Mirabegron, a β3‑adrenoreceptor agonist, regulates right and left atrial arrhythmogenesis differently

Chan,Chao-Shun; Lin,Fong-Jhih; Liu,Chih-Min; Lin,Yung-Kuo; Chen,Yao-Chang; Hsu,Chun-Chun; Higa,Satoshi; Chen,Shih-Ann; Chen,Yi-Jen

doi:10.3892/etm.2022.11656

Mirabegron, a β3‑adrenoreceptor agonist, regulates right and left atrial arrhythmogenesis differently

Authors:
- Chao-Shun Chan
- Fong-Jhih Lin
- Chih-Min Liu
- Yung-Kuo Lin
- Yao-Chang Chen
- Chun-Chun Hsu
- Satoshi Higa
- Shih-Ann Chen
- Yi-Jen Chen
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Affiliations: Department of Internal Medicine, Division of Cardiology, Taipei Medical University Hospital, Taipei 11031, Taiwan, R.O.C., Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C., Department of Medicine, Division of Cardiology, Heart Rhythm Center, Taipei Veterans General Hospital, Taipei 11217, Taiwan, R.O.C., Department of Internal Medicine, Division of Cardiology, School of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C., Department of Biomedical Engineering, National Defense Medical Center, Taipei 11490, Taiwan, R.O.C., School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C., Cardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, Okinawa 9012131, Japan, Department of Internal Medicine, Division of Cardiology, Wan‑Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan, R.O.C.
Published online on: October 18, 2022 https://doi.org/10.3892/etm.2022.11656
Article Number: 720
Copyright: © Chan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Mirabegron increases atrial fibrillation (AF) risk. The left atrium (LA) is the most critical ‘substrate’ for AF and has higher arrhythmogenesis compared with the right atrium (RA). The present study aimed to investigate the electrophysiological and arrhythmogenic effects of mirabegron on the LA and RA and clarify the potential underlying mechanisms. Conventional microelectrodes, a whole‑cell patch clamp and a confocal microscope were used in rabbit LA and RA preparations or single LA and RA myocytes before and after mirabegron administration with or without cotreatment with KT5823 [a cyclic adenosine monophosphate (cAMP)‑dependent protein kinase inhibitor]. The baseline action potential duration at repolarization extents of 20 and 50% (but not 90%) were shorter in the LA than in the RA. Mirabegron at 0.1 and 1 µM (but not 0.01 µM) reduced the action potential duration at repolarization extents of 20 and 50% in the LA and RA. Mirabegron (0.1 µM) increased the occurrence of tachypacing‑induced burst firing in the LA but not in the RA, where it was suppressed by KT5823 (1 µM). Mirabegron (0.1 µM) increased the L‑type Ca²⁺ current (I_Ca‑L), ultrarapid component of delayed rectifier K⁺ current (I_Kur), Ca²⁺ transients and sarcoplasmic reticulum Ca²⁺ content but reduced transient outward K⁺ current (I_to) in the LA myocytes. However, mirabegron did not change the Na⁺ current and delayed rectifier K⁺ current in the LA myocytes. Moreover, pretreatment with KT5823 (1 µM) inhibited the effects of mirabegron on I_Ca‑L, I_to and I_Kur in the LA myocytes. Furthermore, in the RA myocytes, mirabegron reduced I_Ca‑L but did not change I_to. In conclusion, mirabegron differentially regulates electrophysiological characteristics in the LA and RA. Through the activation of the cAMP‑dependent protein kinase pathway and induction of Ca²⁺ dysregulation, mirabegron may increase LA arrhythmogenesis, leading to increased AF risk.

