Regulation of Ion Balance by Vascular β3-Adrenergic Receptors through Endothelial Mechanisms

Gizem Kaykı Mutlu; Ebru Arıoğlu İnan; Ayhanım Elif Müderrisoğlu; İrem Karaömerlioğlu; Betül Rabia Erdoğan Vadacca; Vecdi Melih Altan

doi:10.26650/IstanbulJPharm.2025.1623707

Regulation of Ion Balance by Vascular β3-Adrenergic Receptors through Endothelial Mechanisms

Abstract

Background and Aims: Vascular Na+/K+ ATPase (NKA) activity plays a crucial role in regulating vascular tone. β₃-adrenoceptors (β₃-ARs), which are upregulated during sympathetic overactivation, have been demonstrated to stimulate NKA activity in cardiac tissue. However, their role in vascular NKA regulation remains unclear. Our study aimed to investigate whether β₃-AR activation can restore NKA function in vascular tissue under high sympathetic stimulation. Methods: Male Sprague Dawley rats were treated with noradrenaline (NA) to mimic chronic sympathetic activation, with or without BRL 37344, a β₃-AR agonist. Vascular NKA activity was assessed in the aortic rings using KCl-induced relaxation responses in K+-free buffer. The role of the endothelium was also examined. Results: NA treatment impaired vascular NKA activity, as evidenced by reduced KCl-induced relaxation. Activation of β₃-AR restored this relaxation in an endothelium-dependent manner. In contrast, ouabain abolished the response, confirming its dependence on NKA activity. Conclusion: These findings indicate that β₃-AR activation can restore vascular NKA activity under sympathetic stress via an endothelium-dependent mechanism. This highlights a novel vasoprotective role for β₃-ARs and support their potential as therapeutic targets in vascular pathologies associated with impaired NKA function.

Keywords

References

Aragón, J. P., Condit, M. E., Bhushan, S., Predmore, B. L., Patel, S. S., Grinsfelder, D. B., Gundewar, S., Jha, S., Calvert, J. W., Barouch, L. A., Lavu, M., Wright, H. M., & Lefer, D. J. (2011). Beta3-adrenoreceptor stimulation ameliorates myocardial ischemia-reperfusion injury via endothelial nitric oxide synthase and neuronal nitric oxide synthase activation. Journal of the American College of Cardiologyl, 58(25), 2683-2691. https://doi.org/10.1016/j.jacc.2011.09.033
Belge, C., Hammond, J., Dubois-Deruy, E., Manoury, B., Hamelet, J., Beauloye, C., Markl, A., Pouleur, A. C., Bertrand, L., Esfahani, H., Jnaoui, K., Götz, K. R., Nikolaev, V. O., Vanderper, A., Herijgers, P., Lobysheva, I., Iaccarino, G., Hilfiker-Kleiner, D., Tavernier, G., Balligand, J. L. (2014). Enhanced expression of β3-adrenoceptors in cardiac myocytes attenuates neurohormone-induced hypertrophic remodeling through nitric oxide synthase. Circulation, 129(4), 451-462. https://doi.org/10.1161/circulationaha.113.004940
Bers, D. M., & Despa, S. (2009). Na/K-ATPase–an integral player in the adrenergic fightor-flight response. Trends in Cardiovascular Medicine, 19(4), 111-118. https://doi.org/10.1016/j.tcm.2009.07.001
Bruno, R. M., Ghiadoni, L., Seravalle, G., Dell'oro, R., Taddei, S., & Grassi, G. (2012). Sympathetic regulation of vascular function in health and disease. Frontiers in Physiology 3, 284. https://doi.org/10.3389/fphys.2012.00284
Bundgaard, H., Liu, C. C., Garcia, A., Hamilton, E. J., Huang, Y., Chia, K. K., Hunyor, S. N., Figtree, G. A., & Rasmussen, H. H. (2010). β(3) adrenergic stimulation of the cardiac Na+-K+ pump by reversal of an inhibitory oxidative modification. Circulation, 122(25), 2699-2708. https://doi.org/10.1161/circulationaha.110.964619
Cannavo, A., & Koch, W. J. (2017). Targeting β3-Adrenergic Receptors in the Heart: Selective Agonism and β-Blockade. Journal of Cardiovascular Pharmacology 69(2), 71-78. https://doi.org/10.1097/fjc.0000000000000444
Chanda, D., Krishna, A. V., Gupta, P. K., Singh, T. U., Prakash, V. R., Sharma, B., Joshi, P., & Mishra, S. K. (2008). Role of low ouabain-sensitive isoform of Na+-K+- ATPase in the regulation of basal tone and agonist-induced contractility in ovine pulmonary artery. J Cardiovasc Pharmacol, 52(2), 167-175. https://doi.org/10.1097/FJC.0b013e31818127dd
Dhot, J., Ferron, M., Prat, V., Persello, A., Roul, D., Stévant, D., Guijarro, D., Piriou, N., Aillerie, V., Erraud, A., Toumaniantz, G., Erfanian, M., Tesse, A., Grabherr, A., Tesson, L., Menoret, S., Anegon, I., Trochu, J. N., Steenman, M., Gauthier, C. (2020). Overexpression of endothelial β(3) -adrenergic receptor induces diastolic dysfunction in rats. ESC Heart Failure 7(6), 4159-4171. https://doi.org/10.1002/ehf2.13040

