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Short- and long-term inhibition of cardiac inward-rectifier potassium channel current by an antiarrhythmic drug bepridil

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An Erratum to this article was published on 25 February 2016

Abstract

Bepridil is an effective antiarrhythmic drug on supraventricular and ventricular arrhythmias, and inhibitor of calmodulin. Recent investigations have been elucidating that bepridil exerts antiarrhythmic effects through its acute and chronic application for patients. The aim of this study was to identify the efficacy and the potential mechanism of bepridil on the inward-rectifier potassium channel in neonatal rat cardiomyocytes in acute- and long-term conditions. Bepridil inhibited inward-rectifier potassium current (I K1) as a short-term effect with IC50 of 17 μM. Bepridil also reduced I K1 of neonatal cardiomyocytes when applied for 24 h in the culture medium with IC50 of 2.7 μM. Both a calmodulin inhibitor (W-7) and an inhibitor of calmodulin-kinase II (KN93) reduced I K1 when applied for 24 h as a long-term effect in the same fashion, suggesting that the long-term application of bepridil inhibits I K1 more potently than that of the short-term application through the inhibition of calmodulin kinase II pathway in cardiomyocytes.

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References

  1. Wishart DS, Knox C, Guo AC, Shrivastava S, Hassanali M, Stothard P, Chang Z, Woolsey J (2006) DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res 34:D668–D672

    Article  CAS  PubMed  Google Scholar 

  2. Uchino T, Lee TS, Kaku T, Yamashita N, Noguchi T, Ono K (2005) Voltage-dependent and frequency-independent inhibition of recombinant Cav3.2 T-type Ca2+ channel by bepridil. Pharmacology 74:174–181

    Article  CAS  PubMed  Google Scholar 

  3. Berger F, Borchard U, Hafner D (1989) Effects of the calcium entry blocker bepridil on repolarizing and pacemaker currents in sheep cardiac Purkinje fibers. Naunyn Schmiedebergs Arch Pharmacol 339:638–646

    Article  CAS  PubMed  Google Scholar 

  4. Wang JC, Kiyosue T, Kiriyama K, Arita M (1999) Bepridil differentially inhibits two delayed rectifier K+ currents, I Kr and I Ks, in guinea pig ventricular myocytes. Br J Pharmacol 128:1733–1738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kobayashi S, Reien Y, Ogura T, Saito T, Masuda Y, Nakaya H (2001) Inhibitory effect of bepridil on hKv1.5 channel current: comparison with amiodarone and E-4031. Eur J Pharmacol 430:149–157

    Article  CAS  PubMed  Google Scholar 

  6. Li Y, Sato T, Arita M (1999) Bepridil blunts the shortening of action potential duration caused by metabolic inhibition via blockade of ATP-sensitive K+ channels and Na+-activated K+ channels. J Pharmacol Exp Ther 291:562–568

    CAS  PubMed  Google Scholar 

  7. Hara Y, Nakaya H (1995) SD-3212, a new class I and IV antiarrhythmic drug: a potent inhibitor of the muscarinic acetylcholine-receptor operated potassium current in guinea-pig atrial cells. Br J Pharmacol 116:2750–2756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Sato T, Costa AD, Saito T, Ogura T, Ishida H, Garlid KD, Nakaya H (2006) Bepridil, an antiarrhythmic drug, opens mitochondrial KATP channels blocks sarcolemmal KATP channels, and confers cardioprotection. J Pharmacol Exp Ther 316:182–188

    Article  CAS  PubMed  Google Scholar 

  9. Sato N, Nishimura M, Kawamura Y, Ward CA, Kikuchi K (1996) Blocks of Na+ channel by bepridil in isolated guinea-pig ventricular myocytes. Eur J Pharmacol 314:373–379

    Article  CAS  PubMed  Google Scholar 

  10. Yatani A, Brown AM, Schwartz A (1986) Bepridil block of cardiac calcium and sodium channels. J Pharmcol Exp Ther 237:9–17

    CAS  Google Scholar 

  11. Watanabe Y, Kimura J (2001) Blocking effect of bepridil on Na+/Ca2+ exchange current in guinea pig cardiac ventricular myocytes. Jpn J Pharmacol 85:370–375

