Mirabegron, a β3‑adrenoreceptor agonist, regulates right and left atrial arrhythmogenesis differently
- Authors:
- Published online on: October 18, 2022 https://doi.org/10.3892/etm.2022.11656
- Article Number: 720
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Copyright: © Chan et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
β3-Adrenoreceptors (β3ARs) are involved in adipocyte metabolism, gut relaxation and vascular vasodilation (1). Mirabegron is a selective β3AR agonist approved for overactive bladder treatment (2-4). Although the role of β3AR in adipose, intestinal and vascular tissues is well established, its existence and function in the heart remain unclear. In human cardiomyocytes, β3ARs couple with the inhibitory G protein to exhibit a negative inotropic effect, which counterbalances the effects of β1- and β2-adrenergic stimulation in heart failure by increasing nitric oxide production (5,6). However, the differential expression of β3ARs can lead to distinct effects in tissues and cells. β3ARs can stimulate the L-type Ca2+ current (ICa-L) in human atrial cells and enhance atrial tissue contractility through the cyclic adenosine monophosphate (cAMP)-dependent protein kinase pathway (7).
In clinical trials, the most commonly reported cardiovascular adverse events in patients receiving mirabegron for overactive bladder are hypertension, tachycardia and atrial fibrillation (AF) (8-10). The number of older patients with AF risk receiving mirabegron treatment has increased recently. However, the mechanisms underlying the potential arrhythmogenic effects of mirabegron remain unclear. Mirabegron might change cardiac electrophysiological characteristics due to its effects on ICa-L activation through the cAMP-dependent pathway, possibly resulting in Ca2+ dysregulation (11-15). The left atrium (LA), the most critical ‘substrate’ of AF (16,17), is vulnerable to oxidative stress and has higher arrhythmogenesis compared with the right atrium (RA) (18). Moreover, our previous studies indicate that the LA is more susceptible to hydrogen sulfide- and chronic obstructive pulmonary disease-related atrial arrhythmogenesis than is the RA (19,20). The differential arrhythmogenic effects between the LA and RA facilitate the maintenance of atrial arrhythmogenesis. Since mirabegron alters cardiac electrophysiological characteristics, resulting in arrhythmogenesis, the effects of mirabegron may differ between the LA and RA. Mirabegron may induce atrial arrhythmogenesis through differential arrhythmogenic effects between the LA and RA. Therefore, the present study aimed to investigate the differences in the effects of mirabegron on the electrophysiological activities of the LA and RA and clarify the underlying mechanisms.
Materials and methods
Rabbit atrial tissue preparations
All the experimental procedures were approved by the Institutional Animal Care and Use Committee of Taipei Veterans General Hospital, Taipei, Taiwan (approval no. IACUC-2021-011). Furthermore, the experimental protocols conformed to the institutional guideline for the care and use of laboratory animals as well as the Guide for the Care and Use of Laboratory Animals, published by the US National Institutes of Health (21). Male New Zealand white rabbits (n=36; weight, 2.5-3.5 kg; age, 6-8 months) used in the present study were purchased from Animal Health Research Institute (Council of Agriculture, Executive Yuan). All of the rabbits were housed in a temperature- and humidity-controlled environment (20-22˚C; 50-70% humidity) with a 12 h light/dark cycle, raised in stainless steel cages and had free access to food and water. Rabbits were anesthetized with an intramuscular injection of a mixture of zoletil (10 mg/kg; Virbac) and xylazine (5 mg/kg; Bayer AG) and sacrificed with an overdose of inhaled isoflurane (5% in oxygen; Panion & BF Biotech, Inc.) from a precision vaporizer (22,23). The anesthesia dosage was confirmed to be adequate on the basis of the absence of corneal reflexes and motor responses to pain stimuli. The hearts were excised through midline thoracotomy. The tissue preparations (1x1.5 cm2) of the LA and RA were separated from the LA and RA appendages, respectively. Electropharmacological measurements were obtained within 2 h after the separation. Tissue preparations (1-1.5 cm) of the RA and LA were superfused at 37˚C with normal Tyrode's solution composed of NaCl (137 mM), KCl (4 mM), NaHCO3 (15 mM), NaH2PO4 (0.5 mM), MgCl2 (0.5 mM), CaCl2 (2.7 mM) and dextrose (11 mM) at a constant rate of 3 ml/min. Tyrode's solution was saturated with a mixture of 97% O2 and 3% CO2 and its pH was adjusted to 7.4 with NaOH.
