Abstract
Patients with primary aldosteronism have an increased risk of developing cardiovascular disease. The response to mineralocorticoid receptor antagonists varies among individuals, indicating diverse mineralocorticoid receptor activities in these patients. This study explored the factors linked to the efficacy of blood pressure reduction through mineralocorticoid receptor antagonists in patients with primary aldosteronism. We examined the relationship between the reduction in blood pressure and patient characteristics in a group of 41 patients with primary aldosteronism (24 males, mean age 55 ± 13 years, including 34 patients diagnosed with bilateral primary aldosteronism) before and after undergoing treatment with mineralocorticoid receptor antagonists. Significant reductions in office blood pressure were observed 3 and 6 months after treatment initiation. Single correlation analyses showed that the urinary chloride-to-potassium ratio displayed the strongest positive association with blood pressure reduction, surpassing plasma aldosterone concentration, plasma renin activity, and urinary sodium-to-potassium ratio, at 3 and 6 months. Multiple correlation analyses revealed a consistent and independent positive correlation between the urinary chloride-to-potassium ratio and blood pressure reduction at 3 and 6 months. The optimal threshold for the urinary chloride-to-potassium ratio with respect to its ability to lower blood pressure, was determined as 3.18. These results imply that the urinary chloride-to-potassium ratio may be independently associated with the effectiveness of blood pressure reduction facilitated by mineralocorticoid receptor antagonists. Moreover, it could potentially serve as a valuable predictor of the effectiveness of these agents and function as an indicator of endogenous mineralocorticoid receptor activity in patients with primary aldosteronism.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Rossi GP, Bernini G, Desideri G, Fabris B, Ferri C, Giacchetti G, et al. Renal damage in primary aldosteronism: results of the PAPY Study. Hypertension. 2006;48:232–8.
Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, et al. The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101:1889–916.
Monticone S, Burrello J, Tizzani D, Bertello C, Viola A, Buffolo F, et al. Prevalence and Clinical Manifestations of Primary Aldosteronism Encountered in Primary Care Practice. J Am Coll Cardiol. 2017;69:1811–20.
Rossi GP, Sechi LA, Giacchetti G, Ronconi V, Strazzullo P, Funder JW. Primary aldosteronism: cardiovascular, renal and metabolic implications. Trends Endocrinol Metab. 2008;19:88–90.
Monticone S, Sconfienza E, D’Ascenzo F, Buffolo F, Satoh F, Sechi LA, et al. Renal damage in primary aldosteronism: a systematic review and meta-analysis. J Hypertens. 2020;38:3–12.
Chen YL, Chen CH, Xu TY, Xu JZ, Zhu LM, Li Y, Wang JG. Non-invasive left ventricular pressure-strain loop study on cardiac fibrosis in primary aldosteronism: a comparative study with cardiac magnetic resonance imaging. Hypertens Res. 2024;47:445–54.
Monticone S, D’Ascenzo F, Moretti C, Williams TA, Veglio F, Gaita F, Mulatero P. Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2018;6:41–50.
Akehi Y, Yanase T, Motonaga R, Umakoshi H, Tsuiki M, Takeda Y, et al. High Prevalence of Diabetes in Patients With Primary Aldosteronism (PA) Associated With Subclinical Hypercortisolism and Prediabetes More Prevalent in Bilateral Than Unilateral PA: A Large, Multicenter Cohort Study in Japan. Diabetes Care. 2019;42:938–45.
Huang WC, Chen YY, Yang SY, Lai CF, Lai TS, Chen HY, et al. Fat mass as an important predictor of persistent hypertension in patients with primary aldosteronism after adrenalectomy. Hypertens Res. 2023;46:1375–84.
Haze T, Ozawa M, Kawano R, Haruna A, Ohki Y, Suzuki S, et al. Effect of the interaction between the visceral-to-subcutaneous fat ratio and aldosterone on cardiac function in patients with primary aldosteronism. Hypertens Res. 2023;46:1132–44.
Born-Frontsberg E, Reincke M, Rump LC, Hahner S, Diederich S, Lorenz R, et al. Cardiovascular and cerebrovascular comorbidities of hypokalemic and normokalemic primary aldosteronism: results of the German Conn’s Registry. J Clin Endocrinol Metab. 2009;94:1125–30.
Savard S, Amar L, Plouin PF, Steichen O. Cardiovascular complications associated with primary aldosteronism: a controlled cross-sectional study. Hypertension. 2013;62:331–6.
Ohno Y, Sone M, Inagaki N, Yamasaki T, Ogawa O, Takeda Y, et al. Prevalence of Cardiovascular Disease and Its Risk Factors in Primary Aldosteronism: A Multicenter Study in Japan. Hypertension. 2018;71:530–7.