    Article  CAS  PubMed  Google Scholar 

  12. Kang L, Zheng MQ, Morishima M, Wang Y, Kaku T, Ono K (2009) Bepridil up-regulates cardiac Na+ channels as a long-term effect by blunting proteasome signals through inhibition of calmodulin activity. Br J Pharmacol 157:404–414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Suzuki S, Kurata Y, Li P, Notsu T, Hasegawa A, Ikeda N, Kato M, Miake J, Sakata S, Shiota G, Yoshida A, Ninomiya H, Higaki K, Yamamoto K, Shirayoshi Y, Hisatome I (2012) Stabilization of Kv1.5 channel protein by bepridil through its action as a chemical chaperone. Eur J Pharmacol 696:28–34

    Article  CAS  PubMed  Google Scholar 

  14. Yamashita T, Ogawa S, Sato T, Aizawa Y, Atarashi H, Fujiki A, Inoue H, Ito M, Katoh T, Kobayashi Y, Koretsune Y, Kumagai K, Niwano S, Okazaki O, Okumura K, Saku K, Tanabe T, Origasa H (2009) J-BAF Investigators. Dose-response effects of bepridil in patients with persistent atrial fibrillation monitored with transtelephonic electrocardiograms: a multicenter, randomized, placebo-controlled, double-blind study (J-BAF Study). Circ J 73:1020–1027

    Article  CAS  PubMed  Google Scholar 

  15. Kato R, Singh BN (1986) Effects of bepridil on the electrophysiologic properties of isolated canine and rabbit myocardial fibers. Am Heart J 111:271–279

    Article  CAS  PubMed  Google Scholar 

  16. Sato D, Niwano S, Imaki R, Masaki Y, Sasaki S, Yuge M, Hirasawa S, Sasaki T, Moriguchi M, Niwano H, Yoshimura H, Izumi T (2006) Bepridil inhibits sub-acute phase of atrial electrical remodeling in canine rapid atrial stimulation model. Circ J 70:206–213

    Article  CAS  PubMed  Google Scholar 

  17. Wang Y, Morishima M, Zheng M, Uchino T, Mannen K, Takahashi A, Nakaya Y, Komuro I, Ono K (2007) Transcription factors Csx/Nkx2.5 and GATA4 distinctly regulate expression of Ca2+ channels in neonatal rat heart. J Mol Cell Cardiol 42:1045–1053

    Article  PubMed  Google Scholar 

  18. Uchino T, Isomoto S, Noguchi T, Ono K (2013) Window current through the T-type Ca2+ channel triggers the mechanism for cellular apoptosis via mitochondrial pathways. Heart Vessels 28:658–666

    Article  PubMed  Google Scholar 

  19. Axon Instruments, Inc. (2012) The axon guide: electrophysiology and biophysics laboratory techniques, 3rd edn. Chapter 1: Bioelectricity, pp 17–38

  20. Duff HJ, Offord J, West J, Catterall WA (1992) Class I and IV antiarrhythmic drugs and cytosolic calcium regulate mRNA encoding the sodium channel alpha subunit in rat cardiac muscle. Mol Pharmacol 42:570–574

    CAS  PubMed  Google Scholar 

  21. Itoh H, Ishikawa T, Hidaka H (1984) Effects on calmodulin of bepridil, an antianginal agent. J Pharmacol Exp Ther 230:737–741

    CAS  PubMed  Google Scholar 

  22. Zimmer M, Hofmann F (1987) Differentiation of the drug-binding sites of calmodulin. Eur J Biochem 164:411–420

    Article  CAS  PubMed  Google Scholar 

  23. Schaeffer P, Lugnier C, Stoclet JC (1991) Interactions of calmodulin antagonists with calcium antagonists binding sites. Eur J Pharmacol 206:325–332

    Article  CAS  PubMed  Google Scholar 

  24. Kawashiri M, Hayashi K, Konno T, Fujino N, Ino H, Yamagishi M (2014) Current perspectives in genetic cardiovascular disorders: from basic to clinical aspects. Heart Vessels 29:129–141

    Article  PubMed  Google Scholar 

  25. Yamazaki M, Honjo H, Nakagawa H, Ishiguro YS, Okuno Y, Amino M, Sakuma I, Kamiya K, Kodama I (2007) Mechanisms of destabilization and early termination of spiral wave reentry in the ventricle by a class III antiarrhythmic agent, nifekalant. Am J Physiol Heart Circ Physiol 292:H539–H548