Evans, C. J. F., Glastras, S. J., Tang, O., & Figtree, G. A. (2023). Therapeutic Potential for Beta-3 Adrenoreceptor Agonists in Peripheral Arterial Disease and Diabetic Foot Ulcers. Biomedicines, 11(12). https://doi.org/10.3390/biomedicines11123187
Fiorim, J., Ribeiro, R. F., Jr., Azevedo, B. F., Simões, M. R., Padilha, A. S., Stefanon, I., Alonso, M. J., Salaices, M., & Vassallo, D. V. (2012). Activation of K+ channels and Na+/K+ ATPase prevents aortic endothelial dysfunction in 7-day lead-treated rats. Toxicology and Applied Pharmacology 262(1), 22-31. https://doi.org/10.1016/j.taap.2012.04.015
Fisher, J. P., Young, C. N., & Fadel, P. J. (2009). Central sympathetic overactivity: maladies and mechanisms. Autonomic Neuroscience, 148(1-2), 5-15. https://doi.org/10.1016/j.autneu.2009.02.003
Fry, N. A. S., Liu, C. C., Garcia, A., Hamilton, E. J., Karimi Galougahi, K., Kim, Y. J., Whalley, D. W., Bundgaard, H., & Rasmussen, H. H. (2020). Targeting Cardiac Myocyte Na(+)- K(+) Pump Function With β3 Adrenergic Agonist in Rabbit Model of Severe Congestive Heart Failure. Circulation: Heart Failure 13(9), e006753. https://doi.org/10.1161/circheartfailure.119.006753
Gambardella, J., Fiordelisi, A., Avvisato, R., Buonaiuto, A., Cerasuolo, F. A., Sorriento, D., & Iaccarino, G. (2023). Adrenergic receptors in endothelial and vascular smooth muscle cells. Current Opinion in Physiology, 36, 100721. https://doi.org/https://doi.org/10.1016/j.cophys.2023.100721
García-Álvarez, A., Pereda, D., García-Lunar, I., Sanz-Rosa, D., Fernández-Jiménez, R., García-Prieto, J., Nuño-Ayala, M., Sierra, F., Santiago, E., Sandoval, E., Campelos, P., Agüero, J., Pizarro, G., Peinado, V. I., Fernández-Friera, L., García-Ruiz, J. M., Barberá, J. A., Castellá, M., Sabaté, M., Ibañez, B. (2016). Beta-3 adrenergic agonists reduce pulmonary vascular resistance and improve right ventricular performance in a porcine model of chronic pulmonary hypertension. Basic Research in Cardiology, 111(4), 49. https://doi.org/10.1007/s00395-016-0567-0
Grassi, G. (1998). Role of the sympathetic nervous system in human hypertension. Journal of Hypertensions, 16(12 Pt 2), 1979-1987. https://doi.org/10.1097/00004872-199816121-00019
Hagimont, E., Lourenco-Rodrigues, M. D., Chousterman, B. G., Yen-Potin, F., Durand, M., & Kimmoun, A. (2024). β3-Adrenergic receptor antagonism improves cardiac and vascular functions but did not modulate survival in a murine resuscitated septic shock model. Intensive Care Medicine Experimental, 12(1), 118. https://doi.org/10.1186/s40635-024-00705-9
Hauck, C., & Frishman, W. H. (2012). Systemic hypertension: the roles of salt, vascular Na+/K+ ATPase and the endogenous glycosides, ouabain and marinobufagenin. Cardiology in Review 20(3), 130-138. https://doi.org/10.1097/CRD.0b013e31823c835c
