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Acehytisine suppresses atrial fibrillation in rats with dilated atria caused by chronic volume overload
Journal of Pharmacological Sciences xxx (xxxx) xxx
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Acehytisine suppresses atrial fibrillation in rats with dilated atria caused by chronic volume overload Xin Cao a, b, *, 1, Yoshinobu Nagasawa b, 1, Chengshun Zhang a, Hanxiao Zhang a, Megumi Aimoto b, Akira Takahara b, ** a Acupuncture and Tuina School/Third Teaching Hospital, Chengdu University of Traditional Chinese Medicine, 37 Shierqiao Road, Jinniu District, Chengdu 610075, Sichuan Province, China b Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 August 2019 Received in revised form 25 October 2019 Accepted 7 November 2019 Available online xxx
Atrial dilation is an independent risk factor for the development of atrial fibrillation (AF) and modulates the efficacy of anti-AF drugs, leading to the unsatisfactory control of AF. Pre-clinical studies showed antiAF effects of acehytisine, a multi-ion channel inhibitor, in atria without structural and/or electrophysiological abnormalities, but information is limited regarding its anti-AF efficacy in dilated atria. We evaluated anti-AF effects of acehytisine at 4 and 10 mg/kg intravenously infused over 10 min using 8week-old Wistar rats (n ¼ 5; male) with atrial dilation caused by aorto-venocaval shunt (AVS). Echocardiography showed that atria were enlarged by þ26.9% after one month of operation in AVS rats compared with sham-operated rats (n ¼ 4; male). Electrophysiological examinations indicated burst pacing-induced AF reached 206 s. Acehytisine at doses of 4 and 10 mg/kg decreased the duration of burst pacing-induced AF with prolongation of Wenckebach cycle length and P wave duration in a dosedependent manner. Importantly, the drug effectively terminated the persistent AF that was resistant to multiple programmed electrical stimulations in one rat. Therefore, these results provide in vivo evidence that acehytisine may be beneficial for preventing and terminating persistent AF in dilated atria. © 2019 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Keywords: Acehytisine Aorto-venocaval shunt Volume overload Atrial fibrillation Dilated atria
1. Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia with an estimated prevalence of 33.5 million individuals globally.1 Nonpharmacological (ablation) therapy is now improving, but effectiveness is imperfect and only a restricted number of patients can be treated.2 Available drug therapy for AF, particularly persistent AF, are less than optimal when considering efficacy, safety and tolerability.3 Ion channel inhibition in the atrium remains the principal strategy for termination of persistent AF and prevention of its recurrence. * Corresponding author. Acupuncture and Tuina School/Third Teaching Hospital, Chengdu University of Traditional Chinese Medicine, 37 Shierqiao Road, jinniu District, Chengdu 610075, Sichuan Province, China. Fax: þ86 28 61800000. ** Corresponding author. Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba, 2748510, Japan. Fax: þ81 47 472 3225. E-mail addresses: [email protected] (X. Cao), [email protected] (A. Takahara). Peer review under responsibility of Japanese Pharmacological Society. 1 Equally contributed.
Practical clinical experience indicates that multi-ion channel blockers are generally more optimal for AF compared to ion channel-selective blockers.4 Recent studies suggest that atrial selective Naþ channel blocker could lead to safe and effective suppression of AF and that concurrent inhibition of Kþ channel may potentiate this effect.4 Acehytisine (Fig. 1) is a multi-ion channel inhibitor, blocking Naþ (IC50 ¼ 48.48 mM), Kþ (IC50 ¼ 466 mM) and L-type Ca2þ currents by 23.5% at 250 mM.5e7 This drug has been approved for the treatment of paroxysmal supraventricular tachycardia in 2005 in China.8 The channeleinhibition profile was similar to that of propafenone, and the efficacy on terminating paroxysmal supraventricular tachycardia was also comparable to it in a double-blinded, randomized multi-center study.8 Animal studies revealed that acehytisine effectively terminated paroxysmal AF via its selective atrial Naþ inhibition in mongrel dogs without structural heart disease, which is induced by vagal stimulation and topical application of acetylcholine.9,10 Atrial dilation is an independent risk factor for atrial fibrillation. In clinical practice, most patients with persistent and/or permanent AF had structural heart disease with significant
https://doi.org/10.1016/j.jphs.2019.11.003 1347-8613/© 2019 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: Cao X et al., Acehytisine suppresses atrial fibrillation in rats with dilated atria caused by chronic volume overload, Journal of Pharmacological Sciences, https://doi.org/10.1016/j.jphs.2019.11.003
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of volume overload on cardiac structure and function. Echocardiography was performed with an ultrasound system (Noblus; Hitachi, Ltd., Tokyo, Japan), equipped with a 5.0e18.0 MHz of wideband frequency-fusion phase-array transducer. The heart was visualized at B mode from a parasternal long axis view. Left ventricular end-diastolic diameter (LVEdD), interventricular septal diastolic thickness, and left ventricle posterior wall diastolic thickness were measured at M-mode. Left ventricle ejection fraction and fractional shortening were calculated from the measurements of wall thickness and chamber diameters. The peak velocities of early diastolic filling wave (E) and atrial contraction wave (A) of left ventricle, and the left atrium major axis (LAMA) were measured from an apical four-chamber view. The E/A ratio was calculated with the E and A. 2.2. Electrophysiological testing
Fig. 1. Chemical structure of acehytisine.
