Inhibition of N-type Ca2+ channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure

Yuko Yamada, Hideyuki Kinoshita, Koichiro Kuwahara, Yasuaki Nakagawa, Yoshihiro Kuwabara, Takeya Minami, Chinatsu Yamada, Junko Shibata, Kazuhiro Nakao, Kosai Cho, Yuji Arai, Shinji Yasuno, Toshio Nishikimi, Kenji Ueshima, Shiro Kamakura, Motohiro Nishida, Shigeki Kiyonaka, Yasuo Mori, Takeshi Kimura, Kenji KangawaKazuwa Nakao

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)183-193
Number of pages11
JournalCardiovascular research
Volume104
Issue number1
DOIs
Publication statusPublished - Oct 1 2014
Externally publishedYes

Fingerprint

Autonomic Pathways
Cardiac Arrhythmias
Heart Failure
Sudden Death
Nitrendipine
Sympathetic Nervous System
Dilated Cardiomyopathy
Survival Rate
Bisoprolol
Parasympathetic Nervous System
Autonomic Nervous System
Sudden Cardiac Death
Peripheral Nerves
Transgenic Mice
Neurotransmitter Agents
Pharmacology
Calcium

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Inhibition of N-type Ca2+ channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure. / Yamada, Yuko; Kinoshita, Hideyuki; Kuwahara, Koichiro; Nakagawa, Yasuaki; Kuwabara, Yoshihiro; Minami, Takeya; Yamada, Chinatsu; Shibata, Junko; Nakao, Kazuhiro; Cho, Kosai; Arai, Yuji; Yasuno, Shinji; Nishikimi, Toshio; Ueshima, Kenji; Kamakura, Shiro; Nishida, Motohiro; Kiyonaka, Shigeki; Mori, Yasuo; Kimura, Takeshi; Kangawa, Kenji; Nakao, Kazuwa.

In: Cardiovascular research, Vol. 104, No. 1, 01.10.2014, p. 183-193.

Research output: Contribution to journalArticle

Yamada, Y, Kinoshita, H, Kuwahara, K, Nakagawa, Y, Kuwabara, Y, Minami, T, Yamada, C, Shibata, J, Nakao, K, Cho, K, Arai, Y, Yasuno, S, Nishikimi, T, Ueshima, K, Kamakura, S, Nishida, M, Kiyonaka, S, Mori, Y, Kimura, T, Kangawa, K & Nakao, K 2014, 'Inhibition of N-type Ca2+ channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure', Cardiovascular research, vol. 104, no. 1, pp. 183-193. https://doi.org/10.1093/cvr/cvu185
Yamada, Yuko ; Kinoshita, Hideyuki ; Kuwahara, Koichiro ; Nakagawa, Yasuaki ; Kuwabara, Yoshihiro ; Minami, Takeya ; Yamada, Chinatsu ; Shibata, Junko ; Nakao, Kazuhiro ; Cho, Kosai ; Arai, Yuji ; Yasuno, Shinji ; Nishikimi, Toshio ; Ueshima, Kenji ; Kamakura, Shiro ; Nishida, Motohiro ; Kiyonaka, Shigeki ; Mori, Yasuo ; Kimura, Takeshi ; Kangawa, Kenji ; 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. In: Cardiovascular research. 2014 ; Vol. 104, No. 1. pp. 183-193.
@article{aeb373bd15a14f348e556718ee3a4a22,
title = "Inhibition of N-type Ca2+ channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure",
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.",
author = "Yuko Yamada and Hideyuki Kinoshita and Koichiro Kuwahara and Yasuaki Nakagawa and Yoshihiro Kuwabara and Takeya Minami and Chinatsu Yamada and Junko Shibata and Kazuhiro Nakao and Kosai Cho and Yuji Arai and Shinji Yasuno and Toshio Nishikimi and Kenji Ueshima and Shiro Kamakura and Motohiro Nishida and Shigeki Kiyonaka and Yasuo Mori and Takeshi Kimura and Kenji Kangawa and Kazuwa Nakao",
year = "2014",
month = "10",
day = "1",
doi = "10.1093/cvr/cvu185",
language = "English",
volume = "104",
pages = "183--193",
journal = "Cardiovascular Research",
issn = "0008-6363",
publisher = "Oxford University Press",
number = "1",

}

TY - JOUR

T1 - Inhibition of N-type Ca2+ channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure

AU - Yamada, Yuko

AU - Kinoshita, Hideyuki

AU - Kuwahara, Koichiro

AU - Nakagawa, Yasuaki

AU - Kuwabara, Yoshihiro

AU - Minami, Takeya

AU - Yamada, Chinatsu

AU - Shibata, Junko

AU - Nakao, Kazuhiro

AU - Cho, Kosai

AU - Arai, Yuji

AU - Yasuno, Shinji

AU - Nishikimi, Toshio

AU - Ueshima, Kenji

AU - Kamakura, Shiro

AU - Nishida, Motohiro

AU - Kiyonaka, Shigeki

AU - Mori, Yasuo

AU - Kimura, Takeshi

AU - Kangawa, Kenji

AU - Nakao, Kazuwa

PY - 2014/10/1

Y1 - 2014/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84913589723&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84913589723&partnerID=8YFLogxK

U2 - 10.1093/cvr/cvu185

DO - 10.1093/cvr/cvu185

M3 - Article

C2 - 25100767

AN - SCOPUS:84913589723

VL - 104

SP - 183

EP - 193

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 1

ER -