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:

Subjects with essential hypertension are more sensitive to the inhibition of 11 β-HSD by liquorice

Abstract

In this intervention study, we have investigated if hypertensive patients are more sensitive to liquorice-induced inhibition of 11 β-hydroxysteroid dehydrogenase (11 β-HSD) type 2 than normotensive (NT) subjects and if the response depends on gender. Healthy volunteers and patients with essential hypertension (HT), consumed 100 g of liquorice daily, for 4 weeks, corresponding to a daily intake of 150 mg glycyrrhetinic acid. Office, 24-h ambulatory blood pressure (BP) and blood samples were measured before, during and after liquorice consumption. Effect on cortisol metabolism was evaluated by determining the urinary total cortisol metabolites and urinary free cortisol/free cortisone quotient (Q). The mean rise in systolic BP with office measurements after 4 weeks of liquorice consumption was 3.5 mmHg (p<0.06) in NT and 15.3 mmHg (p=0.003) in hypertensive subjects, the response being different (p=0.004). The mean rise in diastolic BP was 3.6 mmHg (p=0.01) in NT and 9.3 mmHg (p<0.001) in hypertensive subjects, the response also being different (p=0.03). Liquorice induced more pronounced clinical symptoms in women than in men (p=0.0008), although the difference in the effect on the BP was not significant. The increase in Q was prominent (p<0.0001) and correlated to the rise in BP (p=0.02). The rise in BP was not dependant on age, the change in plasma renin activity or weight. We conclude that patients with essential HT are more sensitive to the inhibition of 11 β-HSD by liquorice than NT subjects, and that this inhibition causes more clinical symptoms in women than in men.

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

Access options

Buy this article

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

Figure 1
Figure 2

Similar content being viewed by others

References

  1. van Uum SHM et al. The role of 11 beta-hydroxysteroid dehydrogenase in the pathogenesis of hypertension. Cardiovasc Res 1998; 38: 16–24.

    Article  CAS  PubMed  Google Scholar 

  2. Funder JW . Mineralocorticoids, glucocorticoids, receptors and response elements. Science 1993; 259 (February 19): 1132–1133.

    Article  CAS  PubMed  Google Scholar 

  3. Farese Jr RV et al. Licorice induced hypermineralcorticoidism. N Engl J Med 1991; 325: 1223–1227.

    Article  PubMed  Google Scholar 

  4. Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS . Cloning and tissue distribution of the human 11 beta-hydroxysteroid dehydrogenase type 2 enzyme. Mol Cell Endocrinol 1994; 105: R11–R17.

    Article  CAS  PubMed  Google Scholar 

  5. Monder C, White PC . 11 Beta-hydroxysteroid dehydrogenase. Vitam Horm 1993; 47: 187–271.

    Article  CAS  PubMed  Google Scholar 

  6. Brown RW, Chapman KE, Edwards CRW, Seckl JR . Human placental 11 beta-hydroxysteroid dehydrogenase. Evidence for and partial purification of a distinct NASD-dependent isoform. Endocrinology 1993; 132: 2614–2621.

    Article  CAS  PubMed  Google Scholar 

  7. Mercer WR, Krozowski SS . Localization of an 11 beta hydroxysteroid dehydrogenase activity to the distal nephron. Evidence for the existence of two species of dehydrogenase in the rat kidney. Endocrinology 1992; 130: 540–543.

    Article  CAS  PubMed  Google Scholar 

  8. Stewart PM, Murry BA, Mason I . Human kidney 11 beta-hydroxysteroid dehydrogenase is a high affinity nicotinamide adenine dinucleotide-dependent enzyme and differs from the cloned type 1 isoform. J Clin Endocr Metab 1994; 79: 480–484.

    CAS  PubMed  Google Scholar 

  9. Walker BR, Campbell JC, Williams BC, Edwards CRW . Tissue-specific distribution of the NAD+-dependent isoform of 11 beta-hydroxysteroid dehydrogenase. Endocrinology 1992; 131: 970–972.

