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.

  • Article
  • Published:

Esaxerenone: blood pressure reduction and cardiorenal protection without reflex sympathetic activation in salt-loaded stroke-prone spontaneously hypertensive rats

Hypertension Research volume 47, pages 2133–2143 (2024)Cite this article

A Comment to this article was published on 08 August 2024

Abstract

Mineralocorticoid receptor (MR) is involved in the mechanisms of blood pressure elevation, organ fibrosis, and inflammation. MR antagonists have been used in patients with hypertension, heart failure, or chronic kidney disease. Esaxerenone, a recently approved MR blocker with a nonsteroidal structure, has demonstrated a strong blood pressure-lowering effect. However, blood pressure reduction may lead to sympathetic activation through the baroreflex. The effect of esaxerenone on the sympathetic nervous system remains unclear. We investigated the effect of esaxerenone on organ damage and the sympathetic nervous system in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP), a well-established model of essential hypertension with sympathoexcitation and organ damage. Three-week administration of esaxerenone or hydralazine successfully attenuated the blood pressure elevation. Both esaxerenone and hydralazine comparably suppressed left ventricular hypertrophy and urinary albumin excretion. However, renal fibrosis and glomerular sclerosis were suppressed by esaxerenone but not hydralazine. Furthermore, plasma norepinephrine level, a parameter of systemic sympathetic activity, was significantly increased by hydralazine but not by esaxerenone. Consistent with these findings, the activity of the control centers of sympathetic nervous system, the parvocellular region of the paraventricular nucleus in the hypothalamus and the rostral ventrolateral medulla, was enhanced by hydralazine but remained unaffected by esaxerenone. These results suggest that esaxerenone effectively lowers blood pressure without inducing reflex sympathetic nervous system activation. Moreover, the organ-protective effects of esaxerenone appear to be partially independent of its blood pressure-lowering effect. In conclusion, esaxerenone demonstrates a blood pressure-lowering effect without concurrent sympathetic activation and exerts organ-protective effects in salt-loaded SHRSP.

Esaxerenone has antihypertensive and cardiorenal protective effects without reflex sympathetic activation in salt-loaded stroke-prone spontaneously hypertensive rats.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Ferreira NS, Tostes RC, Paradis P, Schiffrin EL. Aldosterone, inflammation, immune system, and hypertension. Am J Hypertens. 2021;34:15–27.

    Article  CAS  PubMed  Google Scholar 

  2. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709–17.

    Article  CAS  PubMed  Google Scholar 

  3. Ando K, Ohtsu H, Uchida S, Kaname S, Arakawa Y, Fujita T. Anti-albuminuric effect of the aldosterone blocker eplerenone in non-diabetic hypertensive patients with albuminuria: a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2:944–53.

    Article  CAS  PubMed  Google Scholar 

  4. Liu L, Xu B, Ju Y. Addition of spironolactone in patients with resistant hypertension: a meta-analysis of randomized controlled trials. Clin Exp Hypertens. 2017;39:257–63.

    Article  CAS  PubMed  Google Scholar 

  5. Zhao D, Liu H, Dong P, Zhao J. A meta-analysis of add-on use of spironolactone in patients with resistant hypertension. Int J Cardiol. 2017;233:113–7.

    Article  PubMed  Google Scholar 

  6. Arai K, Homma T, Morikawa Y, Ubukata N, Tsuruoka H, Aoki K, et al. Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist. Eur J Pharmacol. 2015;761:226–34.

    Article  CAS  PubMed  Google Scholar 

  7. Rakugi H, Ito S, Itoh H, Okuda Y, Yamakawa S. Long-term phase 3 study of esaxerenone as mono or combination therapy with other antihypertensive drugs in patients with essential hypertension. Hypertens Res. 2019;42:1932–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Arai K, Tsuruoka H, Homma T. CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist, prevents hypertension and cardiorenal injury in Dahl salt-sensitive hypertensive rats. Eur J Pharmacol. 2015;769:266–73.

    Article  CAS  PubMed  Google Scholar 

  9. Li L, Guan Y, Kobori H, Morishita A, Kobara H, Masaki T, et al. Effects of the novel nonsteroidal mineralocorticoid receptor blocker, esaxerenone (CS-3150), on blood pressure and urinary angiotensinogen in low-renin Dahl salt-sensitive hypertensive rats. Hypertens Res. 2019;42:769–78.

    Article  CAS  PubMed  Google Scholar 

  10. Ito S, Itoh H, Rakugi H, Okuda Y, Yoshimura M, Yamakawa S. Double-blind randomized phase 3 study comparing esaxerenone (CS-3150) and eplerenone in patients with essential hypertension (ESAX-HTN Study). Hypertension. 2020;75:51–8.