electrical and structural remodeling, such as atrial dilation.11 The presence and severity of remodeling in AF patients can significantly modulate the efficacy and safety of anti-AF drugs, leading to the unsatisfactory control of AF, thus, it is imperative to develop new approach and medication for persistent AF control. Recently, we established a rat model to deliver long-term volume overload to the heart by aorto-venocaval shunt (AVS) operation, which is characterized by atrial dilation, hypertrophy and fibrosis with common pathophysiological changes to those patients with congestive heart failure and mitral valve disease.12 Since information is limited regarding the anti-AF effect of acehytisine on remodeled heart, we evaluated it in rats with AVS. 2. Materials and methods Experiments were performed by using 8-week-old male Wistar rats (n ¼ 9), weighing approximately 180e220 g (Sankyo Labo Service, Tokyo, Japan). Animals were kept at 23 ± 1 C under a 12-h lightedark cycle with free access to food and water (ad libitum). All experiments were approved by the Animal Research Committee for Animal Experimentation at Toho University (No. 17-51-359) and Chengdu University of Traditional Chinese Medicine (No. 2018-10) and performed in accordance with the Guidelines for the Care and Use of Laboratory Animal of Toho University and Chengdu University of Traditional Chinese Medicine. Briefly, rats were initially anesthetized with 2% isoflurane (Mylan Seiyaku, Osaka, Japan) vaporized with room air in a chamber. As soon as they lost their consciousness, they were immediately attached to the anesthetic machine with 2% isoflurane via mask. After opening the abdomen, anesthesia was maintained with 1.5% isoflurane, and rats in the AVS group (n ¼ 5) received fistulation between the abdominal aorta and inferior vena cava by an 18-gauge needle, as described previously.13 Rats in the sham group (n ¼ 4) underwent similar operation procedure, but did not receive a fistulation. 2.1. Echocardiography Four weeks later, all rats underwent transthoracic echocardiography under 1.5% isoflurane anesthesia to characterize the effects
After echocardiographic assessment, a tracheal cannula was inserted. Isoflurane of 1.5% vaporized with room air was inhaled with a volume-limited ventilator (SN-480-7; Shinano Manufacturing Co., Ltd., Tokyo, Japan). Tidal volume and respiratory rate were set at 10 mL/kg and 60 breaths/min, respectively. The surface lead II electrocardiogram was obtained from the limb electrodes. The right femoral vein was cannulated for drug administration, and the right femoral artery was cannulated for measurement of the blood pressure. Each measurement of electrocardiogram and blood pressure was the mean of nine recordings of consecutive complexes. An electrodes catheter (3 F, inter-electrode distance of 4 mm, SMC-304; Physio-Tech, Tokyo) was positioned at the septum of atrium via the right jugular vein. The heart was electrically driven with a stimulator (SEN-8203; Nihon Kohden, Tokyo, Japan) and an isolator with rectangular pulses (about 2 times of the diastolic threshold voltage and 3-ms width) (SS104J, Nihon Kohden). The effective refractory period of septum of atrium was assessed by a pacing protocol consisting of eleven beats of basal stimuli (S1) in cycle lengths of 120 ms (ERP (CL120 ms)) and 100 ms (ERP (CL100 ms)) followed by an extra stimulus (S2) of various coupling intervals. Atrioventricular node function was evaluated by measuring the Wenckebach cycle length (WCL), namely, stimulation cycle length at which atrioventricular block occurred by driving 4 s stimuli at various gradually decreased cycle lengths. Atrial tachyarrhythmia was induced by burst pacing (5 V output; 3-ms pulse width; 10-ms cycle length for 20 s) at the septum of atrium for 10 times. An episode of more than 3 continuous premature atrial contractions was regarded as an incidence of AF. AF duration was expressed as an average of the 10 times after burst pacing. If AF lasted more than 10 min, defibrillation was applied by programed stimulation and the duration of AF was defined as 10 min for data analysis. When defibrillation failed to terminate the AF, acehytisine was infused. After the basal control assessment, acehytisine at 4 mg/kg as therapeutic dose was infused over 10 min via the left femoral vein using an infusion pump (KD Scientific Inc, MA, USA), and each parameter was assessed as in basal control. Next, acehytisine at 10 mg/kg as supra-therapeutic dose was additionally infused over 10 min, and each parameter was similarly monitored. Acehytisine (Angene International, Ltd., Hong Kong) was dissolved in saline in concentrations of 2 and 5 mg/mL and administered intravenously at an infusion rate of 2 mL/kg per 10 min. The doses of acehytisine were determined by previous study.8 2.3. Statistical analysis All data are expressed as mean ± standard error of mean (S.E.M.). The statistical significances within a parameter were evaluated by one-way repeated-measures ANOVA followed by Contrasts for mean values comparison, whereas those between the
Please cite this article as: Cao X et al., Acehytisine suppresses atrial fibrillation in rats with dilated atria caused by chronic volume overload, Journal of Pharmacological Sciences, https://doi.org/10.1016/j.jphs.2019.11.003
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groups were analyzed by unpaired t-test. Logarithm transformations was used in AF duration analysis. A P-value less than 0.05 was considered statistically significant. 3. Results
In order to better characterize the effects of volume overload on cardiac structure and function, we compared the variables of cardiac structure and function in AVS rats with sham-operated ones (Table 1). LVEdD, E and A in the AVS group were increased when compared with sham group. Importantly, LAMA in the AVS group
Table 1 The effects of volume overload on cardiac structure and function.
Systolic function Diastolic function
was increased by 26.9% (Table 1). Typical trace showing increased LAMA in a AVS rat is depicted in Fig. 2.
3.2. Electrophysiological testing
3.1. Echocardiography
Structure
3
Parameters
Sham (n ¼ 4)
AVS (n ¼ 5)
LVEdD (mm) IVSd (mm) LVPWd (mm) LAMA (mm) EF (Teich) (%) %FS (%) E A E/A
6.45 ± 0.25 1.79 ± 0.08 1.78 ± 0.14 4.75 ± 0.17 89.69 ± 1.78 55.56 ± 2.69 0.93 ± 0.05 0.74 ± 0.02 1.26 ± 0.08
7.31 ± 0.10* 1.93 ± 0.05 2.13 ± 0.08 6.03 ± 0.21** 89.23 ± 1.47 55.03 ± 2.27 1.11 ± 0.05* 0.82 ± 0.01* 1.36 ± 0.05
Data are presented as mean ± S.E.M. *P < 0.05 vs. Sham, **P < 0.01 vs. Sham. AVS: aorto-venocaval shunt; LVEdD: left ventricular end-diastolic diameter; IVSd: interventricular septum diameter; LVPWd: left ventricular posterior wall thickness; LAMA: left atrium major axis; EF (Teich): ejection fraction assessed with Teichholz method; %FS: %fractional shortening; E: peak velocity of E-wave; A: peak velocity of A-wave; E/A: peak velocity of E-wave/peak velocity of A-wave; P values in each parameter were obtained by unpaired t-test.