Electropharmacological experiments
The transmembrane action potentials of the RA and LA were recorded using machine-pulled glass capillary microelectrodes filled with KCl (3 M) (20). The microelectrodes were connected to an FD223 electrometer (World Precision Instruments) under 150-mg tension. The electrical events were simultaneously displayed on a Gould 4072 oscilloscope (Gould) and a Gould TA11 recorder (Gould). Electrical stimuli were applied using a Grass S88 stimulator (Grass Instruments) through a Grass SIU5B stimulus isolation unit. The action potential parameters were measured by applying 2-Hz electrical stimuli. The action potential amplitude (APA) was calculated as the difference between the resting membrane potential (RMP) and the peak of action potential depolarization. The action potential duration (APD) at repolarization extents of 90, 50 and 20% of the APD were measured and designated as APD90, APD50 and APD20, respectively. Burst firing was defined as the occurrence of accelerated spontaneous activities (faster than the basal rate) with sudden onset and termination. The same RA and LA tissue preparations were sequentially treated with different concentrations (0.01, 0.1 and 1 µM) of mirabegron (Avara Pharmaceutical Technologies) in Tyrode's solution for 30 min to investigate the electrophysiological effects of mirabegron with and without 1 µM KT5823 (an inhibitor of cAMP-dependent protein kinase; MilliporeSigma).
Ionic current measurements
Single LA and RA myocytes from rabbits were enzymatically dissociated, as described previously (24). Whole-cell patch clamp recordings of the single LA and RA myocytes were obtained before and after the administration of mirabegron (0.1 µM) with or without KT5823 (1 µM) using an Axopatch 1D amplifier (Axon Instruments) at 35±1˚C. The ionic currents were recorded at ~3-5 min after rupture or perforation to obtain measurements before ion channel activity decay over time. A small hyperpolarizing step from a holding potential of -50 mV to a test potential of -55 mV for 80 msec was delivered at the beginning of each experiment. The area under the capacitive current curve was divided using the applied voltage step to obtain the total cell capacitance. In general, 60-80% series resistance was electronically compensated. Ionic currents were recorded in the current- and voltage-clamp modes.
The Na+ current (INa) was measured during depolarization from a holding potential of -120 mV to testing potentials ranging from -80-0 mV in 10-mV increments for 40 msec at a 3-Hz frequency and at room temperature (25±1˚C). The external solution contained NaCl (5 mM), CsCl (133 mM), MgCl2 (2 mM), CaCl2 (1.8 mM), nifedipine (0.002 mM), 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES; 5 mM) and glucose (5 mM) adjusted to a pH of 7.3 with KOH. The micropipettes were filled with a solution containing CsCl (133 mM), NaCl (5 mM), ethylene glycol-bis (β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA; 10 mM), tetraethylammonium chloride (TEACl; 20 mM), MgATP (5 mM) and HEPES (5 mM) titrated to a pH of 7.3 with CsOH.
ICa-L was measured as an inward current during depolarization from a holding potential of -50 mV to test potentials ranging from -40-+60 mV in 10-mV increments for 300 msec at a 0.1-Hz frequency by using a perforated patch clamp with amphotericin B. The external solution contained TEACl (20 mM), CsCl (133 mM), HEPES (10 mM), MgCl2 (0.5 mM), CaCl2 (1.8 mM) and glucose (10 mM) titrated to a pH of 7.4 with NaOH. Tetrodotoxin (10 µM) and 4-aminopyridine (2 mM) were added to the external solution to block Na+ channels and transient outward K+ current (Ito), respectively. The micropipettes were filled with a solution containing CsCl (130 mM), MgCl2 (1 mM), Mg2ATP (5 mM), HEPES (10 mM), EGTA (10 mM), NaGTP (0.1 mM) and Na2 phosphocreatine (5 mM) titrated to a pH of 7.2 with CsOH. Steady-state inactivation of ICa-L was evaluated using a standard protocol consisting of a 300-msec prepulse and a 150-msec test pulse. The peak current elicited by the test pulse was divided by the maximal current and plotted as a function of prepulse voltage. Data points were fitted using a Boltzmann function. Recovery from ICa-L inactivation was assessed using a two-pulse protocol with a 200-msec prepulse and test pulse (from -80-+10 mV) separated using varying time intervals. Data points were fitted with a single-exponential function (25).
Ito was estimated using a double-pulse protocol. A 30-msec prepulse from -80--40 mV was used to inactivate the Na+ channels and this was followed by a 300-msec test pulse increasing to +60 mV in 10-mV increments at a 0.1-Hz frequency. CdCl2 (200 µM) was added to the bath solution for ICa-L inhibition. Ito was calculated as the difference between the peak outward current and steady-state current. The external solution contained NaCl (137 mM), KCl (5.4 mM), HEPES (10 mM), MgCl2 (0.5 mM), CaCl2 (1.8 mM) and glucose (10 mM) titrated to a pH of 7.4 with NaOH. The micropipettes were filled with a solution containing KCl (20 mM), K-aspartate (110 mM), MgCl2 (1 mM), MgATP (5 mM), HEPES (10 mM), EGTA (0.5 mM), NaGTP (0.1 mM) and Na2 phosphocreatine (5 mM) titrated to a pH of 7.2 with KOH.
