Serum ATP1A1 and epinephrine as potential biomarkers for essential hypertension ‒ a case-control study
DOI:
https://doi.org/10.15584/ejcem.2026.2.13Keywords:
blood pressure, catecholamines, electrolytes, sodium-potassium-exchanging ATPaseAbstract
Introduction and aim. Essential hypertension is a leading cause of global morbidity driven by complex genetic and physiological interactions. The roles of the Na+/K+-ATPase pump, sympathetic nervous system, and electrolyte balance are critical, yet their simultaneous interaction remains unexplored. This study aimed to investigate the serum levels of Na+/K+-ATPase alpha-1 subunit (ATP1A1), epinephrine, and key electrolytes (sodium, potassium, chloride, and calcium) in hypertensive patients, providing a novel multi-marker approach to evaluate their potential as diagnostic biomarkers.
Material and methods. We enrolled 80 hypertensive patients and 40 normotensive controls in this cross-sectional study. Serum ATP1A1 and epinephrine levels were measured by ELISA, and electrolytes were analyzed using an ion-selective electrode analyzer.
Results. Hypertensive patients exhibited significantly higher serum levels of ATP1A1 (430±190 vs. 161±71.16 ng/L), epinephrine (339±188 vs. 116.5±38.6 ng/L), sodium, chloride, and calcium, with significantly lower potassium (all p<0.001 ROC analysis demonstrated a promising discriminatory ability for ATP1A1 (AUC=0.92) and epinephrine (AUC=0.94). Multiple regression analysis identified ATP1A1, epinephrine, and chloride levels as significant independent predictors of systolic blood pressure.
Conclusion. Patients with essential hypertension display a distinct biochemical signature of elevated serum ATP1A1 and epinephrine levels coupled with significant electrolyte disturbances. These preliminary findings suggest potential value as biomarkers for essential hypertension, although extensive validation in larger, independent cohorts is required before clinical application can be considered.
Downloads
References
Mills KT, Stefanescu A, He J. The global epidemiology of hypertension. Nat Rev Nephrol. 2020;16(4):223-237. doi:10.1038/s41581-019-0244-2
World Health Organization. Global Report on Hypertension: The Race against a Silent Killer. World Health Organization; 2023.
Perry M. Hypertension: an overview. J Community Nurs. 2023;37(6).
Carretero OA, Oparil S. Essential hypertension: part I: definition and etiology. Circulation. 2000;101(3):329-335.
Rimoldi SF, Scherrer U, Messerli FH. Secondary arterial hypertension: when, who, and how to screen? Eur Heart J. 2014;35(19):1245-1254. doi:10.1093/eurheartj/eht534
Feng Earley Y, Pan S, Verma H, et al. Central nervous system mechanisms of salt-sensitive hypertension. Physiol Rev. 2025;105(4):1989-2032.
Sriperumbuduri S, Welling P, Ruzicka M, Hundemer GL, Hiremath S. Potassium and hypertension: a state-of-the-art review. Am J Hypertens. 2024;37(2):91-100.
Stone MS, Martyn L, Weaver CM. Potassium Intake, Bioavailability, Hypertension, and Glucose Control. Nutrients. 2016;8(7). doi:10.3390/nu8070444
Perez V, Chang ET. Sodium-to-potassium ratio and blood pressure, hypertension, and related factors. Adv Nutr. 2014;5(6):712-741. doi:10.3945/an.114.006783
Zhang L, Staehr C, Zeng F, Bouzinova EV, Matchkov VV. The Na,K-ATPase in vascular smooth muscle cells. Curr Top Membr. 2019;83:151-175. doi:10.1016/bs.ctm.2019.01.007
Skou JC. The identification of the sodium pump. Biosci Rep. 1998;18(4):155-169. doi:10.1023/A:1020196612909
Iqbal S, Klammer N, Ekmekcioglu C. The effect of electrolytes on blood pressure: A brief summary of meta-analyses. Nutrients. 2019;11(6). doi:10.3390/nu11061362
Cinarli Yuksel F, Nicolaou P, Spontarelli K, et al. The phenotypic spectrum of pathogenic ATP1A1 variants expands: the novel p.P600R substitution causes demyelinating Charcot-Marie-Tooth disease. J Neurol. 2023;270(5):2576-2590. doi:10.1007/s00415-023-11581-w
Fernandez CJ, Hanna FWF, Pacak K, Nazari MA. Catecholamines and blood pressure regulation. In: Endocrine Hypertension. Elsevier; 2023:19-34.
