Inhibition of N-type Ca2+ channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure.
Inhibition of N-type Ca2+ channels ameliorates an imbalance in cardiac autonomic nerve activity and prevents lethal arrhythmias in mice with heart failure.
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DOI：
10.1093/cvr/cvu185
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发表时间：
2014-10
影响因子：
10.8
通讯作者：
Yuko Yamada;Hideyuki Kinoshita;K. Kuwahara;Y. Nakagawa;Yoshihiro Kuwabara;Takeya Minami;Chinatsu Yamada;J. Shibata;K. Nakao;Kosai Cho;Yuji Arai;S. Yasuno;T. Nishikimi;K. Ueshima;S. Kamakura;M. Nishida;Shigeki Kiyonaka;Y. Mori;Takeshi Kimura;K. Kangawa;K. Nakao
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文献类型：
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作者：
Yuko Yamada;Hideyuki Kinoshita;K. Kuwahara;Y. Nakagawa;Yoshihiro Kuwabara;Takeya Minami;Chinatsu Yamada;J. Shibata;K. Nakao;Kosai Cho;Yuji Arai;S. Yasuno;T. Nishikimi;K. Ueshima;S. Kamakura;M. Nishida;Shigeki Kiyonaka;Y. Mori;Takeshi Kimura;K. Kangawa;K. Nakao
自主神经系统活动失调可引发心力衰竭患者的室性心律失常和猝死。N型Ca（2+）通道（N-typeCa（2+）channels，NCCs）通过调节钙离子内流，触发外周交感神经末梢释放神经递质，在交感神经系统激活中发挥重要作用。我们研究了NCC阻滞剂预防心力衰竭相关致死性心律失常的能力。方法和结果我们比较了西尼地平（一种N-和L-型Ca（2+）通道双重阻滞剂）和尼群地平（一种选择性L-型Ca（2+）通道阻滞剂）在表达心脏特异性、显性阴性形式的神经元限制性沉默因子（dnNRSF-Tg）的转基因小鼠中的作用。在这种扩张型心肌病导致猝死的小鼠模型中，对照组、西尼地平组和尼群地平组之间的心脏结构和功能没有显著差异。然而，西尼地平显着降低dnNRSF-Tg小鼠的心律失常，显着提高其存活率，纠正心脏交感神经和副交感神经系统活动之间的不平衡。β受体阻滞剂比索洛尔在这些小鼠中显示出类似的作用。通过将dnNRSF-Tg小鼠与缺乏CACNA 1B（编码NCC的α1亚基）的小鼠杂交，实现了NCC的遗传滴定，提高了存活率。随着心脏自主平衡的恢复，dnNRSF-Tg; CACNA 1B（+/-）小鼠比dnNRSF-Tg; CACNA 1B（+/+）小鼠表现出更少的恶性心律失常。结论：在扩张型心肌病和猝死的小鼠模型中，NCC的药物阻断和其遗传滴定都改善了心脏自主神经平衡，并预防了致死性心律失常。我们的研究结果表明，NCC阻断是预防心力衰竭患者猝死的潜在有用方法。
AIMS 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. METHODS AND 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.