Nomura M, Kurihara I, Itoh H, Ichijo T, Katabami T, Tsuiki M, et al. Association of cardiovascular disease risk and changes in renin levels by mineralocorticoid receptor antagonists in patients with primary aldosteronism. Hypertens Res. 2022;45:1476–85.
Lee BC, Tsai HH, Chen ZW, Chang CC, Huang JZ, Chang YY, et al. Aldosteronism is associated with more severe cerebral small vessel disease in hypertensive intracerebral hemorrhage. Hypertens Res. 2024;47:608–17.
Naruse M, Katabami T, Shibata H, Sone M, Takahashi K, Tanabe A, et al. Japan Endocrine Society clinical practice guideline for the diagnosis and management of primary aldosteronism 2021. Endocr J. 2022;69:327–59.
Wei J, Ni J, Huang D, Chen M, Yan S, Peng Y. The effect of aldosterone antagonists for ventricular arrhythmia: a meta-analysis. Clin Cardiol. 2010;33:572–7.
Simopoulos V, Tagarakis G, Hatziefthimiou A, Skoularigis I, Triposkiadis F, Trantou V, et al. Effectiveness of aldosterone antagonists for preventing atrial fibrillation after cardiac surgery in patients with systolic heart failure: a retrospective study. Clin Res Cardiol. 2015;104:31–7.
Chung YW, Yang YH, Wu CK, Yu CC, Juang JM, Wang YC, et al. Spironolactone is associated with reduced risk of new-onset atrial fibrillation in patients receiving renal replacement therapy. Int J Cardiol. 2016;202:962–6.
Beygui F, Labbé JP, Cayla G, Ennezat PV, Motreff P, Roubille F, et al. Early mineralocorticoid receptor blockade in primary percutaneous coronary intervention for ST-elevation myocardial infarction is associated with a reduction of life-threatening ventricular arrhythmia. Int J Cardiol. 2013;167:73–9.
Bolignano D, Palmer SC, Navaneethan SD, Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev. 2014;4:Cd007004.
Currie G, Taylor AH, Fujita T, Ohtsu H, Lindhardt M, Rossing P, et al. Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease: a systematic review and meta-analysis. BMC Nephrol. 2016;17:127.
Shimamoto K, Ando K, Fujita T, Hasebe N, Higaki J, Horiuchi M, et al. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2014). Hypertens Res. 2014;37:253–390.
Umemura S, Arima H, Arima S, Asayama K, Dohi Y, Hirooka Y, et al. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2019). Hypertens Res. 2019;42:1235–481.
Tanaka T, Okamura T, Miura K, Kadowaki T, Ueshima H, Nakagawa H, Hashimoto T. A simple method to estimate populational 24-h urinary sodium and potassium excretion using a casual urine specimen. J Hum Hypertens. 2002;16:97–103.
Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92.
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.
Shibata H, Itoh H. Mineralocorticoid receptor-associated hypertension and its organ damage: clinical relevance for resistant hypertension. Am J Hypertens. 2012;25:514–23.
Yoshida Y, Fujiki R, Kinoshita M, Sada K, Miyamoto S, Ozeki Y, et al. Importance of dietary salt restriction for patients with primary aldosteronism during treatment with mineralocorticoid receptor antagonists: The potential importance of post-treatment plasma renin levels. Hypertens Res. 2023;46:100–7.
Ando K, Fujita T. Pathophysiology of salt sensitivity hypertension. Ann Med. 2012;44:S119–26.
Shibata S, Mu S, Kawarazaki H, Muraoka K, Ishizawa K, Yoshida S, et al. Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway. J Clin Invest. 2011;121:3233–43.
Uddin S, Lekmine F, Sharma N, Majchrzak B, Mayer I, Young PR, et al. The Rac1/p38 mitogen-activated protein kinase pathway is required for interferon alpha-dependent transcriptional activation but not serine phosphorylation of Stat proteins. J Biol Chem. 2000;275:27634–40.
Gao G, Shen N, Jiang X, Sun H, Xu N, Zhou D, et al. Periodic mechanical stress activates EGFR-dependent Rac1 mitogenic signals in rat nucleus pulpous cells via ERK1/2. Biochem Biophys Res Commun. 2016;469:723–30.
Nagase M, Ayuzawa N, Kawarazaki W, Ishizawa K, Ueda K, Yoshida S, Fujita T. Oxidative stress causes mineralocorticoid receptor activation in rat cardiomyocytes: role of small GTPase Rac1. Hypertension. 2012;59:500–6.
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.
Shibata S, Ishizawa K, Uchida S. Mineralocorticoid receptor as a therapeutic target in chronic kidney disease and hypertension. Hypertens Res. 2017;40:221–5.
Ando K, Ohtsu H, Uchida S, Kaname S, Arakawa Y, Fujita T, Group ES. 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.
Tabara Y, Takahashi Y, Kumagai K, Setoh K, Kawaguchi T, Takahashi M, et al. Descriptive epidemiology of spot urine sodium-to-potassium ratio clarified close relationship with blood pressure level: the Nagahama study. J Hypertens. 2015;33:2407–13.