Walther LM, von Känel R, Heimgartner N, Zuccarella-Hackl C, Stirnimann G, Wirtz PH. Alpha-adrenergic mechanisms in the cardiovascular hyperreactivity to norepinephrine-infusion in essential hypertension. Front Endocrinol (Lausanne). 2022;13:824616. doi:10.3389/fendo.2022.824616
Oner E, Uruc S, Dokur E, Gorduk O, Sahin Y. Utilization of a selective paper-based flexible electrochemical sensor for epinephrine determination in artificial sweat using nickel oxide and sulfur-doped graphene conductive ink. J Electrochem Soc. 2025;172(2):27508.
Biondo ED, Spontarelli K, Ababioh G, Méndez L, Artigas P. Diseases caused by mutations in the Na(+)/K(+) pump α1 gene ATP1A1. Am J Physiol Cell Physiol. 2021;321(2):C394-C408. doi:10.1152/ajpcell.00059.2021
Ikonomidis I, Michalakeas CA, Lekakis J, Paraskevaidis I, Kremastinos DT. Multimarker approach in cardiovascular risk prediction. Dis Markers. 2009;26(5-6):273-285. doi:10.3233/DMA-2009-0633
Bielecka-Dabrowa A, Gluba-Brzózka A, Michalska-Kasiczak M, Misztal M, Rysz J, Banach M. The multi-biomarker approach for heart failure in patients with hypertension. Int J Mol Sci. 2015;16(5):10715-10733. doi:10.3390/ijms160510715
Staehr C, Aalkjaer C, Matchkov VV. The vascular Na,K-ATPase: clinical implications in stroke, migraine, and hypertension. Clin Sci (Lond). 2023;137(20):1595-1618. doi:10.1042/CS20220796
Herrera VL, Pasion KA, Moran AM, et al. A functional 12T-insertion polymorphism in the ATP1A1 promoter confers decreased susceptibility to hypertension in a male Sardinian population. PLoS One. 2015;10(1):e0116724. doi:10.1371/journal.pone.0116724
Filippini T, Naska A, Kasdagli MI, et al. Potassium intake and blood pressure: A dose-response meta-analysis of randomized controlled trials. J Am Heart Assoc. 2020;9(12):e015719. doi:10.1161/JAHA.119.015719
Gao Y, Xu Y, Bai F, Puri R, Tian J, Liu J. Factors that influence the Na/K-ATPase signaling and function. Front Pharmacol. 2025;16:1639859. doi:10.3389/fphar.2025.1639859
Hayashida K, Bartlett AH, Chen Y, Park PW. Molecular and cellular mechanisms of ectodomain shedding. Anat Rec (Hoboken). 2010;293(6):925-937. doi:10.1002/ar.20757
Wang C, Li H, Zhou H, et al. Intracranial aneurysm circulating exosome-derived LncRNA ATP1A1-AS1 promotes smooth muscle cells phenotype switching and apoptosis. Aging (Albany NY). 2024;16(9):8320-8335. doi:10.18632/aging.205821
Pomatto MAC, Gai C, Bussolati B, Camussi G. Extracellular vesicles in renal pathophysiology. Front Mol Biosci. 2017;4:37. doi:10.3389/fmolb.2017.00037
Nguyen PT, Deisl C, Fine M, et al. Structural basis for gating mechanism of the human sodium-potassium pump. Nat Commun. 2022;13(1):5293. doi:10.1038/s41467-022-32990-x
Park J, Kwock CK, Yang YJ. The effect of the sodium to potassium ratio on hypertension prevalence: A propensity score matching approach. Nutrients. 2016;8(8):482. doi:10.3390/nu8080482
Muroya T, Satoh M, Metoki H, et al. Association between urinary sodium-to-potassium ratio and BNP in a general population without antihypertensive treatment and cardiovascular diseases: the Ohasama study. Hypertens Res. 2025;48(9):2292-2302. doi:10.1038/s41440-025-02266-0