Representative trace of anti-AF effect of pretreatment with acehytisine is depicted in Fig. 3, and the summary of anti-AF effect of pretreatment with acehytisine is shown in Fig. 4. The pre-drug control values of AF duration, WCL, ERP (CL120 ms) and ERP (CL100 ms) were 206 ± 112 s, 110 ± 4 ms, 47 ± 3 ms and 48 ± 3 ms, respectively. Pretreatment with acehytisine at 4 and 10 mg/kg reduced AF duration and prolonged WCL in a doserelated manner. Fig. 5 shows typical traces of electrocardiograms obtained before and after administration of 10 mg/kg of acehytisine in a AVS rat, and Fig. 6 summarizes the effects of acehytisine on heart rate, mean blood pressure, P wave duration, PR interval, QRS width and QT interval, of which the pre-drug control values were 317 ± 5 beats/min, 99 ± 4 mmHg, 19 ± 2 ms, 56 ± 3 ms, 17 ± 1 ms, and 87 ± 4 ms, respectively. Acehytisine at 4 mg/kg significantly decreased the heart rate and mean blood pressure. Acehytisine at 10 mg/kg increased the P wave duration, QRS width and QT interval in addition to the changes by 4 mg/kg. Typical trace is depicted in Fig. 7, showing conversion by acehytisine from persistent atrial fibrillation to sinus rhythm, which was resistant to electrical defibrillation. Burst pacing-induced AF lasted for more than 30 min by chance (n ¼ 1). Multiple defibrillations by programed stimulation were applied when AF lasted more than 10 min, but failed to terminate it. To investigate the effect of acehytisine on stopping AF, acehytisine at 10 mg/kg was infused and managed to terminate it.
Fig. 2. Typical echocardiography from apical four chamber view at 4 weeks after the surgery of aorto-venocaval shunt (AVS) in the sham (left) and AVS (right) rats. Both atria and ventricle were enlarged in the AVS rat. The left atrium major axis (LAMA) is 5.1 mm in sham rat and 6.6 mm in AVS rat. White arrows indicate the LAMA, which was measured three times (dashed line). LA: left atrium; RA: right atrium; LV: left ventricle; RV: right ventricle.
Please cite this article as: Cao X et al., Acehytisine suppresses atrial fibrillation in rats with dilated atria caused by chronic volume overload, Journal of Pharmacological Sciences, https://doi.org/10.1016/j.jphs.2019.11.003
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Fig. 3. Typical traces showing the effects of pretreatment with acehytisine (10 mg/kg) on burst-pacing induced atrial fibrillation (AF) in the electrocardiogram (ECG) in the AVS rat. Note that the duration of burst-pacing induced AF was 290 s at pre-drug control and decreased to 6 s after pretreatment with acehytisine (upper panel). Lower panel shows the magnification of conversion point from AF to sinus rhythm (SR). Black, grey and white bars show the duration of burst pacing, AF and SR, respectively.
Fig. 4. Effects of pretreatment with acehytisine at pre-drug control (white), 4 mg/kg (light grey) and 10 mg/kg (dark grey) on burst pacing-induced atrial fibrillation (AF), Wenckebach cycle length (WCL), the effective refractory periods at pacing cycle lengths of 120 (ERP (CL120 ms)) and 100 ms (ERP (CL100 ms)) in the AVS rats (n ¼ 5). Data are presented as the mean ± S.E.M. (n ¼ 5). Asterisks indicate statistically significant difference from the pre-drug control by P < 0.05. AVS: aorto-venocaval shunt.
4. Discussion In this study, atria were enlarged by 26.9% via volume overload of AVS and burst pacing-induced AF reached 206 s in volume overload-remodeled atria. Acehytisine suppressed the burst pacing-induced AF duration, prolonged WCL in a dose-related manner and terminated the persistent AF in an AVS rat, suggesting its effectiveness in preventing and terminating AF. Therefore, these results provide in vivo evidence that acehytisine may be beneficial in the treatment of certain form of AF in patients. In this study, atria were enlarged by 26.9% via volume overload of AVS and burst pacing-induced AF reached 206 s in volume overload remodeled atria, which was 16 times longer than that in
sham rats without atrial remodeling.14 This persistent AF could be ascribed to the structural remodeling of dilation partly, since large clinical trials have identified atrial dilation as an independent risk factor for the development of AF11 and volume overload-induced elongation of the cardiomyocytes, namely, increased mechanical stretch, led to calcium overload, oxidative stress, inflammation and release of different factors.15 In addition, volume overload-induced electrical remodeling is also a main contributor to this persistent AF. Our previous in vitro information showed a relative slower conduction velocity and a longer ERP,14 and in vivo information from our preliminary experiment indicated a longer P wave duration (19 ms vs. 15 ms) and QT interval (87 ms vs. 63 ms) in AVS rats than sham ones (n ¼ 3), suggesting the decrease in Naþ and Kþ
Please cite this article as: Cao X et al., Acehytisine suppresses atrial fibrillation in rats with dilated atria caused by chronic volume overload, Journal of Pharmacological Sciences, https://doi.org/10.1016/j.jphs.2019.11.003
X. Cao et al. / Journal of Pharmacological Sciences xxx (xxxx) xxx
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Fig. 5. Typical traces showing the surface lead II electrocardiogram (ECG) at pre-drug control (Control) (upper panels) and after the intravenous administration of acehytisine at 10 mg/kg (lower panels). At pre-drug control, heart rate (HR) and P wave duration were 316 bpm and 18 ms, respectively (upper panels). After administration of 10 mg/kg, HR was decreased to 222 bpm and P wave duration was prolonged to 36 ms (lower panels).
Fig. 6. Effects of pretreatment with acehytisine at pre-drug control (white), 4 mg/kg (light grey) and 10 mg/kg (dark grey) on heart rate, mean blood pressure (MBP), P wave duration, PR interval, QRS width and QT interval in the AVS rats (n ¼ 5). Data are presented as the mean ± S.E.M. (n ¼ 5). Asterisks indicate statistically significant difference from the pre-drug control by P < 0.05. AVS: aorto-venocaval shunt.
currents, which may promote reentry-based arrhythmias in AVS rats.16 This fundamental alteration in atrial structure and electrophysiology increases AF vulnerability,3,14 leading to the persistent AF in volume overload-remodeled atria.
