Molecular and Cellular Biochemistry

, Volume 384, Issue 1–2, pp 95–103 | Cite as

Bisoprolol reversed small conductance calcium-activated potassium channel (SK) remodeling in a volume-overload rat model

  • Yajuan Ni
  • Tingzhong Wang
  • Xiaozhen Zhuo
  • Bingxue Song
  • Jing Zhang
  • Feng Wei
  • Hongyuan Bai
  • Xuehui Wang
  • Dandan Yang
  • Li Gao
  • Aiqun Ma


A recent study indicated that apamin-sensitive current (I KAS, mediated by apamin-sensitive small conductance calcium-activated potassium channels subunits) density significantly increased in heart failure and led to recurrent spontaneous ventricular fibrillation. While the underlying molecular correlation with SK channels is still undetermined, we hypothesized that they are remodeled in HF and that bisoprolol could reverse the remodeling. Volume-overload models were created on male Sprague-Dawley rats by producing an abdominal arteriovenous fistula. Confocal microscopy, quantitative real-time PCR, and western blot were performed to investigate the expression of SK channels and observe the influence of β-blocker bisoprolol on the expression of SK channels I KAS, and the effect of bisoprolol on I KAS and the sensitivity of I KAS to [Ca2+]i at single isolated cells were also explored using whole-cell patch clamp techniques. SK channels were remodeled in HF rats, displaying the significant increase of SK1 and SK3 channel expression. After the treatment of HF rats with bisoprolol, the expression of SK1 and SK3 channels was significantly downregulated, and bisoprolol effectively downregulated I KAS density as well as the sensitivity of I KAS to [Ca2+]i. Our data indicated that the expression of SK1 and SK3 increased in HF. Bisoprolol effectively attenuated the change and downregulated I KAS density as well as the sensitivity of I KAS to [Ca2+]i.


Bisoprolol SK channels Remodeling 



We thank Dr Zhenghang Zhao for his help in the analysis of patch clamp data and Lin Yang and Tao Geng for their help in experimental technique. This study was supported by the State Key Program of the National Natural Science Foundation of China (NSFC, No. 30830051).

Conflict of interest

None declared.


