitivity and stress reactivity of Hans Christian Deter supported by the Deutsche Forschungsgemeinschaft (DE224/6-1). We thank Baerbel Girresch for her help with the biochemical analyses.

Author information

Authors and Affiliations

  1. Department of Psychosomatic Medicine and Psychotherapy, Charité Universitätsmedizin, Berlin, Germany

    C S Weber, M Rudat & H C Deter

  2. Institute of Psychology, Ohio State University, Columbus, OH, USA

    J F Thayer

  3. Mannheim Institute of Public Health, Social and Preventive Medicine, Mannheim Medical Faculty, Heidelberg University, Mannheim, Germany

    J F Thayer

  4. Department of Medicine, Cardiovascular Obesity Research and Management, McMaster University, Hamilton, Ontario, Canada

    A M Sharma

  5. Central Institute of Laboratory Medicine and Pathobiochemistry, Charité Universitätsmedizin, Berlin, Germany

    F H Perschel

  6. Department of Internal Medicine IV, Division of Nephrology and General Medicine, University Hospital Freiburg, Freiburg, Germany

    K Buchholz

Authors
  1. C S Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J F Thayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Rudat
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A M Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F H Perschel
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K Buchholz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. H C Deter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C S Weber.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weber, C., Thayer, J., Rudat, M. et al. Salt-sensitive men show reduced heart rate variability, lower norepinephrine and enhanced cortisol during mental stress. J Hum Hypertens 22, 423–431 (2008). https://doi.org/10.1038/jhh.2008.11

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jhh.2008.11

Keywords

This article is cited by

Search

Advanced search

Quick links