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Title: Inhibition of N-type Ca[2+] channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure.
Authors: Yamada, Yuko
Kinoshita, Hideyuki  kyouindb  KAKEN_id
Kuwahara, Koichiro  KAKEN_id
Nakagawa, Yasuaki  kyouindb  KAKEN_id
Kuwabara, Yoshihiro  kyouindb  KAKEN_id
Minami, Takeya
Yamada, Chinatsu
Shibata, Junko
Nakao, Kazuhiro
Cho, Kosai  kyouindb  KAKEN_id
Arai, Yuji
Yasuno, Shinji
Nishikimi, Toshio
Ueshima, Kenji  kyouindb  KAKEN_id
Kamakura, Shiro
Nishida, Motohiro
Kiyonaka, Shigeki
Mori, Yasuo  kyouindb  KAKEN_id
Kimura, Takeshi  kyouindb  KAKEN_id
Kangawa, Kenji
Nakao, Kazuwa
Author's alias: 桑原, 宏一郎
Keywords: Ion channel
Nervous system
Autonomic
Heart failure
Arrhythmia
N-type Ca[2+] channel
Issue Date: 6-Aug-2014
Publisher: Oxford University Press
Journal title: Cardiovascular research
Volume: 104
Issue: 1
Start page: 183
End page: 193
Abstract: Aims Dysregulation of autonomic nervous system activity can trigger ventricular arrhythmias and sudden death in patients with heart failure. N-type Ca2+ channels (NCCs) play an important role in sympathetic nervous system activation by regulating the calcium entry that triggers release of neurotransmitters from peripheral sympathetic nerve terminals. We have investigated the ability of NCC blockade to prevent lethal arrhythmias associated with heart failure. Methods and results We compared the effects of cilnidipine, a dual N- and L-type Ca2+channel blocker, with those of nitrendipine, a selective L-type Ca2+ channel blocker, in transgenic mice expressing a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor (dnNRSF-Tg). In this mouse model of dilated cardiomyopathy leading to sudden arrhythmic death, cardiac structure and function did not significantly differ among the control, cilnidipine, and nitrendipine groups. However, cilnidipine dramatically reduced arrhythmias in dnNRSF-Tg mice, significantly improving their survival rate and correcting the imbalance between cardiac sympathetic and parasympathetic nervous system activity. A β-blocker, bisoprolol, showed similar effects in these mice. Genetic titration of NCCs, achieved by crossing dnNRSF-Tg mice with mice lacking CACNA1B, which encodes the α1 subunit of NCCs, improved the survival rate. With restoration of cardiac autonomic balance, dnNRSF-Tg;CACNA1B+/− mice showed fewer malignant arrhythmias than dnNRSF-Tg;CACNA1B+/+mice. Conclusions Both pharmacological blockade of NCCs and their genetic titration improved cardiac autonomic balance and prevented lethal arrhythmias in a mouse model of dilated cardiomyopathy and sudden arrhythmic death. Our findings suggest that NCC blockade is a potentially useful approach to preventing sudden death in patients with heart failure.
Rights: This is a pre-copyedited, author-produced PDF of an article accepted for publication in Cardiovascular Research following peer review. The version of record [Yamada, Yuko and Kinoshita, Hideyuki and Kuwahara, Koichiro and Nakagawa, Yasuaki and Kuwabara, Yoshihiro and Minami, Takeya and Yamada, Chinatsu and Shibata, Junko and Nakao, Kazuhiro and Cho, Kosai and Arai, Yuji and Yasuno, Shinji and Nishikimi, Toshio and Ueshima, Kenji and Kamakura, Shiro and Nishida, Motohiro and Kiyonaka, Shigeki and Mori, Yasuo and Kimura, Takeshi and Kangawa, Kenji and Nakao, Kazuwa. Inhibition of N-type Ca2+ channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure. 104(1) 183-193. ] is available online at: http://dx.doi.org/10.1093/cvr/cvu185.
許諾条件により本文ファイルは2015-08-06に公開.
この論文は出版社版でありません。引用の際には出版社版をご確認ご利用ください。This is not the published version. Please cite only the published version.
URI: http://hdl.handle.net/2433/198600
DOI(Published Version): 10.1093/cvr/cvu185
PubMed ID: 25100767
Appears in Collections:Journal Articles

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