    Article  CAS  PubMed  Google Scholar 

  11. Itoh H, Ito S, Rakugi H, Okuda Y, Nishioka S. Efficacy and safety of dosage-escalation of low-dosage esaxerenone added to a RAS inhibitor in hypertensive patients with type 2 diabetes and albuminuria: a single-arm, open-label study. Hypertens Res. 2019;42:1572–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Iwahana T, Saito Y, Okada S, Kato H, Ono R, Kobayashi Y. Safety and efficacy of esaxerenone in Japanese hypertensive patients with heart failure with reduced ejection fraction: a retrospective study. PLoS ONE. 2021;16:e0259485. https://doi.org/10.1371/journal.pone.0259485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bhuiyan AS, Rafiq K, Kobara H, Masaki T, Nakano D, Nishiyama A. Effect of a novel nonsteroidal selective mineralocorticoid receptor antagonist, esaxerenone (CS-3150), on blood pressure and renal injury in high salt-treated type 2 diabetic mice. Hypertens Res. 2019;42:892–902.

    Article  CAS  PubMed  Google Scholar 

  14. Rahman A, Sawano T, Sen A, Hossain A, Jahan N, Kobara H, et al. Cardioprotective effects of a nonsteroidal mineralocorticoid receptor blocker, esaxerenone, in Dahl salt-sensitive hypertensive rats. Int J Mol Sci. 2021;22:2069. https://doi.org/10.3390/ijms22042069

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Fu Q, Zhang R, Witkowski S, Arbab-Zadeh A, Prasad A, Okazaki K, et al. Persistent sympathetic activation during chronic antihypertensive therapy: a potential mechanism for long term morbidity? Hypertension. 2005;45:513–21.

    Article  CAS  PubMed  Google Scholar 

  16. Toal CB, Meredith PA, Elliott HL. Long-acting dihydropyridine calcium-channel blockers and sympathetic nervous system activity in hypertension: a literature review comparing amlodipine and nifedipine GITS. Blood Press. 2012;21:3–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dietz R, Schömig A, Rascher W, Strasser R, Kübler W. Enhanced sympathetic activity caused by salt loading in spontaneously hypertensive rats. Clin Sci. 1980;59:171s–3s.

    Article  CAS  Google Scholar 

  18. Dietz R, Schömig A, Rascher W, Strasser R, Lüth JB, Ganten U, et al. Contribution of the sympathetic nervous system to the hypertensive effect of a high sodium diet in stroke-prone spontaneously hypertensive rats. Hypertension. 1982;4:773–81.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang W, Liu AJ, Yi-Ming W, Liu JG, Shen FM, Su DF. Pressor and non-pressor effects of sodium loading on stroke in stroke-prone spontaneously hypertensive rats. Clin Exp Pharmacol Physiol. 2008;35:83–8.

    Article  CAS  PubMed  Google Scholar 

  20. Honda N, Hirooka Y, Ito K, Matsukawa R, Shinohara K, Kishi T, et al. Moxonidine-induced central sympathoinhibition improves prognosis in rats with hypertensive heart failure. J Hypertens. 2013;31:2300–8.

    Article  CAS  PubMed  Google Scholar 

  21. Raij L, Azar S, Keane W. Mesangial immune injury, hypertension, and progressive glomerular damage in Dahl rats. Kidney Int. 1984;26:137–43.

    Article  CAS  PubMed  Google Scholar 

  22. Dampney RAL. Central neural control of the cardiovascular system: current perspectives. Adv Physiol Educ. 2016;40:283–96.

    Article  PubMed  Google Scholar 

  23. Ayuzawa N, Fujita T. The mineralocorticoid receptor in salt-sensitive hypertension and renal injury. J Am Soc Nephrol. 2021;32:279–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Brown NJ. Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis. Nat Rev Nephrol. 2013;9:459–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Shibata S, Nagase M, Yoshida S, Kawarazaki W, Kurihara H, Tanaka H, et al. Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease. Nat Med. 2008;14:1370–6.

    Article  CAS  PubMed  Google Scholar 

  26. Takeda Y, Yoneda T, Demura M, Furukawa K, Miyamori I, Mabuchi H. Effects of high sodium intake on cardiovascular aldosterone synthesis in stroke-prone spontaneously hypertensive rats. J Hypertens. 2001;19:635–9.