    Article  CAS  PubMed  Google Scholar 

  26. Dhamoon AS, Jalife J (2005) The inward rectifier current (I K1) controls cardiac excitability and is involved in arrhythmogenesis. Heart Rhythm 2:316–324

    Article  PubMed  Google Scholar 

  27. Dobrev D, Friedrich A, Voigt N, Jost N, Wettwer E, Christ T, Knaut M, Ravens U (2005) The G protein-gated potassium current I KACh is constitutively active in patients with chronic atrial fibrillation. Circulation 112:3697–3706

    Article  CAS  PubMed  Google Scholar 

  28. Gaborit N, Steenman M, Lamirault G, Le Meur N, Le Bouter S, Lande G, Léger J, Charpentier F, Christ T, Dobrev D, Escande D, Nattel S, Demolombe S (2005) Human atrial ion channel and transporter subunit gene-expression remodeling associated with valvular heart disease and atrial fibrillation. Circulation 112:471–481

    Article  PubMed  Google Scholar 

  29. Girmatsion Z, Biliczki P, Bonauer A, Wimmer-Greinecker G, Scherer M, Moritz A, Bukowska A, Goette A, Nattel S, Hohnloser SH, Ehrlich JR (2009) Changes in microRNA-1 expression and I K1 up-regulation in human atrial fibrillation. Heart Rhythm 6:1802–1809

    Article  PubMed  Google Scholar 

  30. Luo X, Pan Z, Shan H, Xiao J, Sun X, Wang N, Lin H, Xiao L, Maguy A, Qi XY, Li Y, Gao X, Dong D, Zhang Y, Bai Y, Ai J, Sun L, Lu H, Luo XY, Wang Z, Lu Y, Yang B, Nattel S (2013) MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation. J Clin Invest 123:1939–1951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Soeki T, Bando S, Uematsu E, Matsuura T, Niki T, Ise T, Kusunose K, Hotchi J, Ueda Y, Tomita N, Yamaguchi K, Yagi S, Fukuda D, Taketani Y, Iwase T, Yamada H, Wakatsuki T, Shimabukuro M, Sata M (2014) Pentraxin 3 is a local inflammatory marker in atrial fibrillation. Heart Vessels 229:653–658

    Article  Google Scholar 

  32. Okada A, Kashima Y, Tomita T, Takeuchi T, Aizawa K, Takahashi M, Ikeda U (2014) Characterization of cardiac oxidative stress levels in patients with atrial fibrillation. Heart Vessels. doi:10.1007/S00380-014-0582-8

    Google Scholar 

  33. Pandit SV, Berenfeld O, Anumonwo JM, Zaritski RM, Kneller J, Nattel S, Jalife J (2005) Ionic determinants of functional reentry in a 2-D model of human atrial cells during simulated chronic atrial fibrillation. Biophys J 88:3806–3821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Katsouras G, Sakabe M, Comtois P, Maguy A, Burstein B, Guerra PG, Talajic M, Nattel S (2009) Differences in atrial fibrillation properties under vagal nerve stimulation versus atrial tachycardia remodeling. Heart Rhythm 6:1465–1472

    Article  PubMed  Google Scholar 

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Acknowledgments

This study was supported in part by Japanese Ministry of Education, Science, and Culture Grant-in-aid (KAKEN) #25460292 (to K. Ono).

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Authors and Affiliations

  1. Department of Pathophysiology, Oita University School of Medicine, Yufu, 879-5593, Oita, Japan

    Fangfang Ma, Hiroki Takanari, Kimiko Masuda, Masaki Morishima & Katsushige Ono

  2. Department of Cardiology, The 1st Hospital of Hebei Medical University, Shijiazhung, 050031, Hebei, China

    Fangfang Ma

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  1. Fangfang Ma
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Correspondence to Katsushige Ono.

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Ma, F., Takanari, H., Masuda, K. et al. Short- and long-term inhibition of cardiac inward-rectifier potassium channel current by an antiarrhythmic drug bepridil. Heart Vessels 31, 1176–1184 (2016). https://doi.org/10.1007/s00380-015-0762-1

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  • DOI: https://doi.org/10.1007/s00380-015-0762-1

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