  1. 1.
    Hunt SA (2010) 2009 Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines (vol 119, p. e391, 2009). Circulation 121:E258–E258. doi: 10.1161/CIR.0b013e3181d7a6b3 CrossRefGoogle Scholar
  2. 2.
    Xi Y, Wu G, Yang L, Han K, Du Y, Wang T, Lei X, Bai X, Ma A (2009) Increased late sodium currents are related to transcription of neuronal isoforms in a pressure-overload model. Eur J Heart Fail 11:749–757. doi: 10.1093/eurjhf/hfp092 PubMedCrossRefGoogle Scholar
  3. 3.
    Nattel S, Maguy A, Le Bouter S, Yeh Y-H (2007) Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiol Rev 87:425–456. doi: 10.1152/physrev.00014.2006 PubMedCrossRefGoogle Scholar
  4. 4.
    Chua S-K, Chang P-C, Maruyama M, Turker I, Shinohara T, Shen MJ, Chen Z, Shen C, Rubart-von der Lohe M, Lopshire JC, Ogawa M, Weiss JN, Lin S-F, Ai T, Chen P-S (2011) Small-conductance calcium-activated potassium channel and recurrent ventricular fibrillation in failing rabbit ventricles. Circ Res 108:971–979. doi: 10.1161/circresaha.110.238386 PubMedCrossRefGoogle Scholar
  5. 5.
    Barfod ET, Moore AL, Lidofsky SD (2001) Cloning and functional expression of a liver isoform of the small conductance Ca2+-activated K+ channel SK3. Am J Physiol Cell Physiol 280:C836–C842PubMedGoogle Scholar
  6. 6.
    Xu YF, Tuteja D, Zhang Z, Xu DY, Zhang Y, Rodriguez J, Nie LP, Tuxson HR, Young JN, Glatter KA, Vazquez AE, Yamoah EN, Chiamvimonvat N (2003) Molecular identification and functional roles of a Ca2+-activated K+ channel in human and mouse hearts. J Biol Chem 278:49085–49094. doi: 10.1074/jbc.M307508200 PubMedCrossRefGoogle Scholar
  7. 7.
    Doggrell SA, Brown L (1998) Rat models of hypertension, cardiac hypertrophy and failure. Cardiovasc Res 39:89–105. doi: 10.1016/s0008-6363(98)00076-5 PubMedCrossRefGoogle Scholar
  8. 8.
    Flaim SF, Minteer WJ, Zelis R (1980) Acute effects of arteriovenous shunt on cardiovascular hemodynamics in rat. Pflugers Arch 385:203–209. doi: 10.1007/bf00647458 PubMedCrossRefGoogle Scholar
  9. 9.
    Grimm D, Holmer SR, Riegger GAJ, Kromer EP (1999) Effects of beta-receptor blockade and angiotensin II type I receptor antagonism in isoproterenol—induced heart failure in the rat. Cardiovasc Pathol 8:315–323. doi: 10.1016/s1054-8807(99)00021-6 PubMedCrossRefGoogle Scholar
  10. 10.
    Mulder P, Barbier S, Chagraoui A, Richard V, Henry JP, Lallemand F, Renet S, Lerebours G, Mahlberg-Gaudin F, Thuillez C (2004) Long-term heart rate reduction induced by the selective I-f current inhibitor ivabradine improves left ventricular function and intrinsic myocardial structure in congestive heart failure. Circulation 109:1674–1679. doi: 10.1161/01.cir.0000118464.48959.1c PubMedCrossRefGoogle Scholar
  11. 11.
    Watanabe K, Ohta Y, Inoue M, Ma M, Wahed MII, Nakazawa M, Hasegawa G, Naito M, Fuse K, Ito M, Kato K, Hanawa H, Kodama M, Aizawa Y (2001) Bisoprolol improves survival in rats with heart failure. J Cardiovasc Pharmacol 38:S55–S58. doi: 10.1097/00005344-200110001-00012 PubMedCrossRefGoogle Scholar
  12. 12.
    Nagy N, Szuts V, Horvath Z, Seprenyi G, Farkas AS, Acsai K, Prorok J, Bitay M, Kun A, Pataricza J, Papp JG, Nanasi PP, Varro A, Toth A (2009) Does small-conductance calcium-activated potassium channel contribute to cardiac repolarization? J Mol Cell Cardiol 47:656–663. doi: 10.1016/j.yjmcc.2009.07.019 PubMedCrossRefGoogle Scholar
  13. 13.
    Tuteja D, Xu DY, Timofeyev V, Lu L, Sharma D, Zhang Z, Xu YF, Nie LP, Vazquez AE, Young JN, Glatter KA, Chiamvimonvat N (2005) Differential expression of small-conductance Ca2+-activated K+ channels SK1, SK2, and SK3 in mouse atrial and ventricular myocytes. Am J Physiol Heart Circ Physiol 289:H2714–H2723. doi: 10.1152/ajpheart.00534.2005 PubMedCrossRefGoogle Scholar
  14. 14.
    Pagliarulo V, George B, Beil SJ, Groshen S, Laird PW, Cai J, Willey J, Cote RJ, Datar RH (2004) Sensitivity and reproducibility of standardized-competitive RT-PCR for transcript quantification and its comparison with real time RT-PCR. Mol Cancer. doi: 10.1186/1476-4598-3-5 PubMedGoogle Scholar