Pretreatment with acehytisine decreased the AF duration in a dose-related manner. The mechanism may be its potent inhibitory on atrial Naþ current,17 since previous in vitro study showed that acehytisine selectively prolonged the atrial action potential in
Please cite this article as: Cao X et al., Acehytisine suppresses atrial fibrillation in rats with dilated atria caused by chronic volume overload, Journal of Pharmacological Sciences, https://doi.org/10.1016/j.jphs.2019.11.003
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Fig. 7. Typical traces of effects of acehytisine (10 mg/kg) on the burst pacing-induced persistent atrial fibrillation (AF) observed in right atrium (RA) electrogram and lead II electrocardiogram (ECG). Note that burst pacing-induced AF lasted for more than 30 min (upper panel). Multiple defibrillations by programed stimulation were applied, but failed to terminate it. Acehytisine at 10 mg/kg terminated the AF. Lower panel showed the magnification of conversion point from AF to sinus rhythm (SR). Black, grey, white and orange bars show the duration of burst pacing, AF, SR, and infusion of 10 mg/kg acehytisine, respectively.
rabbit by accelerating the rate of Naþ channel inactivation and delaying the course of channel opening.17 Further evidence is the significantly prolonged P wave duration in the AVS rats as shown in Fig. 6, supporting its inhibitory effect on the Naþ current.5 Similar anti-AF effect was observed by a Naþ inhibitor of pilsicainide in chronic atrioventricular block dogs which was also characterized by volume overload-induced atrial dilation. In that study, pilsicainide transdermal patch at 9.8 mg/kg delayed the inter-atrial conduction and decreased the AF duration without affecting the ERP as acehytisine.18 QRS width was also prolonged by acehytisine at the high dose, indicating its blockade action on ventricular Naþ channel. However, the extent of changes in P wave duration and QRS width was 28% and 11%, respectively, reflecting the more potent and selective inhibition on intra-atrial conduction than ventricular conduction.17 In addition, WCL was prolonged after pretreatment with acehytisine, revealing its potent inhibitory on Ca2þ current.6 This delay of atrioventricular conduction implies the strong rate control during AF. Importantly, sustained atrial fibrillation in a rat by chance, which lasted more than 30 min and was resistant to defibrillations by programed stimulation, was completely terminated by acute administration of acehytisine at 10 mg/kg, suggesting its efficacy in rhythm management for AF patients. These observations suggest that inhibition of the Naþ and Ca2þ currents by acehytisine5,6 led to the atrial and atrioventricular conduction delay in this in vivo model, implying its effectiveness in rhythm and rate control during AF management (Fig. 8). Out of our expectation, acehytisine hardly altered ERP, though it was reported to prolong ERP in un-remodeled atria of mongrel dogs induced by vagal stimulation and topical application of acetylcholine.9,10 The reason for lack of ERP prolongation may be its
Fig. 8. A schematic summary of acehytisine on dilated atria. Inhibition of the Naþ and Caþ currents by acehytisine5,6 led to the atrial and atrioventricular conduction delay in this in vivo model, implying its effectiveness in rhythm and rate control during atrial fibrillation (AF) management.
alteration in atrial electrophysiology by volume overload.14 Similar phenomenon was observed in goats with remodeled atria that dofetilide and ibutilide, two agents that selectively and potently block the rapid delayed rectifying Kþ current, partly lost their potential to increase atrial refractoriness.19
Please cite this article as: Cao X et al., Acehytisine suppresses atrial fibrillation in rats with dilated atria caused by chronic volume overload, Journal of Pharmacological Sciences, https://doi.org/10.1016/j.jphs.2019.11.003
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5. Conclusion In conclusion, acehytisine can be considered to be a promising candidate for preventing and terminating persistent AF in remodeled hearts. Modulation of multi-ion channel by acehytisine may become a new pharmacological strategy for rhythm and rate control in AF patients with structural heart disease. Declaration of Competing Interest The authors declare no conflicts of interest. Acknowledgements This study was supported in part by Grant-in-aid for research activity start-up (17H07135), the National Natural Science Foundation of China (81704187), Sichuan Science and Technology Program (2019YJ0587), Sichuan Academy of Medical Sciences & Sichuan People's Hospital Research Fund (2018ZX05). We thank Ms. Riho Murai for her technical assistance. References 1. Bhatia S, Sugrue A, Asirvatham S. Atrial fibrillation: beyond rate control. Mayo Clin Proc. 2018;93:373e380. 2. Ha AC, Wijeysundera HC, Birnie DH, Verma A. Real-world outcomes, complications, and cost of catheter-based ablation for atrial fibrillation: an update. Curr Opin Cardiol. 2017;32:47e52. 3. Calvo D, Filgueiras-Rama D, Jalife J. Mechanisms and drug development in atrial fibrillation. Pharmacol Rev. 2018;70:505e525. 4. Burashnikov A, Antzelevitch C. Novel pharmacological targets for the rhythm control management of atrial fibrillation. Pharmacol Ther. 2011;132:300e313. 5. Jin SS, Guo Q, Xu J, Yu P, Liu JH, Tang YQ. Antiarrhythmic ionic mechanism of Guanfu base A-Selective inhibition of late sodium current in isolated ventricular myocytes from Guinea pigs. Chin J Nat Med. 2015;13:361e367.
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6. Gao X, Pu JL, Yang YM, Wu H, Huang A, Shi SY. Effects of guanfu base A hydrochloride on heart L-type calcium channel of rat ventricular myocytes. Chin J New Drugs. 2006;15:1926e1929. 7. Huang X, Yang Y, Zhu J, Dai Y, Pu J. The effects of a novel anti-arrhythmic drug, acehytisine hydrochloride, on the human ether-a-go-go related gene K channel and its trafficking. Basic Clin Pharmacol Toxicol. 2009;104:145e154. 8. Gao X, Zhu J, Yang YM, Li JD, Yang ZM, Liu JH. Efficacy of intravenous acehytisine hydrochloride versus propafenone on terminating paroxysmal supraventricular tachycardia: a double-blinded, randomized multi-center study. Zhonghua Xinxueguanbing Zazhi. 2007;35:151e154. 9. Dong YL, Chen WZ. Effects of guan-fu base A on experimental cardiac arrhythmias and myocardial contractility. Yao Xue Xue Bao. 1995;30:577e582. 10. Wang M, Zhu J, Yang YM, Li CR, Tian Y, Chen XS. Effects of acehytisine hydrochloride on vagotonic atrial fibrillation in mongrel dogs. Chin J Cardiac Pacing Electrophysiol. 2008;22:148e152. 11. Psaty BM, Manolio TA, Kuller LH, et al. Incidence of and risk factors for atrial fibrillation in older adults. Circulation. 1997;96:2455e2461. 12. Treskatsch S, Feldheiser A, Rosin AT, et al. A modified approach to induce predictable congestive heart failure by volume overload in rats. PLoS One. 2014;9, e87531. 13. Garcia R, Diebold S. Simple, rapid, and effective method of producing aortocaval shunts in the rat. Cardiovasc Res. 1990;24:430e432. 14. Cao X, Aimoto M, Fukumoto M, Nagasawa Y, Tanaka H, Takahara A. Influence of chronic volume overload-induced atrial remodeling on electrophysiological responses to cholinergic receptor stimulation in the isolated rat atria. J Pharmacol Sci. 2018;136:73e78. 15. De Jong AM, Maass AH, Oberdorf-Maass SU, Van Veldhuisen DJ, Van Gilst WH, Van Gelder IC. Mechanisms of atrial structural changes caused by stretch occurring before and during early atrial fibrillation. Cardiovasc Res. 2011;89: 754e765. 16. Hamaguchi S, Tsuneoka Y, Tanaka A, et al. Manifestation of automaticity in the pulmonary-vein myocardium of rats with abdominal aorto-venocaval shunt. J Pharmacol Sci. 2015;128:212e215. 17. Fan X, Wang C, Wang N, et al. Atrial-selective block of sodium channels by acehytisine in rabbit myocardium. J Pharmacol Sci. 2016;132:235e243. 18. Iwasaki H, Takahara A, Nakamura Y, et al. Simultaneous assessment of pharmacokinetics of pilsicainide transdermal patch and its electropharmacological effects on atria of chronic atrioventricular block dogs. J Pharmacol Sci. 2009;110:410e414. €gelein H, Tieleman RG, van Hunnik A, Schotten U, Allessie MA. 19. Blaauw Y, Go ‘Early’ class III drugs for the treatment of atrial fibrillation. Efficacy and atrial selectivity of AVE0118 in remodeled atria of the goat. Circulation. 2004;110: 1717e1724.