    Article  CAS  PubMed  Google Scholar 

  27. Arai K, Morikawa Y, Ubukata N, Tsuruoka H, Homma T. CS-3150, a Novel nonsteroidal mineralocorticoid receptor antagonist, shows preventive and therapeutic effects on renal injury in deoxycorticosterone acetate/salt-induced hypertensive rats. J Pharmacol Exp Ther. 2016;358:548–57.

    Article  CAS  PubMed  Google Scholar 

  28. Kai H, Kuwahara F, Tokuda K, Imaizumi T. Diastolic dysfunction in hypertensive hearts: roles of perivascular inflammation and reactive myocardial fibrosis. Hypertens Res. 2005;28:483–90.

    Article  CAS  PubMed  Google Scholar 

  29. Fujiwara T, Yuasa H, Ogiku N, Kawai Y. Histopathological investigation on salt-loaded stroke-prone spontaneously hypertensive rats, whose biochemical parameters of renal dysfunction were ameliorated by administration of imidapril. Jpn J Pharmacol. 1994;66:231–40.

    Article  CAS  PubMed  Google Scholar 

  30. Bauersachs J, Jaisser F, Toto R. Mineralocorticoid receptor activation and mineralocorticoid receptor antagonist treatment in cardiac and renal diseases. Hypertension. 2015;65:257–63.

    Article  CAS  PubMed  Google Scholar 

  31. Benarroch EE. Paraventricular nucleus, stress response, and cardiovascular disease. Clin Auton Res. 2005;15:254–63.

    Article  PubMed  Google Scholar 

  32. Guyenet PG. The sympathetic control of blood pressure. Nat Rev Neurosci. 2006;7:335–46.

    Article  CAS  PubMed  Google Scholar 

  33. Kim J, Padanilam BJ. Renal nerves drive interstitial fibrogenesis in obstructive nephropathy. J Am Soc Nephrol. 2013;24:229–42.

    Article  CAS  PubMed  Google Scholar 

  34. Kim J, Padanilam BJ. Renal denervation prevents long-term sequelae of ischemic renal injury. Kidney Int. 2015;87:350–8.

    Article  CAS  PubMed  Google Scholar 

  35. Osborn JW, Tyshynsky R, Vulchanova L. Function of renal nerves in kidney physiology and pathophysiology. Annu Rev Physiol. 2021;83:429–50.

    Article  CAS  PubMed  Google Scholar 

  36. Ito K, Hirooka Y, Sunagawa K. Blockade of mineralocorticoid receptors improves salt-induced left-ventricular systolic dysfunction through attenuation of enhanced sympathetic drive in mice with pressure overload. J Hypertens. 2010;28:1449–58.

    Article  CAS  PubMed  Google Scholar 

  37. Nakagaki T, Hirooka Y, Matsukawa R, Nishihara M, Nakano M, Ito K, et al. Activation of mineralocorticoid receptors in the rostral ventrolateral medulla is involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats. Hypertens Res. 2012;35:470–6.

    Article  CAS  PubMed  Google Scholar 

  38. Nakano M, Hirooka Y, Matsukawa R, Ito K, Sunagawa K. Mineralocorticoid receptors/epithelial Na(+) channels in the choroid plexus are involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats. Hypertens Res. 2013;36:277–84.

    Article  CAS  PubMed  Google Scholar 

  39. Iyonaga T, Shinohara K, Mastuura T, Hirooka Y, Tsutsui H. Brain perivascular macrophages contribute to the development of hypertension in stroke-prone spontaneously hypertensive rats via sympathetic activation. Hypertens Res. 2020;43:99–110.

    Article  CAS  PubMed  Google Scholar 

  40. xMaemura S, Niwa M, Ozaki M. Characteristic alterations in adrenal catecholamine contents in SHR, SHRSP, and WKY during development of hypertension and stroke. Jpn Heart J. 1982;23:593–602.

    Article  CAS  PubMed  Google Scholar 

  41. Katsurada K, Kario K. Sympathetic modulation by antihypertensive drugs. J Clin Hypertens. 2021;23:1715–7.

    Article  Google Scholar 

  42. Hirooka Y. Sympathetic activation in hypertension: importance of the central nervous system. Am J Hypertens. 2020;33:914–26.

    Article  CAS  PubMed  Google Scholar 

  43. Malpas SC. Sympathetic nervous system overactivity and its role in the development of cardiovascular disease. Physiol Rev. 2010;90:513–57.

