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:

The role of sustained release isosorbide mononitrate on corticosteroid-induced hypertension in healthy human subjects

Journal of Human Hypertension volume 29, pages 737–743 (2015)Cite this article

Subjects

Abstract

There is evidence implicating abnormalities in the nitric oxide (NO) pathway in the development of glucocorticoid-induced hypertension (GC-HT). In humans, a reduction in NO availability during cortisol treatment has been observed. This study examined whether the NO donation may reverse the elevated blood pressure (BP) observed with cortisol treatment. A randomised double-blind, placebo-controlled, crossover study was undertaken in eight healthy men to address the effect of co-administration of isosorbide mononitrate (ISMN, 60 mg single dose, day 5) with cortisol (200 mg per day, days 1−6) and then compared with placebo (single dose, day 5) with cortisol. After a 2-week washout period, subjects crossed over to the alternate treatment. BP measurements were obtained using a mercury sphygmomanometer. Tonometry was used to estimate central pressures. There was a significant rise in mean arterial pressure with cortisol: 80±3 vs 89±3 mm Hg (day 1 vs day 5, cortisol+ISMN phase, P<0.001) and 81±3 vs 89±3 mm Hg (day 1 vs day 5, cortisol+placebo phase, P<0.01). ISMN significantly decreased aortic augmentation index: –17.3±3.2 vs 1.8±3.5%, (differences calculated from day 5–day 1, cortisol/ISMN vs cortisol+placebo, P<0.001). These results demonstrated that GC-HT can be modified by co-administration of exogenous NO donors, consistent with the hypothesis that GC-HT is accompanied by reduced NO activity in humans.

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. Kelly JJ, Mangos G, Williamson PM, Whitworth JA . Cortisol and hypertension. Clin Exp Pharmacol Physiol Suppl 1998; 25: S51–S56.

    Article  CAS  Google Scholar 

  2. Whitworth JA, Gordon D, Andrews J, Scoggins BA . The hypertensive effect of synthetic glucocorticoids in man: role of sodium and volume. J Hypertens 1989; 7 (7): 537–549.

    Article  CAS  Google Scholar 

  3. Williamson PM, Kelly JJ, Whitworth JA . Dose-response relationships and mineralocorticoid activity in cortisol-induced hypertension in humans. J Hypertens 1996; 14 (Suppl 5): S37–S41.

    CAS  Google Scholar 

  4. Sudhir K, Jennings GL, Esler MD, Korner PI, Blomberg PA, Lambert GW et al. Hydrocortisone-induced hypertension in man. Pressor responsiveness and sympathetic function. Hypertension 1989; 13: 416.

    Article  CAS  Google Scholar 

  5. Tam SH, Kelly JJ, Williamson PM, Whitworth JA . Reflex sympathetic function in cortisol-induced hypertension in humans. Clin Exp Hypertens 1997; 19 (4): 479–493.

    Article  CAS  Google Scholar 

  6. Whitworth JA, Williamson PM, Brown MA, Morris MJ . Neuropeptide Y in cortisol-induced hypertension in male volunteers. Clin Exp Pharmacol Physiol 1994; 21 (5): 435–438.

    Article  CAS  Google Scholar 

  7. Williamson PM, Tam SH, Kelly JJ, Whitworth JA . Ganglion blockade does not prevent cortisol-induced hypertension in man. Clin Exp Pharmacol Physiol 2005; 32 (4): 294–296.

    Article  CAS  Google Scholar 

  8. Pirpiris M, Yeung S, Dewar E, Jennings GL, Whitworth JA . Hydrocortisone-induced hypertension in men. The role of cardiac output. Am J Hypertens 1993; 6 (4): 287–294.

    Article  CAS  Google Scholar 

  9. Whitworth JA, Williamson PM, Ramsay D . Haemodynamic responses to cortisol in man: Effects of felodipine. Hypertens Res 1994; 1994 (17): 134–172.

    Google Scholar 

  10. Tam SH, Williamson PM, Kelly JJ, Whitworth JA . Autonomic blockade amplifies cortisol-induced hypertension in man. Clin Exp Pharmacol Physiol 1997; 24 (1): 31–33.