Please cite this article as: Cao X et al., Acehytisine suppresses atrial fibrillation in rats with dilated atria caused by chronic volume overload, Journal of Pharmacological Sciences, https://doi.org/10.1016/j.jphs.2019.11.003
Contents lists available at ScienceDirect
Journal of Pharmacological Sciences journal homepage: www.elsevier.com/locate/jphs
Full Paper
Acehytisine suppresses atrial fibrillation in rats with dilated atria caused by chronic volume overload Xin Cao a, b, *, 1, Yoshinobu Nagasawa b, 1, Chengshun Zhang a, Hanxiao Zhang a, Megumi Aimoto b, Akira Takahara b, ** a Acupuncture and Tuina School/Third Teaching Hospital, Chengdu University of Traditional Chinese Medicine, 37 Shierqiao Road, Jinniu District, Chengdu 610075, Sichuan Province, China b Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 August 2019 Received in revised form 25 October 2019 Accepted 7 November 2019 Available online xxx
Atrial dilation is an independent risk factor for the development of atrial fibrillation (AF) and modulates the efficacy of anti-AF drugs, leading to the unsatisfactory control of AF. Pre-clinical studies showed antiAF effects of acehytisine, a multi-ion channel inhibitor, in atria without structural and/or electrophysiological abnormalities, but information is limited regarding its anti-AF efficacy in dilated atria. We evaluated anti-AF effects of acehytisine at 4 and 10 mg/kg intravenously infused over 10 min using 8week-old Wistar rats (n ¼ 5; male) with atrial dilation caused by aorto-venocaval shunt (AVS). Echocardiography showed that atria were enlarged by þ26.9% after one month of operation in AVS rats compared with sham-operated rats (n ¼ 4; male). Electrophysiological examinations indicated burst pacing-induced AF reached 206 s. Acehytisine at doses of 4 and 10 mg/kg decreased the duration of burst pacing-induced AF with prolongation of Wenckebach cycle length and P wave duration in a dosedependent manner. Importantly, the drug effectively terminated the persistent AF that was resistant to multiple programmed electrical stimulations in one rat. Therefore, these results provide in vivo evidence that acehytisine may be beneficial for preventing and terminating persistent AF in dilated atria. © 2019 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Keywords: Acehytisine Aorto-venocaval shunt Volume overload Atrial fibrillation Dilated atria
1. Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia with an estimated prevalence of 33.5 million individuals globally.1 Nonpharmacological (ablation) therapy is now improving, but effectiveness is imperfect and only a restricted number of patients can be treated.2 Available drug therapy for AF, particularly persistent AF, are less than optimal when considering efficacy, safety and tolerability.3 Ion channel inhibition in the atrium remains the principal strategy for termination of persistent AF and prevention of its recurrence. * Corresponding author. Acupuncture and Tuina School/Third Teaching Hospital, Chengdu University of Traditional Chinese Medicine, 37 Shierqiao Road, jinniu District, Chengdu 610075, Sichuan Province, China. Fax: þ86 28 61800000. ** Corresponding author. Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba, 2748510, Japan. Fax: þ81 47 472 3225. E-mail addresses: [email protected] (X. Cao), [email protected] (A. Takahara). Peer review under responsibility of Japanese Pharmacological Society. 1 Equally contributed.
Practical clinical experience indicates that multi-ion channel blockers are generally more optimal for AF compared to ion channel-selective blockers.4 Recent studies suggest that atrial selective Naþ channel blocker could lead to safe and effective suppression of AF and that concurrent inhibition of Kþ channel may potentiate this effect.4 Acehytisine (Fig. 1) is a multi-ion channel inhibitor, blocking Naþ (IC50 ¼ 48.48 mM), Kþ (IC50 ¼ 466 mM) and L-type Ca2þ currents by 23.5% at 250 mM.5e7 This drug has been approved for the treatment of paroxysmal supraventricular tachycardia in 2005 in China.8 The channeleinhibition profile was similar to that of propafenone, and the efficacy on terminating paroxysmal supraventricular tachycardia was also comparable to it in a double-blinded, randomized multi-center study.8 Animal studies revealed that acehytisine effectively terminated paroxysmal AF via its selective atrial Naþ inhibition in mongrel dogs without structural heart disease, which is induced by vagal stimulation and topical application of acetylcholine.9,10 Atrial dilation is an independent risk factor for atrial fibrillation. In clinical practice, most patients with persistent and/or permanent AF had structural heart disease with significant
https://doi.org/10.1016/j.jphs.2019.11.003 1347-8613/© 2019 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: Cao X et al., Acehytisine suppresses atrial fibrillation in rats with dilated atria caused by chronic volume overload, Journal of Pharmacological Sciences, https://doi.org/10.1016/j.jphs.2019.11.003
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of volume overload on cardiac structure and function. Echocardiography was performed with an ultrasound system (Noblus; Hitachi, Ltd., Tokyo, Japan), equipped with a 5.0e18.0 MHz of wideband frequency-fusion phase-array transducer. The heart was visualized at B mode from a parasternal long axis view. Left ventricular end-diastolic diameter (LVEdD), interventricular septal diastolic thickness, and left ventricle posterior wall diastolic thickness were measured at M-mode. Left ventricle ejection fraction and fractional shortening were calculated from the measurements of wall thickness and chamber diameters. The peak velocities of early diastolic filling wave (E) and atrial contraction wave (A) of left ventricle, and the left atrium major axis (LAMA) were measured from an apical four-chamber view. The E/A ratio was calculated with the E and A. 2.2. Electrophysiological testing
Fig. 1. Chemical structure of acehytisine.