The ultrarapid component of the delayed rectifier K+ current (IKur) was examined using a double-pulse protocol, consisting of a 100-msec depolarizing prepulse increasing to +40 mV from a holding potential of -50 mV, which was followed by 150-msec voltage steps from -40-+60 mV in 10-mV increments at room temperature to provide an adequate temporal resolution. IKur was measured as the 4-aminopyridine (1 mM)-sensitive current. The external solution contained NaCl (137 mM), KCl (5.4 mM), HEPES (10 mM), MgCl2 (0.5 mM), CaCl2 (1.8 mM) and glucose (10 mM) titrated to a pH of 7.4 with NaOH. The micropipettes were filled with a solution containing KCl (20 mM), K-aspartate (110 mM), MgCl2 (1 mM), MgATP (5 mM), HEPES (10 mM), EGTA (0.5 mM), NaGTP (0.1 mM) and Na2 phosphocreatine (5 mM) titrated to a pH of 7.2 with KOH.
The delayed rectifier K+ current (IKr-tail) was measured as the outward peak tail current density after 3 sec of prepulse increasing from a holding potential of -40 mV to a voltage between -40 and +60 mV in 10-mV steps at a 0.1-Hz frequency in the presence of chromanol 293B (30 µM) and CdCl2 (200 µM) in normal Tyrode's solution. The micropipettes were filled with a solution containing KCl (120 mM), MgCl2 (5 mM), CaCl2 (0.36 mM), EGTA (5 mM), HEPES (5 mM), glucose (5 mM), K2ATP (5 mM), Na2CrP (5 mM) and NaGTP (0.25 mM) adjusted to a pH of 7.2 with KOH.
Measurements of Ca2+ transients (Ca2+i) and intracellular Ca2+
Intracellular Ca2+ was measured in single LA myocytes, as described previously (26). In brief, LA myocytes were loaded with fluorescent Ca2+ (10 µM) fluo-3/AM for 30 min at room temperature. After intracellular hydrolysis of fluo-3/AM for 30 min, the excess extracellular dye was removed by changing the bath solution. Fluo-3 fluorescence was triggered using a 488-nm argon-ion laser line, with the emission recorded at >515 nm. The LA myocytes were repetitively scanned at 2-msec intervals for line scan imaging (8-bit). Fluorescence imaging was performed using a laser scanning confocal microscope (Zeiss LSM 510; Zeiss GmbH) and an inverted microscope (Axiovert 100; Zeiss GmbH). To exclude variations in the fluorescence intensity due to different volumes of injected dye and to correct for variations in dye concentrations, the fluorescent signals were calculated by normalizing the fluorescence (F) against the baseline fluorescence (F0); in this manner, reliable information was obtained on transient intracellular Ca2+ changes from baseline values [ΔF=(F-F0)/F0]. The intracellular Ca2+ changes, including transient Ca2+i, peak systolic Ca2+i and diastolic Ca2+i, were obtained during a 2-Hz field stimulation with 10-msec twice-threshold-strength square-wave pulses. Through the addition of 20 mM caffeine after electric stimulation at 2 Hz for at least 30 sec, the estimated sarcoplasmic reticulum (SR) Ca2+ content was measured as the total SR Ca2+ content from the peak amplitude of the caffeine induced Ca2+i.
Statistical analysis
All continuous variables are expressed as means ± standard deviations. Paired t test, one-way or two-way repeated-measures analysis of variance with the Bonferroni post hoc test was used to compare the difference between LA and RA or the effects of mirabegron on the LA and RA tissue preparations and isolated single myocytes. The McNemar test was used to compare the incidence of burst firing before and after drug administration in the LA and RA tissue preparations. P<0.05 was considered to indicate a statistically significant difference.
