Abstract
Background
Zhigancao decoction (ZD) has a long history in China as a traditional Chinese medicine compound for the treatment of tachyarrhythmias. This study mainly explored the pharmacological mechanism of Zhigancao Decoction in preventing atrial fibrillation by altering the electrical and structural remodeling of the atrial in rabbits.
Methods
In total, 30 male New Zealand white rabbits were randomly divided into 3 groups (ten rabbits for each). The first group was sham-operated (control group). The second group was intervened by the rapid right atrium pacing (RAP) to induce atrial fibrillation (AF group), while the third group was given ZD gavage and RAP (AF + ZD group). All rabbits were anesthetized before two monophasic action potential (MAP) catheters were sequentially inserted into the right atrium. After 8 h of rapid right atrial pacing, the electrophysiological indexes and the induction rate of atrial fibrillation were observed in the three groups of rabbits, and the left atrial myocardium samples were taken to observe the ultrastructure. Single atrial myocytes were separated by enzymolysis, and the L-type calcium current (ICa-L) of atrial myocytes in different experimental groups was observed by whole-cell patch clamp technique. The fluorescence intensity of Ca2+ in atrial myocytes was observed after Fluo-3/AM fluorescent staining. The main components of ZD were identified by liquid chromatography-mass spectrometry-mass spectrometry (LC–MS/MS) method.
Results
Compared with the AF group, the maximum ascent rate (Max dV/dt) and plateau potential were significantly reduced in the ZD group, the action potential duration at 10% and 20% (APD10, APD20) were significantly shortened (P < 0.01), action potential duration at 50%, 70%, and 90% (APD50, APD70, APD90) were significantly prolonged, and atrial effective refractory period (AERP) was significantly prolonged (P < 0.01) in the ZD group. In the ZD group, the ICa-L amplitudes of rabbit atrial myocytes under each clamping voltage were significantly smaller than those in the AF group (P < 0.01) and the control group (P < 0.05). The Ca2+ fluorescence intensity in the rabbit atrial myocytes in the ZD group was significantly weaker than that in the AF group (P < 0.01) and the control group (P < 0.05). Electron microscopy displayed that the control group had neatly arranged atrial tissue myofilaments and intact mitochondria. However, the ultrastructural damage of the AF group was severe compared with that of the ZD group. LC–MS/MS analysis confirmed that ZD contained several antiarrhythmic compounds including ginsenoside, isoliensinine, catalpol, glycyrrhizinate and hesperetin.
Conclusion
Rapid atrial pacing (RAP) could cause the electrical and structural remodeling of rabbit atrial myocytes. ZD might reverse the atrial electrical remodeling but could have little effect on structural remodeling, which might be the mechanism of ZD treatment on atrial fibrillation.
Similar content being viewed by others
References
Haim M, Hoshen M, Reges O, et al. Prospective national study of the prevalence, incidence, management and outcome of a large contemporary cohort of patients with incident non-valvular atrial fibrillation. J Am Heart Assoc. 2015;4(1):e001486. https://doi.org/10.1161/JAHA.114.001486.
Sibley S, Muscedere J. New-onset atrial fibrillation in critically ill patients. Can Respir J. 2015;22(3):179–82. https://doi.org/10.1155/2015/394961.
Chugh SS, Havmoeller R, Narayanan K, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129(8):837–47. https://doi.org/10.1161/CIRCULATIONAHA.113.005119.
Burstein B, Nattel S. Atrial fibrosis: mechanisms and clinical relevance in atrial fibrillation. J Am Coll Cardiol. 2008;51(8):802–9. https://doi.org/10.1016/j.jacc.2007.09.064.
Casaclang-Verzosa G, Gersh BJ, Tsang TS. Structural and functional remodeling of the left atrium: clinical and therapeutic implications for atrial fibrillation. J Am Coll Cardiol. 2008;51(1):1–11. https://doi.org/10.1016/j.jacc.2007.09.026.
Thomas L, Abhayaratna WP. Left atrial reverse remodeling: mechanisms, evaluation, and clinical significance. JACC Cardiovasc Imag. 2017;10(1):65–77. https://doi.org/10.1016/j.jcmg.2016.11.003.
Liu W, Xiong X, Feng B, et al. Classic herbal formula Zhigancao Decoction for the treatment of premature ventricular contractions (PVCs): a systematic review of randomized controlled trials. Complement Ther Med. 2015;23(1):100–15. https://doi.org/10.1016/j.ctim.2014.12.008.