electrical and structural remodeling, such as atrial dilation.11 The presence and severity of remodeling in AF patients can significantly modulate the efficacy and safety of anti-AF drugs, leading to the unsatisfactory control of AF, thus, it is imperative to develop new approach and medication for persistent AF control. Recently, we established a rat model to deliver long-term volume overload to the heart by aorto-venocaval shunt (AVS) operation, which is characterized by atrial dilation, hypertrophy and fibrosis with common pathophysiological changes to those patients with congestive heart failure and mitral valve disease.12 Since information is limited regarding the anti-AF effect of acehytisine on remodeled heart, we evaluated it in rats with AVS. 2. Materials and methods Experiments were performed by using 8-week-old male Wistar rats (n ¼ 9), weighing approximately 180e220 g (Sankyo Labo Service, Tokyo, Japan). Animals were kept at 23 ± 1 C under a 12-h lightedark cycle with free access to food and water (ad libitum). All experiments were approved by the Animal Research Committee for Animal Experimentation at Toho University (No. 17-51-359) and Chengdu University of Traditional Chinese Medicine (No. 2018-10) and performed in accordance with the Guidelines for the Care and Use of Laboratory Animal of Toho University and Chengdu University of Traditional Chinese Medicine. Briefly, rats were initially anesthetized with 2% isoflurane (Mylan Seiyaku, Osaka, Japan) vaporized with room air in a chamber. As soon as they lost their consciousness, they were immediately attached to the anesthetic machine with 2% isoflurane via mask. After opening the abdomen, anesthesia was maintained with 1.5% isoflurane, and rats in the AVS group (n ¼ 5) received fistulation between the abdominal aorta and inferior vena cava by an 18-gauge needle, as described previously.13 Rats in the sham group (n ¼ 4) underwent similar operation procedure, but did not receive a fistulation. 2.1. Echocardiography Four weeks later, all rats underwent transthoracic echocardiography under 1.5% isoflurane anesthesia to characterize the effects
After echocardiographic assessment, a tracheal cannula was inserted. Isoflurane of 1.5% vaporized with room air was inhaled with a volume-limited ventilator (SN-480-7; Shinano Manufacturing Co., Ltd., Tokyo, Japan). Tidal volume and respiratory rate were set at 10 mL/kg and 60 breaths/min, respectively. The surface lead II electrocardiogram was obtained from the limb electrodes. The right femoral vein was cannulated for drug administration, and the right femoral artery was cannulated for measurement of the blood pressure. Each measurement of electrocardiogram and blood pressure was the mean of nine recordings of consecutive complexes. An electrodes catheter (3 F, inter-electrode distance of 4 mm, SMC-304; Physio-Tech, Tokyo) was positioned at the septum of atrium via the right jugular vein. The heart was electrically driven with a stimulator (SEN-8203; Nihon Kohden, Tokyo, Japan) and an isolator with rectangular pulses (about 2 times of the diastolic threshold voltage and 3-ms width) (SS104J, Nihon Kohden). The effective refractory period of septum of atrium was assessed by a pacing protocol consisting of eleven beats of basal stimuli (S1) in cycle lengths of 120 ms (ERP (CL120 ms)) and 100 ms (ERP (CL100 ms)) followed by an extra stimulus (S2) of various coupling intervals. Atrioventricular node function was evaluated by measuring the Wenckebach cycle length (WCL), namely, stimulation cycle length at which atrioventricular block occurred by driving 4 s stimuli at various gradually decreased cycle lengths. Atrial tachyarrhythmia was induced by burst pacing (5 V output; 3-ms pulse width; 10-ms cycle length for 20 s) at the septum of atrium for 10 times. An episode of more than 3 continuous premature atrial contractions was regarded as an incidence of AF. AF duration was expressed as an average of the 10 times after burst pacing. If AF lasted more than 10 min, defibrillation was applied by programed stimulation and the duration of AF was defined as 10 min for data analysis. When defibrillation failed to terminate the AF, acehytisine was infused. After the basal control assessment, acehytisine at 4 mg/kg as therapeutic dose was infused over 10 min via the left femoral vein using an infusion pump (KD Scientific Inc, MA, USA), and each parameter was assessed as in basal control. Next, acehytisine at 10 mg/kg as supra-therapeutic dose was additionally infused over 10 min, and each parameter was similarly monitored. Acehytisine (Angene International, Ltd., Hong Kong) was dissolved in saline in concentrations of 2 and 5 mg/mL and administered intravenously at an infusion rate of 2 mL/kg per 10 min. The doses of acehytisine were determined by previous study.8 2.3. Statistical analysis All data are expressed as mean ± standard error of mean (S.E.M.). The statistical significances within a parameter were evaluated by one-way repeated-measures ANOVA followed by Contrasts for mean values comparison, whereas those between the
Please cite this article as: Cao X et al., Acehytisine suppresses atrial fibrillation in rats with dilated atria caused by chronic volume overload, Journal of Pharmacological Sciences, https://doi.org/10.1016/j.jphs.2019.11.003
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groups were analyzed by unpaired t-test. Logarithm transformations was used in AF duration analysis. A P-value less than 0.05 was considered statistically significant. 3. Results
In order to better characterize the effects of volume overload on cardiac structure and function, we compared the variables of cardiac structure and function in AVS rats with sham-operated ones (Table 1). LVEdD, E and A in the AVS group were increased when compared with sham group. Importantly, LAMA in the AVS group
Table 1 The effects of volume overload on cardiac structure and function.
Systolic function Diastolic function
was increased by 26.9% (Table 1). Typical trace showing increased LAMA in a AVS rat is depicted in Fig. 2.