    Article  CAS  PubMed  Google Scholar 

  11. Kelly JJ, Tam SH, Williamson PM, Lawson J, Whitworth JA . The nitric oxide system and cortisol-induced hypertension in humans. Clin Exp Pharmacol Physiol 1998; 25 (11): 945–946.

    Article  CAS  PubMed  Google Scholar 

  12. Ong SLH, Whitworth JA . How do glucocorticoids cause hypertension: role of nitric oxide deficiency, oxidative stress, and eicosanoids. Endocrinol Metab Clin North Am 2011; 40 (2): 393–407.

    Article  CAS  PubMed  Google Scholar 

  13. Ong SLH, Whitworth JA . Glucocorticoid-induced hypertension and the nitric oxide system. Expert Rev Endocrinol Metab 2012; 7 (3): 273–280.

    Article  CAS  PubMed  Google Scholar 

  14. Kelly JJ, Tam SH, Williamson PM, Whitworth JA . Decreased threshold for the nitric oxide donor glyceryl trinitrate in cortisol-induced hypertension in humans. Clin Exp Pharmacol Physiol 2007; 34 (12): 1317–1318.

    Article  CAS  PubMed  Google Scholar 

  15. Lou Y, Wen C, Li M, Adams DJ, Wang M, Yang F et al. Decreased renal expression of nitric oxide synthase isoforms in adrenocorticotropin-induced and corticosterone-induced hypertension. Hypertension 2001; 37 (4): 1164–1170.

    Article  CAS  PubMed  Google Scholar 

  16. Ong SLH, Zhang Y, Whitworth JA . Reactive oxygen species and glucocorticoid-induced hypertension. Clin Exp Pharmacol Physiol 2008; 35 (4): 477–482.

    Article  CAS  PubMed  Google Scholar 

  17. Kelly JJ, Williamson P, Martin A, Whitworth JA . Effects of oral L-arginine on plasma nitrate and blood pressure in cortisol-treated humans. J Hypertens 2001; 19 (2): 263–268.

    Article  CAS  PubMed  Google Scholar 

  18. Mangos GJ, Walker BR, Kelly JJ, Lawson JA, Webb DJ, Whitworth JA . Cortisol inhibits cholinergic vasodilation in the human forearm. Am J Hypertens 2000; 13 (11): 1155–1160.

    Article  CAS  PubMed  Google Scholar 

  19. Macefield VG, Williamson PM, Wilson LR, Kelly JJ, Gandevia SC, Whitworth JA . Muscle sympathetic vasoconstrictor activity in hydrocortisone-induced hypertension in humans. Blood Press 1998; 7 (4): 215–222.

    Article  CAS  PubMed  Google Scholar 

  20. Nyberg G . Current status of isosorbide-5-mononitrate therapy in chronic stable angina pectoris. Am J Ther 1994; 1 (1): 93–101.

    Article  Google Scholar 

  21. Andrews MC, Schyvens CG, Zhang Y, McKenzie KU, Whitworth JA . Nitric oxide donation lowers blood pressure in adrenocorticotrophic hormone-induced hypertensive rats. Clin Exp Hypertens 2004; 26 (6): 499–509.

    Article  CAS  Google Scholar 

  22. Stokes GS, Barin ES, Gilfillan KL . Effects of isosorbide mononitrate and aii inhibition on pulse wave reflection in hypertension. Hypertension 2003; 41 (2): 297–301.

    Article  CAS  PubMed  Google Scholar 

  23. O'Rourke MF, Seward JB . Central arterial pressure and arterial pressure pulse: new views entering the second century after Korotkov. Mayo Clin Proc 2006; 81 (8): 1057–1068.

    Article  Google Scholar 

  24. Mangos GJ, Turner SW, Fraser TB, Whitworth JA . The role of corticosterone in corticotrophin (ACTH)-induced hypertension in the rat. J Hypertens 2000; 18 (12): 1849–1855.