Hayakawa, H., & Raij, L. (1997). The link among nitric oxide synthase activity, endothelial function, and aortic and ventricular hypertrophy in hypertension. Hypertension, 29(1 Pt 2), 235-241. https://doi.org/10.1161/01.hyp.29.1.235
Karimi Galougahi, K., Liu, C. C., Garcia, A., Fry, N. A., Hamilton, E. J., Figtree, G. A., & Rasmussen, H. H. (2015). β3-Adrenoceptor activation relieves oxidative inhibition of the cardiac Na+-K+ pump in hyperglycemia induced by insulin receptor blockade. American Journal of Physiology$Cell Physiology, 309(5), C286-295. https://doi.org/10.1152/ajpcell.00071.2015
Karimi Galougahi, K., Zhang, Y., Kienzle, V., Liu, C. C., Quek, L. E., Patel, S., Lau, E., Cordina, R. L., Figtree, G. A., & Celermajer, D. S. (2023). β3 adrenergic agonism: A novel pathway which improves right ventricular-pulmonary arterial hemodynamics in pulmonary arterial hypertension. Physiological Reports, 11(1), e15549. https://doi.org/10.14814/phy2.15549
Kayki Mutlu, G., Arioglu Inan, E., Karaomerlioglu, I., Altan, V. M., Yersal, N., Korkusuz, P., Rocchetti, M., & Zaza, A. (2018). Role of the β(3)-adrenergic receptor subtype in catecholamine-induced myocardial remodeling. Molecular and Cellular Biochemistry, 446(1-2), 149-160. https://doi.org/10.1007/s11010-018-3282-3
Kayki-Mutlu, G., Karaomerlioglu, I., Arioglu-Inan, E., & Altan, V. M. (2019). Beta-3 adrenoceptors: A potential therapeutic target for heart disease. The European Journal of Pharmacology, 858, 172468. https://doi.org/10.1016/j.ejphar.2019.172468
Leblanc, C., & Tabrizchi, R. (2018). Role of β(2-) and β(3)-adrenoceptors in arterial stiffness in a state of hypertension. The European Journal of Pharmacology, 819, 136-143. https://doi.org/10.1016/j.ejphar.2017.11.050
Lucchesi, M., Di Marsico, L., Guidotti, L., Lulli, M., Filippi, L., Marracci, S., & Dal Monte, M. (2025). Hypoxia-Dependent Upregulation of VEGF Relies on β3-Adrenoceptor Signaling in Human Retinal Endothelial and Müller Cells. International Journal of Molecular Sciences 26(9). https://doi.org/10.3390/ijms26094043
Michel, L. Y. M., Farah, C., & Balligand, J. L. (2020). The Beta3 Adrenergic Receptor in Healthy and Pathological Cardiovascular Tissues. Cells, 9(12). https://doi.org/10.3390/cells9122584
Motiejunaite, J., Amar, L., & Vidal-Petiot, E. (2021). Adrenergic receptors and cardiovascular effects of catecholamines. Annales d'endocrinologie (Paris), 82(3-4), 193-197. https://doi.org/10.1016/j.ando.2020.03.012