    Article  CAS  PubMed  Google Scholar 

  44. Mancia G, Grassi G. The autonomic nervous system and hypertension. Circ Res. 2014;114:1804–14.

    Article  CAS  PubMed  Google Scholar 

  45. Arai K, Morikawa Y, Ubukata N, Sugimoto K. Synergistic reduction in albuminuria in type 2 diabetic mice by esaxerenone (CS-3150), a novel nonsteroidal selective mineralocorticoid receptor blocker, combined with an angiotensin II receptor blocker. Hypertens Res. 2020;43:1204–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kario K, Nishizawa M, Kato M, Ishii H, Uchiyama K, Nagai M, et al. Nighttime home blood pressure lowering effect of esaxerenone in patients with uncontrolled nocturnal hypertension: the EARLY-NH study. Hypertens Res. 2023;46:1782–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Katsuya T, Inobe Y, Uchiyama K, Nishikawa T, Hirano K, Kato M, et al. Exploratory study on the relationship between urinary sodium/potassium ratio, salt intake, and the antihypertensive effect of esaxerenone: the ENaK Study. Hypertens Res. 2024. https://doi.org/10.1038/s41440-023-01519-0

  48. Mogi M. Aldosterone breakthrough from a pharmacological perspective. Hypertens Res. 2022;45:967–75.

    Article  PubMed  Google Scholar 

  49. Kishi T, Hirooka Y, Sunagawa K. Telmisartan reduces mortality and left ventricular hypertrophy with sympathoinhibition in rats with hypertension and heart failure. Am J Hypertens. 2014;27:260–7.

    Article  CAS  PubMed  Google Scholar 

  50. Siegel AK, Kossmehl P, Planert M, Schulz A, Wehland M, Stoll M, et al. Genetic linkage of albuminuria and renal injury in Dahl salt-sensitive rats on a high-salt diet: comparison with spontaneously hypertensive rats. Physiol Genomics. 2004;18:218–25.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from Daiichi Sankyo Co., Ltd. and, in part, JSPS (KAKENHI Grant Number JP21K08032) to KS.

Author information

Authors and Affiliations

  1. Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan

    Shota Ikeda, Keisuke Shinohara, Soichiro Kashihara, Sho Matsumoto, Daisuke Yoshida, Ryosuke Nakashima, Yoshiyasu Ono, Shouji Matsushima, Hiroyuki Tsutsui & Shintaro Kinugawa

  2. Division of Cardiovascular Medicine, Research Institute of Angiocardiology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan

    Shota Ikeda, Keisuke Shinohara, Soichiro Kashihara, Sho Matsumoto, Daisuke Yoshida, Ryosuke Nakashima, Yoshiyasu Ono, Shouji Matsushima, Hiroyuki Tsutsui & Shintaro Kinugawa

  3. School of Medicine and Graduate School, International University of Health and Welfare, Fukuoka, Japan

    Hiroyuki Tsutsui

Authors
  1. Shota Ikeda
    View author publications

    Search author on:PubMed Google Scholar

  2. Keisuke Shinohara
    View author publications

    Search author on:PubMed Google Scholar

  3. Soichiro Kashihara
    View author publications

    Search author on:PubMed Google Scholar

  4. Sho Matsumoto
    View author publications

    Search author on:PubMed Google Scholar

  5. Daisuke Yoshida
    View author publications

    Search author on:PubMed Google Scholar

  6. Ryosuke Nakashima
    View author publications

    Search author on:PubMed Google Scholar

  7. Yoshiyasu Ono
    View author publications

    Search author on:PubMed Google Scholar

  8. Shouji Matsushima
    View author publications

    Search author on:PubMed Google Scholar

  9. Hiroyuki Tsutsui
    View author publications

    Search author on:PubMed Google Scholar

  10. Shintaro Kinugawa
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Keisuke Shinohara.

Ethics declarations

Conflict of interest

KS reports grants from Daiichi Sankyo, Nippon Boehringer Ingelheim, and Otsuka Medical Devices. HT reports grants and/or personal fees from Daiichi Sankyo, Novartis Pharma, Otsuka Pharmaceutical, Pfizer Japan, Mitsubishi Tanabe Pharma, Teijin Pharma, Nippon Boehringer Ingelheim, AstraZeneca, Ono Pharmaceutical, Kowa, IQVIA Service Japan, MEDINET, Medical Innovation Kyushu, Bayer Yakuhin, Johnson & Johnson, NEC, Nippon Rinsho and Japanese Heart Failure Society. The other authors report no conflicts of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ikeda, S., Shinohara, K., Kashihara, S. et al. Esaxerenone: blood pressure reduction and cardiorenal protection without reflex sympathetic activation in salt-loaded stroke-prone spontaneously hypertensive rats. Hypertens Res 47, 2133–2143 (2024). https://doi.org/10.1038/s41440-024-01733-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41440-024-01733-4

Keywords

This article is cited by

Search

Advanced search

Quick links