    Article  CAS  Google Scholar 

  25. Wen C, Li M, Fraser T, Wang J, Turner SW, Whitworth JA . L-Arginine partially reverses established adrenocorticotrophin-induced hypertension and nitric oxide deficiency in the rat. Blood Press 2000; 9 (5): 298–304.

    Article  CAS  Google Scholar 

  26. Turner SW, Wen C, Li M, Whitworth JA . L-Arginine prevents corticotropin-induced increases in blood pressure in the rat. Hypertension 1996; 27 (2): 184–189.

    Article  CAS  Google Scholar 

  27. Zhang Y, Schyvens CG, McKenzie KU, Morris BJ, Whitworth JA . Lipopolysaccharide reverses adrenocorticotrophic hormone-induced hypertension in the rat. Hypertens Res 2003; 26 (5): 427–432.

    Article  CAS  Google Scholar 

  28. Schyvens CG, Cowden WB, Zhang Y, McKenzie KU, Whitworth JA . Hemodynamic effects of the nitric oxide donor DETA/NO in mice. Clin Exp Hypertens 2004; 26 (6): 525–535.

    Article  CAS  Google Scholar 

  29. Liu Y, Mladinov D, Pietrusz JL, Usa K, Liang M . Glucocorticoid response elements and 11β-hydroxysteroid dehydrogenases in the regulation of endothelial nitric oxide synthase expression. Cardiovasc Res 2009; 81 (1): 140–147.

    Article  CAS  Google Scholar 

  30. Zhang Y, Jang R, Mori TA, Croft KD, Schyvens CG, McKenzie KU et al. The anti-oxidant Tempol reverses and partially prevents adrenocorticotrophic hormone-induced hypertension in the rat. J Hypertens 2003; 21 (8): 1513–1518.

    Article  CAS  PubMed  Google Scholar 

  31. Mondo CK, Zhang Y, VdM Possamai, Miao Y, Schyvens CG, McKenzie KUS et al. N-Acetylcysteine antagonizes the development but does not reverse ACTH-induced hypertension in the rat. Clin Exp Hypertens 2006; 28 (2): 73–84.

    Article  CAS  PubMed  Google Scholar 

  32. Zhang Y, Miao Y, Whitworth JA . Aspirin prevents and partially reverses adrenocorticotropic hormone-induced hypertension in the rat. Am J Hypertens 2007; 20 (11): 1222–1228.

    CAS  PubMed  Google Scholar 

  33. Zhang Y, Chan MMK, Andrews MC, Mori TA, Croft KD, McKenzie KUS et al. Apocynin but not allopurinol prevents and reverses adrenocorticotropic hormone-induced hypertension in the rat. Am J Hypertens 2005; 18 (7): 910–916.

    Article  CAS  PubMed  Google Scholar 

  34. Miao Y, Zhang Y, Lim PS, Kanjanapan Y, Mori TA, Croft KD et al. Folic acid prevents and partially reverses glucocorticoid-induced hypertension in the rat. Am J Hypertens 2007; 20 (3): 304–310.

    Article  CAS  PubMed  Google Scholar 

  35. Chin-Dusting JPF, Ahlers BA, Kaye DM, Kelly JJ, Whitworth JA . L-Arginine transport in humans with cortisol-induced hypertension. Hypertension 2003; 41 (6): 1336–1340.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Pathology services were provided by SEALS courtesy of the Division of Medicine, St. George Hospital also by the John Curtin Medical Research Institute.

Author information

Authors and Affiliations

  1. Department of Medicine, University of New South Wales, Sydney, New South Wales, Australia

    P M Williamson, S L H Ong & J J Kelly

  2. Department of Renal Medicine, St George Hospital, Kogarah, New South Wales, Australia

    S L H Ong & J J Kelly

  3. John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia

    J A Whitworth

Authors
  1. P M Williamson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S L H Ong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J A Whitworth
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J J Kelly
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J J Kelly.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Williamson, P., Ong, S., Whitworth, J. et al. The role of sustained release isosorbide mononitrate on corticosteroid-induced hypertension in healthy human subjects. J Hum Hypertens 29, 737–743 (2015). https://doi.org/10.1038/jhh.2015.14

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/jhh.2015.14

Search

Advanced search

Quick links