Results
Effects of mirabegron on atrial electric activity
As shown in Fig. 1, the baseline APA and RMP of the LA and RA were similar. However, the baseline APD20 and APD50 but not APD90 were shorter in the LA than in the RA. Mirabegron, at 0.1 and 1 µM (but not 0.01 µM), reduced the APD20 and APD50 of the LA, but it did not alter the APA, RMP, or APD90 of the LA at 0.01, 0.1, or 1 µM. Similarly, mirabegron at 0.1 and 1 µM (but not 0.01 µM), reduced the APD20 and APD50 of the RA, but it did not alter the APA, RMP, or APD90 of the RA at 0.01, 01, or 1 µM. Moreover, as shown in Fig. 2A, under mirabegron treatment at 0.1 and 1 µM (but not 0.01 µM), 20-Hz tachypacing induced burst firing in 7 of the 10 LAs (70% vs. 0% at baseline, P<0.05). By contrast, 20-Hz tachypacing did not induce burst firing in any of the 10 RAs under mirabegron treatment at 0.01, 01 and 1 µM. However, with the addition of KT5823 (1 µM), burst firing was suppressed in 5 of the 6 LAs (83.3% vs. 0% at baseline, P<0.05, Fig. 2B).
Effects of mirabegron on ionic currents and Ca2+ homeostasis
The present study compared baseline ICa-L and Ito in the LA and RA myocytes and found that the LA myocytes had a smaller ICa-L but a larger Ito than the RA myocytes (Fig. S1).
The effects of mirabegron on INa, ICa-L, Ito, IKur and IKr-tail in the LA myocytes were investigated. As shown in Fig. 3, INa in the LA myocytes remained unchanged after mirabegron (0.1 µM) treatment. Moreover, mirabegron (0.1 µM) significantly increased ICa-L in the LA myocytes (Fig. 4A). KT5823 (1 µM) pretreatment attenuated the effects of mirabegron on ICa-L (Fig. 4B). Additionally, as shown in Fig. 4C, mirabegron (0.1 µM) did not alter the voltage-dependent inactivation of ICa-L (-32.4±5.3 mV vs. -29.5±4.2 mV, P>0.05) and time constants of recovery from inactivation of ICa-L (40.5±21.4 msec vs. 53.1±13.4 msec, P>0.05).
As shown in Fig. 5, mirabegron (0.1 µM) significantly increased IKur but reduced Ito. Similarly, KT5823 (1 µM) pretreatment attenuated the effects of mirabegron on IKur and Ito. By contrast, IKr-tail in the LA myocytes remained unchanged after 0.1 µM mirabegron treatment (Fig. 6). Moreover, mirabegron (0.1 µM) increased Ca2+i and SR Ca2+ contents in the LA myocytes (Fig. 7).
To clarify whether mirabegron may have different ionic effects between RA and LA myocytes, the present study investigated the effects of mirabegron on ICa-L and Ito in the RA myocytes. In contrast to the effects of mirabegron on ICa-L and Ito in LA myocytes, mirabegron (0.1 µM) reduced ICa-L and did not alter Ito in RA myocytes (Fig. 8).
Discussion
The present study, for the first time to the best of the authors' knowledge, found that mirabegron significantly increased the inducibility of burst firing through tachypacing in the LA but not in the RA, suggesting that mirabegron differentially induces atrial arrhythmogenesis in the LA but not the RA. Moreover, the results indicated that KT5823, a cAMP-dependent protein kinase inhibitor, suppressed burst firing induced by 20-Hz tachypacing and mirabegron in the LA. These results suggested that the cAMP-dependent protein kinase pathway may serve a role in mirabegron-induced atrial arrhythmogenesis.
cAMP-dependent protein kinase phosphorylates several key intracellular Ca2+ regulatory proteins such as Ca2+ channels, sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), phospholamban (PLB), ryanodine receptor channel (RyR) and Na+/Ca2+ exchangers (NCXs). In particular, cAMP-dependent protein kinase activation increases PLB, RyR and NCX phosphorylation, resulting in Ca2+ dysregulation and arrhythmogenesis (11-13,27). In the whole-cell patch clamp experiments, mirabegron significantly increased ICa-L in the LA myocytes. A prolonged increase in ICa-L causes Ca2+ overload, which may contribute to arrhythmogenesis (28). Moreover, KT5823 pretreatment inhibited the effects of mirabegron on ICa-L in the LA myocytes in the current study and mirabegron significantly increased Ca2+i and SR Ca2+ content in these myocytes. Therefore, the findings indicated that mirabegron may change the electrophysiological characteristics of the LA and cause LA arrhythmogenesis by activating the cAMP-dependent protein kinase pathway and inducing Ca2+ dysregulation.
