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