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
N1 - Funding Information:
This research was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (23390210, 24659386 to K.K., 24591095 to H.K., 22590810 to Y.N., 21229013 to N.K.); the Japanese Ministry of Health, Labor and Welfare (N.K.); the Japan Foundation for Applied Enzymology (K.K.); the UBE foundation (K.K.); the Ichiro Kanehara Foundation (K.K.); the Takeda Science Foundation (K.K.); the Hoh-ansha Foundation (K.K.); the SENSHIN Medical Research Foundation (K.K.).
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.
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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 -