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1	Gauthier C, Tavernier G, Charpentier F, Langin D and Le Marec H: Functional β3-adrenoceptor in the human heart. J Clin Invest. 98:556–562. 1996.PubMed/NCBI View Article : Google Scholar
2	Khullar V, Amarenco G, Angulo JC, Cambronero J, Høye K, Milsom I, Radziszewski P, Rechberger T, Boerrigter P, Drogendijk T, et al: Efficacy and tolerability of mirabegron, a β3-adrenoceptor agonist, in patients with overactive bladder: Results from a randomised European-Australian phase 3 trial. Eur Urol. 63:283–295. 2013.PubMed/NCBI View Article : Google Scholar
3	Wagg A, Cardozo L, Nitti VW, Castro-Diaz D, Auerbach S, Blauwet MB and Siddiqui E: The efficacy and tolerability of the β3-adrenoceptor agonist mirabegron for the treatment of symptoms of overactive bladder in older patients. Age Ageing. 43:666–675. 2014.PubMed/NCBI View Article : Google Scholar
4	Wagg A, Staskin D, Engel E, Herschorn S, Kristy RM and Schermer CR: Efficacy, safety, and tolerability of mirabegron in patients aged ≥ 65yr with overactive bladder wet: A phase IV, double-blind, randomised, placebo-controlled study (PILLAR). Eur Urol. 77:211–220. 2020.PubMed/NCBI View Article : Google Scholar
5	Gauthier C, Leblais V, Kobzik L, Trochu JN, Khandoudi N, Bril A, Balligand JL and Marec HL: The negative inotropic effect of beta3-adrenoceptor stimulation is mediated by activation of a nitric oxide synthase pathway in human ventricle. J Clin Invest. 102:1377–1384. 1998.PubMed/NCBI View Article : Google Scholar
6	Moniotte S, Kobzik L, Feron O, Trochu JN, Gauthier C and Balligand JL: Upregulation of beta3-adrenoceptors and altered contractile response to inotropic amines in human failing myocardium. Circulation. 103:1649–1655. 2001.PubMed/NCBI View Article : Google Scholar
7	Skeberdis VA, Gendvilienė C, Zablockaitė D, Treinys R, Macianskiene R, Bogdelis A, Jurevicius J and Fischmeister R: β3-adrenergic receptor activation increases human atrial tissue contractility and stimulates the L-type Ca²⁺ current. J Clin Invest. 118:3219–3227. 2008.PubMed/NCBI View Article : Google Scholar
8	Nitti VW, Khullar V, Kerrebroeck P, Herschorn S, Cambronero J, Angulo JC, Blauwet MB, Dorrepaal C, Siddiqui E and Martin NE: Mirabegron for the treatment of overactive bladder: A prespecified pooled efficacy analysis and pooled safety analysis of three randomised, double-blind, placebo-controlled, phase III studies. Int J Clin Pract. 67:619–632. 2013.PubMed/NCBI View Article : Google Scholar
9	Batista JE, Kölbl H, Herschorn S, Rechberger T, Cambronero J, Halaska M, Coppell A, Kaper M, Huang M and Siddiqui E: The efficacy and safety of mirabegron compared with solifenacin in overactive bladder patients dissatisfied with previous antimuscarinic treatment due to lack of efficacy: results of a noninferiority, randomized, phase IIIb trial. Ther Adv Urol. 7:167–179. 2015.PubMed/NCBI View Article : Google Scholar
10	Nitti VW, Chapple CR, Walters C, Blauwet MB, Herschorn S, Milsom I, Auerbach S and Radziszewski P: Safety and tolerability of the β3-adrenoceptor agonist mirabegron, for the treatment of overactive bladder: Results of a prospective pooled analysis of three 12-week randomised phase III trials and of a 1-year randomised phase III trial. Int J Clin Pract. 68:972–985. 2014.PubMed/NCBI View Article : Google Scholar
11	Lindemann JP, Jones LR, Hathaway DR, Henry BG and Watanabe AM: β-Adrenergic stimulation of phospholamban phosphorylation and Ca²⁺-ATPase activity in guinea pig ventricles. J Biol Chem. 258:464–471. 1983.PubMed/NCBI
12	Takasago T, Imagawa T and Shigekawa M: Phosphorylation of the cardiac ryanodine receptor by cAMP-dependent protein kinase. J Biochem. 106:872–877. 1989.PubMed/NCBI View Article : Google Scholar
13	Perchenet L, Hinde AK, Patel KC, Hancox JC and Levi AJ: Stimulation of Na⁺/Ca²⁺ exchange by the β-adrenergic/protein kinase A pathway in guinea-pig ventricular myocytes at 37 degrees C. Pflugers Arch. 439:822–828. 2000.PubMed/NCBI View Article : Google Scholar
