|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.|
|Author's alias:||桑原, 宏一郎|
N-type Ca[2+] channel
|Publisher:||Oxford University Press|
|Journal title:||Cardiovascular research|
|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.|
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|Appears in Collections:||Journal Articles |
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