3.2. Electrophysiological testing
3.1. Echocardiography
Structure
3
Parameters
Sham (n ¼ 4)
AVS (n ¼ 5)
LVEdD (mm) IVSd (mm) LVPWd (mm) LAMA (mm) EF (Teich) (%) %FS (%) E A E/A
6.45 ± 0.25 1.79 ± 0.08 1.78 ± 0.14 4.75 ± 0.17 89.69 ± 1.78 55.56 ± 2.69 0.93 ± 0.05 0.74 ± 0.02 1.26 ± 0.08
7.31 ± 0.10* 1.93 ± 0.05 2.13 ± 0.08 6.03 ± 0.21** 89.23 ± 1.47 55.03 ± 2.27 1.11 ± 0.05* 0.82 ± 0.01* 1.36 ± 0.05
Data are presented as mean ± S.E.M. *P < 0.05 vs. Sham, **P < 0.01 vs. Sham. AVS: aorto-venocaval shunt; LVEdD: left ventricular end-diastolic diameter; IVSd: interventricular septum diameter; LVPWd: left ventricular posterior wall thickness; LAMA: left atrium major axis; EF (Teich): ejection fraction assessed with Teichholz method; %FS: %fractional shortening; E: peak velocity of E-wave; A: peak velocity of A-wave; E/A: peak velocity of E-wave/peak velocity of A-wave; P values in each parameter were obtained by unpaired t-test.
Representative trace of anti-AF effect of pretreatment with acehytisine is depicted in Fig. 3, and the summary of anti-AF effect of pretreatment with acehytisine is shown in Fig. 4. The pre-drug control values of AF duration, WCL, ERP (CL120 ms) and ERP (CL100 ms) were 206 ± 112 s, 110 ± 4 ms, 47 ± 3 ms and 48 ± 3 ms, respectively. Pretreatment with acehytisine at 4 and 10 mg/kg reduced AF duration and prolonged WCL in a doserelated manner. Fig. 5 shows typical traces of electrocardiograms obtained before and after administration of 10 mg/kg of acehytisine in a AVS rat, and Fig. 6 summarizes the effects of acehytisine on heart rate, mean blood pressure, P wave duration, PR interval, QRS width and QT interval, of which the pre-drug control values were 317 ± 5 beats/min, 99 ± 4 mmHg, 19 ± 2 ms, 56 ± 3 ms, 17 ± 1 ms, and 87 ± 4 ms, respectively. Acehytisine at 4 mg/kg significantly decreased the heart rate and mean blood pressure. Acehytisine at 10 mg/kg increased the P wave duration, QRS width and QT interval in addition to the changes by 4 mg/kg. Typical trace is depicted in Fig. 7, showing conversion by acehytisine from persistent atrial fibrillation to sinus rhythm, which was resistant to electrical defibrillation. Burst pacing-induced AF lasted for more than 30 min by chance (n ¼ 1). Multiple defibrillations by programed stimulation were applied when AF lasted more than 10 min, but failed to terminate it. To investigate the effect of acehytisine on stopping AF, acehytisine at 10 mg/kg was infused and managed to terminate it.
Fig. 2. Typical echocardiography from apical four chamber view at 4 weeks after the surgery of aorto-venocaval shunt (AVS) in the sham (left) and AVS (right) rats. Both atria and ventricle were enlarged in the AVS rat. The left atrium major axis (LAMA) is 5.1 mm in sham rat and 6.6 mm in AVS rat. White arrows indicate the LAMA, which was measured three times (dashed line). LA: left atrium; RA: right atrium; LV: left ventricle; RV: right ventricle.
Please cite this article as: Cao X et al., Acehytisine suppresses atrial fibrillation in rats with dilated atria caused by chronic volume overload, Journal of Pharmacological Sciences, https://doi.org/10.1016/j.jphs.2019.11.003
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Fig. 3. Typical traces showing the effects of pretreatment with acehytisine (10 mg/kg) on burst-pacing induced atrial fibrillation (AF) in the electrocardiogram (ECG) in the AVS rat. Note that the duration of burst-pacing induced AF was 290 s at pre-drug control and decreased to 6 s after pretreatment with acehytisine (upper panel). Lower panel shows the magnification of conversion point from AF to sinus rhythm (SR). Black, grey and white bars show the duration of burst pacing, AF and SR, respectively.
Fig. 4. Effects of pretreatment with acehytisine at pre-drug control (white), 4 mg/kg (light grey) and 10 mg/kg (dark grey) on burst pacing-induced atrial fibrillation (AF), Wenckebach cycle length (WCL), the effective refractory periods at pacing cycle lengths of 120 (ERP (CL120 ms)) and 100 ms (ERP (CL100 ms)) in the AVS rats (n ¼ 5). Data are presented as the mean ± S.E.M. (n ¼ 5). Asterisks indicate statistically significant difference from the pre-drug control by P < 0.05. AVS: aorto-venocaval shunt.
4. Discussion In this study, atria were enlarged by 26.9% via volume overload of AVS and burst pacing-induced AF reached 206 s in volume overload-remodeled atria. Acehytisine suppressed the burst pacing-induced AF duration, prolonged WCL in a dose-related manner and terminated the persistent AF in an AVS rat, suggesting its effectiveness in preventing and terminating AF. Therefore, these results provide in vivo evidence that acehytisine may be beneficial in the treatment of certain form of AF in patients. In this study, atria were enlarged by 26.9% via volume overload of AVS and burst pacing-induced AF reached 206 s in volume overload remodeled atria, which was 16 times longer than that in
sham rats without atrial remodeling.14 This persistent AF could be ascribed to the structural remodeling of dilation partly, since large clinical trials have identified atrial dilation as an independent risk factor for the development of AF11 and volume overload-induced elongation of the cardiomyocytes, namely, increased mechanical stretch, led to calcium overload, oxidative stress, inflammation and release of different factors.15 In addition, volume overload-induced electrical remodeling is also a main contributor to this persistent AF. Our previous in vitro information showed a relative slower conduction velocity and a longer ERP,14 and in vivo information from our preliminary experiment indicated a longer P wave duration (19 ms vs. 15 ms) and QT interval (87 ms vs. 63 ms) in AVS rats than sham ones (n ¼ 3), suggesting the decrease in Naþ and Kþ
Please cite this article as: Cao X et al., Acehytisine suppresses atrial fibrillation in rats with dilated atria caused by chronic volume overload, Journal of Pharmacological Sciences, https://doi.org/10.1016/j.jphs.2019.11.003
X. Cao et al. / Journal of Pharmacological Sciences xxx (xxxx) xxx
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Fig. 5. Typical traces showing the surface lead II electrocardiogram (ECG) at pre-drug control (Control) (upper panels) and after the intravenous administration of acehytisine at 10 mg/kg (lower panels). At pre-drug control, heart rate (HR) and P wave duration were 316 bpm and 18 ms, respectively (upper panels). After administration of 10 mg/kg, HR was decreased to 222 bpm and P wave duration was prolonged to 36 ms (lower panels).