14	Lou Q, Janardhan A and Efimov IR: Remodeling of calcium handling in human heart failure. Adv Exp Med Biol. 740:1145–1174. 2012.PubMed/NCBI View Article : Google Scholar
15	Heijman J, Voigt N, Wehrens XH and Dobrev D: Calcium dysregulation in atrial fibrillation: the role of CaMKII. Front Pharmacol. 5(30)2014.PubMed/NCBI View Article : Google Scholar
16	Pappone C, Rosanio S, Oreto G, Tocchi M, Gugliotta F, Vicedomini G, Salvati A, Dicandia C, Mazzone P, Santinelli V, et al: Circumferential radiofrequency ablation of pulmonary vein ostia: A new anatomic approach for curing atrial fibrillation. Circulation. 102:2619–2628. 2000.PubMed/NCBI View Article : Google Scholar
17	Roithinger FX, Steiner PR, Goseki Y, Sparks PB and Lesh MD: Electrophysiologic effects of selective right versus left atrial linear lesions in a canine model of chronic atrial fibrillation. J Cardiovasc Electrophysiol. 10:1564–1574. 1999.PubMed/NCBI View Article : Google Scholar
18	Lin YK, Lai MS, Chen YC, Cheng CC, Huang JH, Chen SA, Chen YJ and Lin CI: Hypoxia and reoxygenation modulate the arrhythmogenic activity of the pulmonary vein and atrium. Clin Sci. 122:121–132. 2012.PubMed/NCBI View Article : Google Scholar
19	Chan CS, Lin YK, Chen YC, Kao YH, Chen SA and Chen YJ: Hydrogen sulphide increases pulmonary veins and atrial arrhythmogenesis with activation of protein kinase C. J Cell Mol Med. 22:3503–3513. 2018.PubMed/NCBI View Article : Google Scholar
20	Chan CS, Lin YS, Lin YK, Chen YC, Kao YH, Hsu CC, Chen SA and Chen YJ: Atrial arrhythmogenesis in a rabbit model of chronic obstructive pulmonary disease. Transl Res. 223:25–39. 2020.PubMed/NCBI View Article : Google Scholar
21	National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals: Guide for the care and use of laboratory animals. 8th edition. National Academies Press (US), Washington, DC, 2011.
22	Chan CS, Chen YC, Chang SL, Lin YK, Kao YH, Chen SA and Chen YJ: Heart failure differentially modulates the effects of ivabradine on the electrical activity of the sinoatrial node and pulmonary veins. J Card Fail. 24:763–772. 2018.PubMed/NCBI View Article : Google Scholar
23	Calvo-Guirado JL, Satorres M, Negri B, Ramirez-Fernandez P, Maté-Sánchez JE, Delgado-Ruiz R, Gomez-Moreno G, Abboud M and Romanos GE: Biomechanical and histological evaluation of four different titanium implant surface modifications: An experimental study in the rabbit tibia. Clin Oral Invest. 18:1495–1505. 2014.PubMed/NCBI View Article : Google Scholar
24	Chen YJ, Chen YC, Wongcharoen W, Lin CI and Chen SA: Effect of K201, a novel antiarrhythmic drug on calcium handling and arrhythmogenic activity of pulmonary vein cardiomyocytes. Br J Pharmacol. 153:915–925. 2008.PubMed/NCBI View Article : Google Scholar
25	Lu YY, Chung FB, Chen YC, Tsai CF, Kao YH, Chao TF, Huang JH, Chen SA and Chen YJ: Distinctive electrophysiological characteristics of right ventricular outflow tract cardiomyocytes. J Cell Mol Med. 18:1540–1548. 2014.PubMed/NCBI View Article : Google Scholar
26	Huang SY, Lu YY, Lin YK, Chen YC, Chen YA, Chung CC, Lin WS, Chen SA and Chen YJ: Ceramide modulates electrophysiological characteristics and oxidative stress of pulmonary vein cardiomyocytes. Eur J Clin Invest. 52(e13690)2022.PubMed/NCBI View Article : Google Scholar
27	McDonald TF, Pelzer S, Trautwein W and Pelzer DJ: Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells. Physiol Rev. 74:365–507. 1994.PubMed/NCBI View Article : Google Scholar
28	Landstrom AP, Dobrev D and Wehrens XHT: Calcium signaling and cardiac arrhythmias. Circ Res. 120:1969–1993. 2017.PubMed/NCBI View Article : Google Scholar
29	Li D, Zhang L, Kneller J and Nattel S: Potential ionic mechanism for repolarization differences between canine right and left atrium. Circ Res. 88:1168–1175. 2001.PubMed/NCBI View Article : Google Scholar
30	Grand AO: Cardiac ion channels. Circ Arrhythm Electrophysiol. 2:185–194. 2009.PubMed/NCBI View Article : Google Scholar