Natarajan, D., Ekambaram, S., Tarantini, S., Nagaraja, R. Y., Yabluchanskiy, A., Hedrick, A. F., Awasthi, V., Subramanian, M., Csiszar, A., & Balasubramanian, P. (2025). Chronic β3 adrenergic agonist treatment improves neurovascular coupling responses, attenuates blood-brain barrier leakage and neuroinflammation, and enhances cognition in aged mice. Aging (Albany NY), 17(2), 448-463. https://doi.org/10.18632/aging.206203
Niu, X., Watts, V. L., Cingolani, O. H., Sivakumaran, V., Leyton-Mange, J. S., Ellis, C. L., Miller, K. L., Vandegaer, K., Bedja, D., Gabrielson, K. L., Paolocci, N., Kass, D. A., & Barouch, L. A. (2012). Cardioprotective effect of beta-3 adrenergic receptor agonism: role of neuronal nitric oxide synthase. The Journal of the American College of Cardiology 59(22), 1979-1987. https://doi.org/10.1016/j.jacc.2011.12.046
Pasha, A., Tondo, A., Favre, C., & Calvani, M. (2024). Inside the Biology of the β3- Adrenoceptor. Biomolecules, 14(2). https://doi.org/10.3390/biom14020159
Rautureau, Y., Toumaniantz, G., Serpillon, S., Jourdon, P., Trochu, J. N., & Gauthier, C. (2002). Beta 3-adrenoceptor in rat aorta: molecular and biochemical characterization and signalling pathway. British Journal of Pharmacology 137(2), 153-161. https://doi.org/10.1038/sj.bjp.0704867
Samanta, S., Bagchi, D., & Bagchi, M. (2024). Physiological and metabolic functions of the β(3)-adrenergic receptor and an approach to therapeutic achievements. Journal of Physiology and Biochemistry, 80(4), 757-774. https://doi.org/10.1007/s13105-024-01040-z
Staehr, C., Aalkjaer, C., & Matchkov, V. V. (2023). The vascular Na,K-ATPase: clinical implications in stroke, migraine, and hypertension. Clinical Science (Lond), 137(20), 1595-1618. https://doi.org/10.1042/cs20220796
Suhail, M. (2010). Na, K-ATPase: Ubiquitous Multifunctional Transmembrane Protein and its Relevance to Various Pathophysiological Conditions. Journal of Clinical Medicine Research, 2(1), 1-17. https://doi.org/10.4021/jocmr2010.02.263w
Watts, V. L., Sepulveda, F. M., Cingolani, O. H., Ho, A. S., Niu, X., Kim, R., Miller, K. L., Vandegaer, K., Bedja, D., Gabrielson, K. L., Rameau, G., O'Rourke, B., Kass, D. A., & Barouch, L. A. (2013). Anti-hypertrophic and anti-oxidant effect of beta3-adrenergic stimulation in myocytes requires differential neuronal NOS phosphorylation. The Journal of Molecular and Cellular Cardiology, 62, 8-17. https://doi.org/10.1016/j.yjmcc.2013.04.025
Zhang, Z. B., Cheng, Y. W., Xu, L., Li, J. Q., Pan, X., Zhu, M., Chen, X. H., Sun, A. J., Lin, J. R., & Gao, P. J. (2024). Activation of β3-adrenergic receptor by mirabegron prevents aortic dissection/aneurysm by promoting lymphangiogenesis in perivascular adipose tissue. Cardiovascular Research, 120(17), 2307-2319. https://doi.org/10.1093/cvr/cvae213