Higo Y, Nagashima S, Tabara Y, Setoh K, Kawaguchi T, Takahashi Y, et al. Association of the spot urine sodium-to-potassium ratio with blood pressure is independent of urinary Na and K levels: The Nagahama study. Hypertens Res. 2019;42:1624–30.
Kato H, Taguchi T, Okuda H, Kondo M, Takara M. Antihypertensive effect of chitosan in rats and humans. Journal of Traditional Medicine. 1994;11:198–205.
Rushworth CA, Guy JL, Turner AJ. Residues affecting the chloride regulation and substrate selectivity of the angiotensin-converting enzymes (ACE and ACE2) identified by site-directed mutagenesis. FEBS J. 2008;275:6033–42.
Masuyer G, Yates CJ, Sturrock ED, Acharya KR. Angiotensin-I converting enzyme (ACE): structure, biological roles, and molecular basis for chloride ion dependence. Biol Chem. 2014;395:1135–49.
Kotchen TA, Galla JH, Luke RG. Failure of NaHCO3 and KHCO3 to inhibit renin in the rat. Am J Physiol. 1976;231:1050–6.
Kotchen TA, Luke RG, Ott CE, Galla JH, Whitescarver S. Effect of chloride on renin and blood pressure responses to sodium chloride. Ann Intern Med. 1983;98:817–22.
Kurtz TW, Morris RC Jr. Dietary chloride as a determinant of “sodium-dependent” hypertension. Science. 1983;222:1139–41.
Kurtz TW, Al-Bander HA, Morris RC Jr. “Salt-sensitive” essential hypertension in men. Is the sodium ion alone important? N Engl J Med. 1987;317:1043–8.
Luft FC, Zemel MB, Sowers JA, Fineberg NS, Weinberger MH. Sodium bicarbonate and sodium chloride: effects on blood pressure and electrolyte homeostasis in normal and hypertensive man. J Hypertens. 1990;8:663–70.
Schorr U, Distler A, Sharma AM. Effect of sodium chloride- and sodium bicarbonate-rich mineral water on blood pressure and metabolic parameters in elderly normotensive individuals: a randomized double-blind crossover trial. J Hypertens. 1996;14:131–5.
Rivera FB, Alfonso P, Golbin JM, Lo K, Lerma E, Volgman AS, Kazory A. The Role of Serum Chloride in Acute and Chronic Heart Failure: A Narrative Review. Cardiorenal Med. 2021;11:87–98.
Schmidlin O, Tanaka M, Bollen AW, Yi SL, Morris RC Jr. Chloride-dominant salt sensitivity in the stroke-prone spontaneously hypertensive rat. Hypertension. 2005;45:867–73.
Schmidlin O, Tanaka M, Sebastian A, Morris RC Jr. Selective chloride loading is pressor in the stroke-prone spontaneously hypertensive rat despite hydrochlorothiazide-induced natriuresis. J Hypertens. 2010;28:87–94.
McCallum L, Lip S, Padmanabhan S. The hidden hand of chloride in hypertension. Pflugers Arch. 2015;467:595–603.
Urbanet R, Nguyen Dinh Cat A, Feraco A, Venteclef N, El Mogrhabi S, Sierra-Ramos C, et al. Adipocyte Mineralocorticoid Receptor Activation Leads to Metabolic Syndrome and Induction of Prostaglandin D2 Synthase. Hypertension. 2015;66:149–57.
Hirata A, Maeda N, Hiuge A, Hibuse T, Fujita K, Okada T, et al. Blockade of mineralocorticoid receptor reverses adipocyte dysfunction and insulin resistance in obese mice. Cardiovasc Res. 2009;84:164–72.
Johansen ML, Schou M, Rossignol P, Holm MR, Rasmussen J, Brandt N, et al. Effect of the mineralocorticoid receptor antagonist eplerenone on liver fat and metabolism in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled trial (MIRAD trial). Diabetes Obes Metab. 2019;21:2305–14.
Garg R, Kneen L, Williams GH, Adler GK. Effect of mineralocorticoid receptor antagonist on insulin resistance and endothelial function in obese subjects. Diabetes Obes Metab. 2014;16:268–72.
Acknowledgements
We express our gratitude to the physicians and medical staff in our department who provided care to the patients enrolled in the study.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
SM and AI received honorariums as a lecture fee from Daiichi Sankyo Company Limited.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
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.
About this article
Cite this article
Ikemoto, M., Morimoto, S. & Ichihara, A. Prediction of endogenous mineralocorticoid receptor activity by depressor effects of mineralocorticoid receptor antagonists in patients with primary aldosteronism. Hypertens Res (2024). https://doi.org/10.1038/s41440-024-01651-5
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41440-024-01651-5