Yoon Y, Son M. Association between blood pressure control in hypertension and urine sodium to potassium ratio: From the Korea National Health and Nutrition Examination Survey (2016-2021). PLoS One. 2024;19(11):e0314531. doi:10.1371/journal.pone.0314531
Wu D, Chen Y, Guan H, Sun Y. Association of abnormal serum electrolyte levels with hypertension in a population with high salt intake. Public Health Nutr. 2019;22(9):1635-1645. doi:10.1017/S1368980019000260
Grassi G, Mark A, Esler M. The sympathetic nervous system alterations in human hypertension. Circ Res. 2015;116(6):976-990. doi:10.1161/CIRCRESAHA.116.303604
Seravalle G, Grassi G. Sympathetic nervous system and hypertension: New evidences. Auton Neurosci. 2022;238:102954. doi:10.1016/j.autneu.2022.102954
Duan Y, Wu C, Lai Z, et al. Autonomous epinephrine release by KCNJ5 mutation drives familial thoracic aortic aneurysm and dissection. Hypertens (Dallas, Tex 1979). 2025;82(4):752-764. doi:10.1161/HYPERTENSIONAHA.124.23795
Nakajima J, Sawada Y, Isshiki Y, et al. Influence of the prehospital administered dosage of epinephrine on the plasma levels of catecholamines in patients with out-of-hospital cardiac arrest. Heliyon. 2021;7(8):e07708. doi:10.1016/j.heliyon.2021.e07708
Palmu J, Tikkanen E, Havulinna AS, et al. Comprehensive biomarker profiling of hypertension in 36 985 Finnish individuals. J Hypertens. 2022;40(3):579-587. doi:10.1097/HJH.0000000000003051
Vasan RS. Biomarkers of cardiovascular disease: molecular basis and practical considerations. Circulation. 2006;113(19):2335-2362. doi:10.1161/CIRCULATIONAHA.104.482570
Hua Q, Fan L, Wang ZW, Li J. 2023 Guideline for the management of hypertension in the elderly population in China. J Geriatr Cardiol. 2024;21(6):589-630. doi:10.26599/1671-5411.2024.06.001
Wu IC, Chen YK, Wu CC, et al. Overexpression of ATPase Na+/+ transporting alpha 1 polypeptide, ATP1A1, correlates with clinical diagnosis and progression of esophageal squamous cell carcinoma. Oncotarget. 2016;7(51):85244-85258. doi:10.18632/oncotarget.13267
Cordeiro BM, Leite Fontes CF, Meyer-Fernandes JR. Molecular Basis of Na, K-ATPase Regulation of Diseases: Hormone and FXYD2 Interactions. Int J Mol Sci. 2024;25(24). doi:10.3390/ijms252413398
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 European Journal of Clinical and Experimental Medicine
This work is licensed under a Creative Commons Attribution 4.0 International License.
Our open access policy is in accordance with the Budapest Open Access Initiative (BOAI) definition: this means that articles have free availability on the public Internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from having access to the Internet itself.
All articles are published with free open access under the CC-BY Creative Commons attribution license (the current version is CC-BY, version 4.0). If you submit your paper for publication by the Eur J Clin Exp Med, you agree to have the CC-BY license applied to your work. Under this Open Access license, you, as the author, agree that anyone may download and read the paper for free. In addition, the article may be reused and quoted provided that the original published version is cited. This facilitates freedom in re-use and also ensures that Eur J Clin Exp Med content can be mined without barriers for the research needs.