Details

Primary Language

English

Subjects

Basic Pharmacology

Journal Section

Research Article

Authors

Gizem Kaykı Mutlu ^*
0000-0002-3177-9438
Türkiye

Ebru Arıoğlu İnan
0000-0002-0860-0815
Türkiye

Ayhanım Elif Müderrisoğlu
0000-0002-2027-0118
Türkiye

İrem Karaömerlioğlu
0000-0001-6851-8226
Türkiye

Betül Rabia Erdoğan Vadacca
0000-0001-7377-4777
Türkiye

Vecdi Melih Altan
0000-0001-7125-3900
Türkiye

Publication Date

January 14, 2026

Submission Date

January 21, 2025

Acceptance Date

August 13, 2025

Published in Issue

Year 2025 Volume: 55 Number: 3

DOI

https://doi.org/10.26650/IstanbulJPharm.2025.1623707

IZ

https://izlik.org/JA82NR24FZ

Cite

RIS / Bibtex

APA

Kaykı Mutlu, G., Arıoğlu İnan, E., Müderrisoğlu, A. E., Karaömerlioğlu, İ., Erdoğan Vadacca, B. R., & Altan, V. M. (2026). Regulation of Ion Balance by Vascular β3-Adrenergic Receptors through Endothelial Mechanisms. İstanbul Journal of Pharmacy, 55(3), 404-410. https://doi.org/10.26650/IstanbulJPharm.2025.1623707

AMA

1.Kaykı Mutlu G, Arıoğlu İnan E, Müderrisoğlu AE, Karaömerlioğlu İ, Erdoğan Vadacca BR, Altan VM. Regulation of Ion Balance by Vascular β3-Adrenergic Receptors through Endothelial Mechanisms. iujp. 2026;55(3):404-410. doi:10.26650/IstanbulJPharm.2025.1623707

Chicago

Kaykı Mutlu, Gizem, Ebru Arıoğlu İnan, Ayhanım Elif Müderrisoğlu, İrem Karaömerlioğlu, Betül Rabia Erdoğan Vadacca, and Vecdi Melih Altan. 2026. “Regulation of Ion Balance by Vascular β3-Adrenergic Receptors through Endothelial Mechanisms”. İstanbul Journal of Pharmacy 55 (3): 404-10. https://doi.org/10.26650/IstanbulJPharm.2025.1623707.

EndNote

Kaykı Mutlu G, Arıoğlu İnan E, Müderrisoğlu AE, Karaömerlioğlu İ, Erdoğan Vadacca BR, Altan VM (January 1, 2026) Regulation of Ion Balance by Vascular β3-Adrenergic Receptors through Endothelial Mechanisms. İstanbul Journal of Pharmacy 55 3 404–410.

IEEE

[1]G. Kaykı Mutlu, E. Arıoğlu İnan, A. E. Müderrisoğlu, İ. Karaömerlioğlu, B. R. Erdoğan Vadacca, and V. M. Altan, “Regulation of Ion Balance by Vascular β3-Adrenergic Receptors through Endothelial Mechanisms”, iujp, vol. 55, no. 3, pp. 404–410, Jan. 2026, doi: 10.26650/IstanbulJPharm.2025.1623707.

ISNAD

Kaykı Mutlu, Gizem - Arıoğlu İnan, Ebru - Müderrisoğlu, Ayhanım Elif - Karaömerlioğlu, İrem - Erdoğan Vadacca, Betül Rabia - Altan, Vecdi Melih. “Regulation of Ion Balance by Vascular β3-Adrenergic Receptors through Endothelial Mechanisms”. İstanbul Journal of Pharmacy 55/3 (January 1, 2026): 404-410. https://doi.org/10.26650/IstanbulJPharm.2025.1623707.

JAMA

1.Kaykı Mutlu G, Arıoğlu İnan E, Müderrisoğlu AE, Karaömerlioğlu İ, Erdoğan Vadacca BR, Altan VM. Regulation of Ion Balance by Vascular β3-Adrenergic Receptors through Endothelial Mechanisms. iujp. 2026;55:404–410.

MLA

Kaykı Mutlu, Gizem, et al. “Regulation of Ion Balance by Vascular β3-Adrenergic Receptors through Endothelial Mechanisms”. İstanbul Journal of Pharmacy, vol. 55, no. 3, Jan. 2026, pp. 404-10, doi:10.26650/IstanbulJPharm.2025.1623707.

Vancouver

1.Gizem Kaykı Mutlu, Ebru Arıoğlu İnan, Ayhanım Elif Müderrisoğlu, İrem Karaömerlioğlu, Betül Rabia Erdoğan Vadacca, Vecdi Melih Altan. Regulation of Ion Balance by Vascular β3-Adrenergic Receptors through Endothelial Mechanisms. iujp. 2026 Jan. 1;55(3):404-10. doi:10.26650/IstanbulJPharm.2025.1623707