    CAS  PubMed  Google Scholar 

  10. Ferrari P, Krozowski Z . Role of the 11 beta-hydroxysteroid dehydrogenase type 2 in blood pressure regulation. Kidney Int 2000; 57: 1374–1381.

    Article  CAS  PubMed  Google Scholar 

  11. Milford DV, Shackleton CHL, Stewart PM . Mineralocorticoid hypertension and congenital deficiency of 11 beta-hydroxysteroid dehydrogenase in a family with the syndrome of ‘apparent’ mineralocorticoid excess. Clin Endocrinology 1994; 43: 241–246.

    Article  Google Scholar 

  12. Ulick S et al. A syndrome of apparent mineralocortocoid excess associated with defects in the peripheral metabolism of cortisol. J Clin Endocr Metab 1979; 49: 757–764.

    Article  CAS  PubMed  Google Scholar 

  13. Walker BR, Edwards CRW . Licorice-induced hypertension and syndromes of apparent mineralocorticoid excess. Endocrinol Metab Clin North Am 1994; 23: 359–377.

    Article  CAS  PubMed  Google Scholar 

  14. Epstein MT, Espiner EA, Donald RA, Hughes H . Liquorice toxicity and the renin–angiotensin–aldosterone axis in man. BMJ 1977; (January 22): 209–210.

  15. Megia A, Herran L, Martin-Almendra MA, Martinez I . Angiotensin I-converting enzyme levels and renin–aldosterone axis recovery after cessation of chronic licorice ingestion. Nephron 1993; 65: 329–330.

    Article  CAS  PubMed  Google Scholar 

  16. Funder JW, Pierce PT, Smith R, Campell J . Vascular type I aldosterone binding sites are physiological mineralocortocoid receptors. Endocrinology (Baltimore) 1989; 125: 2224–2226.

    Article  CAS  PubMed  Google Scholar 

  17. Hatakeyama H, Satoru I, Miyamori I . 11 Beta-hydroxysteroid dehydrogenase in cultured human vascular cells. Possible role in the development of hypertension. Hypertension 1999; 33: 1179–1184.

    Article  CAS  PubMed  Google Scholar 

  18. Takeda Y et al. Gene expression of 11 beta-hydroxysteroid dehydrogenase in the mesenteric arteries of genetically hypertensive rats. Hypertension 1994; 23: 577–580.

    Article  CAS  PubMed  Google Scholar 

  19. Slight SH et al. High affinity NAD+-dependent 11 beta-hydroxysteroid dehydrogenase in the human heart. J Mol Cell Cardiol 1996; 28: 781–787.

    Article  CAS  PubMed  Google Scholar 

  20. Walker BR, Connacher AA, Webb DJ, Edwards CRW . Glucocorticoids and blood pressure: a role for the cortisol/cortisone shuttle in the control of vascular tone in man. Clin Sci 1992; 83: 171–178.

    Article  CAS  Google Scholar 

  21. Walker BR et al. Increased vasoconstrictor sensitivity to glucocorticoids in essential hypertension. Hypertension 1996; 27: 190–196.

    Article  CAS  PubMed  Google Scholar 

  22. Walker BR et al. Deficient inactivation of cortisol by 11 beta-hydroxysteroid dehydrogenase in essential hypertension. Clin Endocrinol (oxf) 1993; 39: 221–227.

    Article  CAS  Google Scholar 

  23. Soro A et al. Evidence of coexisting changes in 11 beta-hydroxysteroid dehydrogenase and 5 beta-reductase activity in subjects with untreated essential hypertension. Hypertension 1995; 25: 67–70.

    Article  CAS  PubMed  Google Scholar 

  24. Takeda Y et al. Endogenous renal 11 beta-hydroxysteroid dehydrogenase inhibitory factors in patients with low-renin essential hypertension. Hypertension 1996; 27: 197–201.

    Article  CAS  PubMed  Google Scholar 

  25. Walker BR et al. Endogenous inhibitors of 11-beta hydroxysteroid dehydrogenase in hypertension. J Clin Endocr Metab 1995; 80: 529–533.