  15. 15.
    Patton C, Thompson S, Epel D (2004) Some precautions in using chelators to buffer metals in biological solutions. Cell Calcium 35:427–431. doi: 10.1016/j.ceca.2003.10.006 PubMedCrossRefGoogle Scholar
  16. 16.
    Nishio M, Sakata Y, Mano T, Ohtani T, Takeda Y, Miwa T, Hori M, Masuyama T, Kondo T, Yamamoto K (2008) Beneficial effects of bisoprolol on the survival of hypertensive diastolic heart failure model rats. Eur J Heart Fail 10:446–453. doi: 10.1016/j.ejheart.2008.03.002 PubMedCrossRefGoogle Scholar
  17. 17.
    Diness JG, Skibsbye L, Jespersen T, Bartels ED, Sorensen US, Hansen RS, Grunnet M (2011) Effects on atrial fibrillation in aged hypertensive rats by Ca2+-activated K+ channel inhibition. Hypertension 57:1129–1135. doi: 10.1161/hypertensionaha.111.170613 PubMedCrossRefGoogle Scholar
  18. 18.
    Diness JG, Sorensen US, Nissen JD, Al-Shahib B, Jespersen T, Grunnet M, Hansen RS (2010) Inhibition of small-conductance Ca2+-activated K+ channels terminates and protects against atrial fibrillation. Circ Arrhythm Electrophysiol 3:380–390. doi: 10.1161/circep.110.957407 PubMedCrossRefGoogle Scholar
  19. 19.
    Skibsbye L, Diness JG, Sorensen US, Hansen RS, Grunnet M (2011) The duration of pacing-induced atrial fibrillation is reduced in vivo by inhibition of small conductance Ca2+-activated K+ channels. J Cardiovasc Pharmacol 57:672–681. doi: 10.1097/FJC.0b013e318217943d PubMedCrossRefGoogle Scholar
  20. 20.
    Li W, Halling DB, Hall AW, Aldrich RW (2009) EF hands at the N-lobe of calmodulin are required for both SK channel gating and stable SK-calmodulin interaction. J Gen Physiol 134:281–293. doi: 10.1085/jgp.200910295 PubMedCrossRefGoogle Scholar
  21. 21.
    Schumacher MA, Rivard AF, Bachinger HP, Adelman JP (2001) Structure of the gating domain of a Ca2+-activated K+ channel complexed with Ca2+/calmodulin. Nature 410:1120–1124. doi: 10.1038/35074145 PubMedCrossRefGoogle Scholar
  22. 22.
    Allen D, Fakler B, Maylie J, Adelman JP (2007) Organization and regulation of small conductance Ca2+-activated K+ channel multiprotein complexes. J Neurosci 27:2369–2376. doi: 10.1523/jneurosci.3565-06.2007 PubMedCrossRefGoogle Scholar
  23. 23.
    Bildl W, Strassmaier T, Thurm H, Andersen J, Eble S, Oliver D, Knipper M, Mann M, Schulte U, Adelman JP, Fakler B (2004) Protein kinase CK2 is coassembled with small conductance Ca2+-activated K+ channels and regulates channel gating. Neuron 43:847–858. doi: 10.1016/j.neuron.2004.08.033 PubMedCrossRefGoogle Scholar
  24. 24.
    Pullar CE, Chen J, Isseroff RR (2003) PP2A activation by beta 2-adrenergic receptor agonists—novel regulatory mechanism of keratinocyte migration. J Biol Chem 278:22555–22562. doi: 10.1074/jbc.M300205200 PubMedCrossRefGoogle Scholar
  25. 25.
    Kong ID, Koh SD, Bayguinov O, Sanders KM (2000) Small conductance Ca2+-activated K+ channels are regulated by Ca2+-calmodulin-dependent protein kinase II in murine colonic myocytes. J Physiol 524:331–337. doi: 10.1111/j.1469-7793.2000.t01-1-00331.x PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Yajuan Ni
    • 1
  • Tingzhong Wang
    • 1
  • Xiaozhen Zhuo
    • 1
  • Bingxue Song
    • 1
  • Jing Zhang
    • 2
  • Feng Wei
    • 1
  • Hongyuan Bai
    • 1
  • Xuehui Wang
    • 3
  • Dandan Yang
    • 1
  • Li Gao
    • 1
  • Aiqun Ma
    • 1
  1. 1.Department of Cardiovascular Medicine, Key Laboratory of Environment and Genes Related to Diseases, Ministry of EducationFirst Affiliated Hospital of Xi’an Jiaotong University School of MedicineXi’anChina
  2. 2.Department of CardiologyThe Affiliated Chinese Traditional Hospital of Xinjiang Medical UniversityÜrümqiChina
  3. 3.Department of Cardiovascular MedicineThe First Affiliated Hospital of Xinxiang Medical UniversityWeihuiChina

Personalised recommendations