In the present study, mirabegron was found to accelerate LA and RA repolarization, which possibly reduces the effective refractory period, favoring the genesis of reentry (29). The results of the present study revealed that mirabegron significantly shortened the APD20 and APD50 but not APD90 of the LA and RA. In theory, APD20 and APD50 are affected by not only Ca2+ channels but also other ion channels, such as voltage-gated K+ channels (Ito and IKur). The present study found that mirabegron reduced ICa-L but did not alter Ito in the RA myocytes. By contrast, mirabegron significantly increased ICa-L but reduced Ito in the LA myocytes. These findings suggested that mirabegron affected the electrophysiological characteristics of the LA and RA differentially, ultimately leading to atrial arrhythmogenesis. The whole-cell patch clamp experiments demonstrated that mirabegron increased ICa-L and IKur but reduced Ito in the LA myocytes. These results suggested that the shortening of the APD20 and APD50 of the LA is mainly attributable to the composite effects of mirabegron on ICa-L, IKur and Ito. The results also indicated that mirabegron did not alter the APD90 of the LA and RA. Phase 3 repolarization occurs because of the time-dependent inactivation of ICa-L and activation of IKr-tail. The IKr-tail, rapid component of IKr-tail and slow component of IKr-tail all play major roles in phase 3 repolarization (30). In the current study, IKr-tail in the LA myocytes remained unchanged after mirabegron treatment and this unchanged IKr-tail was responsible for APD90 expression caused by mirabegron in the LA.
The present study had some limitations. First, it found that mirabegron has a direct electrophysiological effect on the LA (an AF substrate), suggesting that mirabegron possibly contributed to atrial arrhythmogenesis. However, simply investigating the acute effects of mirabegron may not reveal the complete mechanisms underlying the arrhythmogenesis induction caused by mirabegron. Chronic mirabegron treatment in patients with overactive bladder may result in the various electrophysiological effects involved in arrhythmogenesis. Second, in the present study, mirabegron increased ICa-L in the LA myocytes, whereas KT5823 suppressed this effect as well as arrhythmogenesis in the LA. It was also observed that mirabegron significantly increased Ca2+i and SR Ca2+ content, which may result in Ca2+ dysregulation. Therefore, mirabegron may induce LA arrhythmogenesis through Ca2+ overload induction and activation of cAMP-dependent protein kinase. Although acute mirabegron administration may not alter the expression of RyR, SERCA and PLB due to short experimental periods, it is not clear whether mirabegron may change the phosphorylation of RyR, SERCA and PLB, leading to Ca2+ dysregulation in the present study. The precise signaling pathways underlying mirabegron-induced LA arrhythmogenesis were not completely elucidated.
In conclusion, mirabegron differentially modulated the electrophysiological and arrhythmogenic effects 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, increasing AF risk in patients receiving mirabegron treatment.
Supplementary Material
Comparison of baseline ICa-L and Ito in the LA and RA myocytes. (A) Tracings and current-voltage relationship of ICa-L in the LA (n=11) and RA (n=12) myocytes. (B) Tracings and current-voltage relationship of Ito in the LA (n=9) and RA (n=10) myocytes. Insets in the current traces show various clamp protocols. *P<0.05, **P<0.01, ***P<0.005 compared with LA group at same mV. ICa-L, Ca2+ current; Ito, transient outward K+ current; LA, left atrium; RA, right atrium.
Acknowledgements
Not applicable.
Funding
Funding: This work was supported by the Ministry of Science and Technology of Taiwan (grant no. MOST 110-2314-B-038-126-MY2), Taipei Medical University-Taipei Medical University Hospital (grant no. 108TMU-TMUH-25), Taipei Medical University (grant no. TMU109-AE1-B29) and the Foundation for the Development of Internal Medicine in Okinawa (grant no. 03-009).
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding authors on reasonable request.
Authors' contributions
CC, YL and CH contributed to analyzing the experimental results and writing the manuscript. FL, CL and YCC contributed to the in vitro experiments and provided technical assistance. SH, SC and YJC contributed to conceiving and designing the study and reviewing the manuscript. CC and YCC confirm the authenticity of all the raw data. All authors read and approved the final manuscript.
Ethics approval and consent to participate
All the experimental procedures were approved by the Institutional Animal Care and Use Committee of Taipei Veterans General Hospital, Taipei, Taiwan (approval no. IACUC-2021-011). Furthermore, the experimental protocols conform to the institutional guideline for the care and use of laboratory animals and the Guide for the Care and Use of Laboratory Animals published by the United States National Institutes of Health.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
References
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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. | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
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 | |
|
Landstrom AP, Dobrev D and Wehrens XHT: Calcium signaling and cardiac arrhythmias. Circ Res. 120:1969–1993. 2017.PubMed/NCBI View Article : Google Scholar | |
|
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 | |
|
Grand AO: Cardiac ion channels. Circ Arrhythm Electrophysiol. 2:185–194. 2009.PubMed/NCBI View Article : Google Scholar |
