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: OBJECTIVE
  Dysregulation of autonomic nervous system activity can trigger ventricular arrhythmias and sudden death in patients with heart failure. N-type Ca(2+) 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.
  
  
  RESULTS
  We compared the effects of cilnidipine, a dual N- and L-type Ca(2+) channel blocker, with those of nitrendipine, a selective L-type Ca(2+) 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.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan Department of Peptide Research, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kinoshita
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan kuwa@kuhp.kyoto-u.ac.jp.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kuwahara
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan Department of EBM Research, Institute for Advanced of Clinical and Translational Science, Kyoto University Hospital, Kyoto 606-8507, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kuwabara
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Takeya
authors.initials: T
authors.lastname: Minami
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Yamada
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Shibata
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan Department of Peptide Research, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan Department of Primary Care and Emergency Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Kosai
authors.initials: K
authors.lastname: Cho
authors.affiliation: Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, Suita 565-8565, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Arai
authors.affiliation: Department of EBM Research, Institute for Advanced of Clinical and Translational Science, Kyoto University Hospital, Kyoto 606-8507, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Yasuno
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Nishikimi
authors.affiliation: Department of EBM Research, Institute for Advanced of Clinical and Translational Science, Kyoto University Hospital, Kyoto 606-8507, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ueshima
authors.affiliation: Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita 565-8565, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Kamakura
authors.affiliation: Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institute for Natural Sciences, Aichi 444-8787, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Nishida
authors.affiliation: Department of Synthetic Chemistry and Biological Chemistry, Kyoto University Graduated School of Engineering, Kyoto 615-8530, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kiyonaka
authors.affiliation: Department of Synthetic Chemistry and Biological Chemistry, Kyoto University Graduated School of Engineering, Kyoto 615-8530, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Peptide Research, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita 606-8507, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawaharacho, Sakyo-ku, Kyoto 606-8507, Japan Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D001341:Autonomic Nervous System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D016757:Death, Sudden, Cardiac / Q000209:etiology / Q000517:prevention & control*; D004095:Dihydropyridines / Q000494:pharmacology*; D004195:Disease Models, Animal; D006321:Heart / Q000294:innervation*; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009568:Nitrendipine / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects; D000099229:RE1-Silencing Transcription Factor
chemical_list: D000319:Adrenergic beta-Antagonists; D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D004095:Dihydropyridines; D009568:Nitrendipine; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C500963:Cacna1b protein, mouse; C065927:cilnidipine
keywords: Arrhythmia; Autonomic; Heart failure; Ion channel; N-type Ca2+ channel; Nervous system