Fig. 6. Effects of pretreatment with acehytisine at pre-drug control (white), 4 mg/kg (light grey) and 10 mg/kg (dark grey) on heart rate, mean blood pressure (MBP), P wave duration, PR interval, QRS width and QT interval in the AVS rats (n ¼ 5). Data are presented as the mean ± S.E.M. (n ¼ 5). Asterisks indicate statistically significant difference from the pre-drug control by P < 0.05. AVS: aorto-venocaval shunt.
currents, which may promote reentry-based arrhythmias in AVS rats.16 This fundamental alteration in atrial structure and electrophysiology increases AF vulnerability,3,14 leading to the persistent AF in volume overload-remodeled atria.
Pretreatment with acehytisine decreased the AF duration in a dose-related manner. The mechanism may be its potent inhibitory on atrial Naþ current,17 since previous in vitro study showed that acehytisine selectively prolonged the atrial action potential in
Please cite this article as: Cao X et al., Acehytisine suppresses atrial fibrillation in rats with dilated atria caused by chronic volume overload, Journal of Pharmacological Sciences, https://doi.org/10.1016/j.jphs.2019.11.003
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Fig. 7. Typical traces of effects of acehytisine (10 mg/kg) on the burst pacing-induced persistent atrial fibrillation (AF) observed in right atrium (RA) electrogram and lead II electrocardiogram (ECG). Note that burst pacing-induced AF lasted for more than 30 min (upper panel). Multiple defibrillations by programed stimulation were applied, but failed to terminate it. Acehytisine at 10 mg/kg terminated the AF. Lower panel showed the magnification of conversion point from AF to sinus rhythm (SR). Black, grey, white and orange bars show the duration of burst pacing, AF, SR, and infusion of 10 mg/kg acehytisine, respectively.
rabbit by accelerating the rate of Naþ channel inactivation and delaying the course of channel opening.17 Further evidence is the significantly prolonged P wave duration in the AVS rats as shown in Fig. 6, supporting its inhibitory effect on the Naþ current.5 Similar anti-AF effect was observed by a Naþ inhibitor of pilsicainide in chronic atrioventricular block dogs which was also characterized by volume overload-induced atrial dilation. In that study, pilsicainide transdermal patch at 9.8 mg/kg delayed the inter-atrial conduction and decreased the AF duration without affecting the ERP as acehytisine.18 QRS width was also prolonged by acehytisine at the high dose, indicating its blockade action on ventricular Naþ channel. However, the extent of changes in P wave duration and QRS width was 28% and 11%, respectively, reflecting the more potent and selective inhibition on intra-atrial conduction than ventricular conduction.17 In addition, WCL was prolonged after pretreatment with acehytisine, revealing its potent inhibitory on Ca2þ current.6 This delay of atrioventricular conduction implies the strong rate control during AF. Importantly, sustained atrial fibrillation in a rat by chance, which lasted more than 30 min and was resistant to defibrillations by programed stimulation, was completely terminated by acute administration of acehytisine at 10 mg/kg, suggesting its efficacy in rhythm management for AF patients. These observations suggest that inhibition of the Naþ and Ca2þ currents by acehytisine5,6 led to the atrial and atrioventricular conduction delay in this in vivo model, implying its effectiveness in rhythm and rate control during AF management (Fig. 8). Out of our expectation, acehytisine hardly altered ERP, though it was reported to prolong ERP in un-remodeled atria of mongrel dogs induced by vagal stimulation and topical application of acetylcholine.9,10 The reason for lack of ERP prolongation may be its
Fig. 8. A schematic summary of acehytisine on dilated atria. Inhibition of the Naþ and Caþ currents by acehytisine5,6 led to the atrial and atrioventricular conduction delay in this in vivo model, implying its effectiveness in rhythm and rate control during atrial fibrillation (AF) management.
alteration in atrial electrophysiology by volume overload.14 Similar phenomenon was observed in goats with remodeled atria that dofetilide and ibutilide, two agents that selectively and potently block the rapid delayed rectifying Kþ current, partly lost their potential to increase atrial refractoriness.19
Please cite this article as: Cao X et al., Acehytisine suppresses atrial fibrillation in rats with dilated atria caused by chronic volume overload, Journal of Pharmacological Sciences, https://doi.org/10.1016/j.jphs.2019.11.003
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5. Conclusion In conclusion, acehytisine can be considered to be a promising candidate for preventing and terminating persistent AF in remodeled hearts. Modulation of multi-ion channel by acehytisine may become a new pharmacological strategy for rhythm and rate control in AF patients with structural heart disease. Declaration of Competing Interest The authors declare no conflicts of interest. Acknowledgements This study was supported in part by Grant-in-aid for research activity start-up (17H07135), the National Natural Science Foundation of China (81704187), Sichuan Science and Technology Program (2019YJ0587), Sichuan Academy of Medical Sciences & Sichuan People's Hospital Research Fund (2018ZX05). We thank Ms. Riho Murai for her technical assistance. References 1. Bhatia S, Sugrue A, Asirvatham S. Atrial fibrillation: beyond rate control. Mayo Clin Proc. 2018;93:373e380. 2. Ha AC, Wijeysundera HC, Birnie DH, Verma A. Real-world outcomes, complications, and cost of catheter-based ablation for atrial fibrillation: an update. Curr Opin Cardiol. 2017;32:47e52. 3. Calvo D, Filgueiras-Rama D, Jalife J. Mechanisms and drug development in atrial fibrillation. Pharmacol Rev. 2018;70:505e525. 4. Burashnikov A, Antzelevitch C. Novel pharmacological targets for the rhythm control management of atrial fibrillation. Pharmacol Ther. 2011;132:300e313. 5. Jin SS, Guo Q, Xu J, Yu P, Liu JH, Tang YQ. Antiarrhythmic ionic mechanism of Guanfu base A-Selective inhibition of late sodium current in isolated ventricular myocytes from Guinea pigs. Chin J Nat Med. 2015;13:361e367.
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Please cite this article as: Cao X et al., Acehytisine suppresses atrial fibrillation in rats with dilated atria caused by chronic volume overload, Journal of Pharmacological Sciences, https://doi.org/10.1016/j.jphs.2019.11.003