    CAS  PubMed  Google Scholar 

  26. Sigurjonsdottir HA, Franzson L, Manhem K, Ragnarsson J, Sigurdsson G, Wallerstedts . Liquorice-induced rise in blood pressure: a linear dose-response relationship. J Hum Hypertens 2001; 15: 549–552.

    Article  CAS  PubMed  Google Scholar 

  27. Shea S, Cook F, Kannel W, Golman L . Treatment of hypertension and its effect on cardiovascular risk factors: data from the Framingham Heart Study. Circulation 1985; 71: 22–30.

    Article  CAS  PubMed  Google Scholar 

  28. Axelson M, Sahlberg BL, Sjövall J . Analysis of profiles of conjugated steroids in urine by ion-exchange separation and gas chromatography-mass spectrometry. J Chromatogr 1981; 224: 355–370.

    Article  CAS  Google Scholar 

  29. Mantel N . Chi-square tests with one degree of freedom; extensions of the Mantel–Haenszel procedure. J Am Statist Assoc 1963; 58: 690–700.

    Google Scholar 

  30. Bradley JW . Distribution-free Statistical Tests. Prentice-Hall: London, 1968.

    Google Scholar 

  31. Odén A, Wedel H . Arguments for Fisher's permutations test. Ann Statist 1975; 3: 518–520.

    Article  Google Scholar 

  32. Kannel WB . Fifty years of Framingham Study contributions to understanding hypertension. J Hum Hypertens 2000; 14: 83–90.

    Article  CAS  PubMed  Google Scholar 

  33. Sigurjonsdottir HA, Ragnarsson J, Franzson L, Sigurdsson G . Is blood pressure commonly raised by moderate consumption of liquorice? J Hum Hypertens 1995; 9: 345–348.

    CAS  PubMed  Google Scholar 

  34. Fuster D et al. Furosemide inhibits 11 beta-hydroxysteroid dehydrogenase type 2. Endocrinology 1998; 139: 3849–3854.

    Article  CAS  PubMed  Google Scholar 

  35. Escher G et al. Furosemide inhibits 11 beta-hydroxysteroid dehydrogenase in vitro and in vivo. Endocrinology 1995; 136: 1759–1765.

    Article  CAS  PubMed  Google Scholar 

  36. Valentino R et al. Alcohol inhibits 11-beta-hydroxysteroid dehydrogenase activity in rat kidney and liver. Horm Res 1995; 43: 176–180.

    Article  CAS  PubMed  Google Scholar 

  37. Blachley JD, Knochel JP . Tobacco chewer's hypokalemia: licorice revisited. N Engl J Med 1980; 302: 784–785.

    Article  CAS  PubMed  Google Scholar 

  38. Westman EC . Does smokeless tobacco cause hypertension. South Med J 1995; 88: 716–720.

    Article  CAS  PubMed  Google Scholar 

  39. Riddle MC, McDaniel PA . Renal 11 beta-hydroxysteroid dehydrogenase activity is enhanced by ramipril and captopril. J Clin Endocr Metab 1994; 78: 830–834.

    CAS  PubMed  Google Scholar 

  40. Homma M et al. Activation of 11 beta-hydroxysteroid dehydrogenase by dehydroepiandrosterone sulphate as an anti-hypertensive agent in spontaneously hypertensive rats. J Pharm Pharmacol 1998; 50: 1139–1145.

    Article  CAS  PubMed  Google Scholar 

  41. Baulieu E-E . Dehydroepiandrosterone (DHEA): a fountain of youth? J Clin Endocr Metab 1996; 81: 3147–3151.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the Malaco sweet factory in Sweden for kindly supplying all liquorice. This study was supported by a grant from The Göteborg Medical Society.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to H A Sigurjonsdottir.

Additional information

Competing interests

None declared.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sigurjonsdottir, H., Manhem, K., Axelson, M. et al. Subjects with essential hypertension are more sensitive to the inhibition of 11 β-HSD by liquorice. J Hum Hypertens 17, 125–131 (2003). https://doi.org/10.1038/sj.jhh.1001504

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.jhh.1001504

Keywords

This article is cited by

Search

Quick links