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Arrhythmogenic β-adrenergic signaling in cardiac hypertrophy : The role of small-conductance calcium-activated potassium channels via activation of CaMKII

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Title: Arrhythmogenic β-adrenergic signaling in cardiac hypertrophy : The role of small-conductance calcium-activated potassium channels via activation of CaMKII
Authors: Kamada, Rui Browse this author →KAKEN DB
Yokoshiki, Hisashi Browse this author →KAKEN DB
Mitsuyama, Hirofumi Browse this author
Watanabe, Masaya Browse this author →KAKEN DB
Mizukami, Kazuya Browse this author
Tenma, Taro Browse this author →KAKEN DB
Takahashi, Masayuki Browse this author
Takada, Shingo Browse this author →KAKEN DB
Anzai, Toshihisa Browse this author →KAKEN DB
Keywords: SK channels
β- adrenoreceptor stimulation
Cardiac hypertrophy
Issue Date: 5-Feb-2019
Publisher: Elsevier
Journal Title: European journal of pharmacology
Volume: 844
Start Page: 110
End Page: 117
Publisher DOI: 10.1016/j.ejphar.2018.12.011
Abstract: Sustained ventricular arrhythmias (SVAs) lead to sudden cardiac death, for which β- adrenoreceptor blockers are effective. We hypothesized that electrophysiological changes and arrhythmias by β- adrenoreceptor stimulation are crucially related to activation of small-conductance calcium-activated potassium (SK) channels via the increase in Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity. We used normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs). The latter served as a model of left ventricular hypertrophy. We performed dual optical mapping of action potentials and Ca2+ transients, and the effects of isoproterenol and apamin, an SK channel blocker, were evaluated in the Langendorff-perfused hearts. Action potential duration was abbreviated by isoproterenol (100 nM) in both WKY rats and SHRs. In contrast, the CaMKII activity was increased by isoproterenol only in SHRs. In the presence of isoproterenol, apamin prolonged the action potential duration only in SHRs (n = 10, from 116.6 ± 5.05 ms to 125.4 ± 3.80 ms, P = 0.011), which was prevented by KN-93, a CaMKII inhibitor. Increase in Ca2+ transients and shortening of Ca2+ transient duration by isoproterenol were similarly observed in both animals, which was not affected by apamin. Apamin reduced the isoproterenol-induced SVAs and maximal slope of action potential duration restitution curve specifically in SHRs. In conclusion, β- adrenoreceptor stimulation creates arrhythmogenic substrates via the CaMKII-dependent activation of SK channels in cardiac hypertrophy.
Rights: © 2019. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
Type: article (author version)
Appears in Collections:北海道大学病院 (Hokkaido University Hospital) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 鎌田 塁

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