Xiong XJ. Exploration on connotation of Zhigancao Decoction formula syndrome from the perspective of modern pathophysiology and severe cases of critical care and its clinical efficacy on cardioversion, maintenance of sinus rhythm, hemostasis, increasing platelets count, and tonifying deficiency. Zhongguo Zhong Yao Za Zhi. 2019;44(18):3842–60. https://doi.org/10.19540/j.cnki.cjcmm.20190416.501.
Scott L Jr, Fender AC, Saljic A, et al. NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmias. Cardiovasc Res. 2021;117(7):1746–59. https://doi.org/10.1093/cvr/cvab024.
Sun J, Wugeti N, Mahemuti A. Reversal effect of Zhigancao decoction on myocardial fibrosis in a rapid pacing-induced atrial fibrillation model in New Zealand rabbits. J Int Med Res. 2019;47(2):884–92. https://doi.org/10.1177/0300060518799819.
Fei YD, Chen M, Guo S, et al. Simultaneous activation of the small conductance calcium-activated potassium current by acetylcholine and inhibition of sodium current by ajmaline cause J-wave syndrome in Langendorff-perfused rabbit ventricles. Heart Rhythm. 2021;18(1):98–108. https://doi.org/10.1016/j.hrthm.2020.07.036.
Rouet R, Worou ME, Puddu PE, et al. Nifedipine blocks ondansetron electrophysiological effects in rabbit Purkinje fibers and decreases early after depolarization incidence. Curr Clin Pharmacol. 2012;7(1):41–8. https://doi.org/10.2174/157488412799218789.
Fan YY, Xu F, Zhu C, et al. Effects of febuxostat on atrial remodeling in a rabbit model of atrial fibrillation induced by rapid atrial pacing. J Geriatr Cardiol. 2019;16(7):540–51. https://doi.org/10.11909/j.issn.1671-5411.2019.07.003.
Jiang W, Zeng M, Cao Z, et al. Icariin, a novel blocker of sodium and calcium channels, eliminates early and delayed afterdepolarizations, as well as triggered activity, in rabbit cardiomyocytes. Front Physiol. 2017;8:342. https://doi.org/10.3389/fphys.2017.00342.
Wu CY, Zhang DL, Zhou CZ, et al. Effect of zhigancao decoction on atrial monophasic action potential in rabbits. New Chin Med. 2013;45(03):173–5. https://doi.org/10.13457/j.cnki.jncm.2013.03.077.
Wijesurendra RS, Casadei B. Mechanisms of atrial fibrillation. Heart. 2019;105(24):1860–7. https://doi.org/10.1136/heartjnl-2018-314267.
Heijman J, Voigt N, Nattel S, et al. Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. Circ Res. 2014;114(9):1483–99. https://doi.org/10.1161/CIRCRESAHA.114.302226.
Chang CJ, Chen YC, Lin YK, et al. Rivaroxaban modulates electrical and mechanical characteristics of left atrium. J Biomed Sci. 2013;20(1):17. https://doi.org/10.1186/1423-0127-20-17.
Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res. 2002;54(2):230–46. https://doi.org/10.1016/s0008-6363(02)00258-4.
Moore-Morris T, Guimarães-Camboa N, Banerjee I, et al. Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis. J Clin Invest. 2014;124(7):2921–34. https://doi.org/10.1172/JCI74783.
Jalife J, Kaur K. Atrial remodeling, fibrosis, and atrial fibrillation. Trends Cardiovasc Med. 2015;25(6):475–84. https://doi.org/10.1016/j.tcm.2014.12.015.
Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation A study in awake chronically instrumented goats. Circulation. 1995;92(7):1954–68. https://doi.org/10.1161/01.cir.92.7.1954.
Wakili R, Voigt N, Kääb S, et al. Recent advances in the molecular pathophysiology of atrial fibrillation. J Clin Invest. 2011;121(8):2955–68. https://doi.org/10.1172/JCI46315.
Yue L, Feng J, Gaspo R, et al. Ionic remodeling underlying action potential changes in a canine model of atrial fibrillation. Circ Res. 1997;81(4):512–25. https://doi.org/10.1161/01.res.81.4.512.
Pandit SV, Berenfeld O, Anumonwo JM, et al. Ionic determinants of functional reentry in a 2-D model of human atrial cells during simulated chronic atrial fibrillation. Biophys J. 2005;88(6):3806–21. https://doi.org/10.1529/biophysj.105.060459.
Tong YQ, Sun M, Hu CJ, et al. Changes of QT dispersion in hemodialysis patients after administrating zhigancao decoction (). Chin J Integr Med. 2018;24(8):627–31. https://doi.org/10.1007/s11655-016-2599-6.
Sun J, Lu Y, Yan H, et al. Application of the myocardial tissue/silicon substrate microelectrode array technology on detecting the effection of Zhigancao Decoction medicated serum on cardiac electrophysiology. Int J Clin Exp Med. 2015;8(2):2017–23.
Zhang XY, Xu AW, Ma JW, et al. Electrophysiological effects of zhigancao decoction on guinea pigs with ischemia-hypoxia-induced arrhythmia [J]. Tradit Chin Drug Res Clin Pharmacol. 2008;19(2):102–5. https://doi.org/10.19378/j.issn.1003-9783.2008.02.008.
Qi XY, Huang H, Ordog B, et al. Fibroblast inward-rectifier potassium current upregulation in profibrillatory atrial remodeling. Circ Res. 2015;116(5):836–45. https://doi.org/10.1161/CIRCRESAHA.116.305326.
Yang L, Deng N, He J, et al. Calcineurin Aβ gene knockdown inhibits transient outward potassium current ion channel remodeling in hypertrophic ventricular myocyte. Open Life Sci. 2021;16(1):1010–21. https://doi.org/10.1515/biol-2021-0107.
Wu L, Ma J, Li H, et al. Late sodium current contributes to the reverse rate-dependent effect of IKr inhibition on ventricular repolarization. Circulation. 2011;123(16):1713–20. https://doi.org/10.1161/CIRCULATIONAHA.110.000661.
Gan TY, Qiao W, Xu GJ, et al. Aging-associated changes in L-type calcium channels in the left atria of dogs. Exp Ther Med. 2013;6(4):919–24. https://doi.org/10.3892/etm.2013.1266.
Zhao Z, Liu M, Zhang Y, et al. Cardioprotective effect of monoammonium glycyrrhizinate injection against myocardial ischemic injury in vivo and in vitro: involvement of inhibiting oxidative stress and regulating Ca2+ homeostasis by L-type calcium channels. Drug Des Devel Ther. 2020;14:331–46. https://doi.org/10.2147/DDDT.S232130.
Liu Z, Song L, Zhang P, et al. Ginsenoside Rb1 exerts antiarrhythmic effects by inhibiting INa and ICaL in rabbit ventricular myocytes. Sci Rep. 2019;9(1):20425. https://doi.org/10.1038/s41598-019-57010-9.
Zhang J, Luo D, Li F, et al. Ginsenoside Rg3 alleviates antithyroid cancer drug vandetanib-induced QT interval prolongation. Oxid Med Cell Longev. 2021;2021:3520034. https://doi.org/10.1155/2021/3520034.
Liu Z, Hu L, Zhang Z, et al. Isoliensinine eliminates afterdepolarizations through inhibiting late sodium current and L-type calcium current. Cardiovasc Toxicol. 2021;21(1):67–78. https://doi.org/10.1007/s12012-020-09597-z.
Huang C, Cui Y, Ji L, et al. Catalpol decreases peroxynitrite formation and consequently exerts cardioprotective effects against ischemia/reperfusion insult. Pharm Biol. 2013;51(4):463–73. https://doi.org/10.3109/13880209.2012.740052.
Liu P, Li J, Liu M, et al. Hesperetin modulates the Sirt1/Nrf2 signaling pathway in counteracting myocardial ischemia through suppression of oxidative stress, inflammation, and apoptosis. Biomed Pharmacother. 2021;139:111552. https://doi.org/10.1016/j.biopha.2021.111552.
Acknowledgements
The authors would like to acknowledge all the staff at Cardiac Electrophysiology Laboratory of Wuhan University for their tireless work and professionalism.
Funding
This study was supported by the Hubei Provincial Health Committee of Traditional Chinese Medicine and Integrated Traditional Chinese and Western Medicine Research Guidance Project (2013Z-B01).
Author information
Authors and Affiliations
Contributions
Sheng Guo and Yao-jun Xue are first co-authors and contributed equally to this study.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflicts of interest regarding the publication of this paper.
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Guo, S., Xue, Yj., Zhu, X. et al. Effects and pharmacological mechanism of Zhigancao Decoction on electrical and structural remodeling of the atrium of rabbits induced by rapid atrial pacing. J Interv Card Electrophysiol 66, 597–609 (2023). https://doi.org/10.1007/s10840-022-01356-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10840-022-01356-0