New evidence for coupled clock regulation of the normal automaticity of sinoatrial nodal pacemaker cells: bradycardic effects of ivabradine are linked to suppression of intracellular Ca²⁺ cycling.
New evidence for coupled clock regulation of the normal automaticity of sinoatrial nodal pacemaker cells: bradycardic effects of ivabradine are linked to suppression of intracellular Ca²⁺ cycling.
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DOI：
10.1016/j.yjmcc.2013.04.026
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发表时间：
2013-09
影响因子：
5
通讯作者：
Lakatta, Edward G.
中科院分区：
文献类型：
--
作者：
Yaniv, Yael;Sirenko, Syevda;Ziman, Bruce D.;Spurgeon, Harold A.;Maltsev, Victor A.;Lakatta, Edward G.
伊伐布雷定（IVA）的有益临床心动过缓作用仅基于If抑制进行解释，因为IVA特异性抑制窦房结起搏细胞（SANC）中的If。然而，最近有人假设SANC正常自律性是由“M时钟”（表面膜离子通道的集合）和“Ca 2+时钟”（肌浆网（SR））之间的串扰调节的。我们测试的假设，这两个时钟之间的串扰调节SANC自律性，和间接抑制的Ca 2+时钟进一步有助于IVA诱导的心动过缓。IVA（3μM）不仅使离体兔SANC的If振幅降低45±6%，而且IVA引起的动作电位（AP）放电频率的减慢伴随着SR Ca 2+负荷的降低，细胞内Ca 2+循环动力学减慢，舒张期去极化过程中自发性局部Ca 2+释放（LCR）的时间延长。环匹阿尼酸（CPA）直接特异性抑制SERCA 2对LCR周期和AP周期长度的影响与IVA相似。具体地，LCR周期和AP周期长度通过M时钟（IVA）或Ca 2+时钟（CPA）的直接扰动几乎相等地向更长时间偏移，指示LCR周期报告时钟之间的串扰。我们的数值模型模拟预测，在舒张期去极化过程中，需要两个时钟之间的夹带，涉及INCX的减少，以解释实验AP放电率降低IVA。总之，我们的研究提供了新的证据，耦合时钟系统调节正常的心脏起搏细胞自动化。因此，IVA诱导的心动过缓包括该系统内的两个时钟的抑制。
Beneficial clinical bradycardic effects of ivabradine (IVA) have been interpreted solely on the basis of If inhibition, because IVA specifically inhibits If in sinoatrial nodal pacemaker cells (SANC). However, it has been recently hypothesized that SANC normal automaticity is regulated by crosstalk between an “M clock,” the ensemble of surface membrane ion channels, and a “Ca2+ clock,” the sarcoplasmic reticulum (SR). We tested the hypothesis that crosstalk between the two clocks regulates SANC automaticity, and that indirect suppression of the Ca2+ clock further contributes to IVA-induced bradycardia. IVA (3μM) not only reduced If amplitude by 45±6% in isolated rabbit SANC, but the IVA-induced slowing of the action potential (AP) firing rate was accompanied by reduced SR Ca2+ load, slowed intracellular Ca2+ cycling kinetics, and prolonged the period of spontaneous local Ca2+ releases (LCRs) occurring during diastolic depolarization. Direct and specific inhibition of SERCA2 by cyclopiazonic acid (CPA) had effects similar to IVA on LCR period and AP cycle length. Specifically, the LCR period and AP cycle length shift toward longer times almost equally by either direct perturbations of the M clock (IVA) or the Ca2+ clock (CPA), indicating that the LCR period reports the crosstalk between the clocks. Our numerical model simulations predict that entrainment between the two clocks that involves a reduction in INCX during diastolic depolarization is required to explain the experimentally AP firing rate reduction by IVA. In summary, our study provides new evidence that a coupled-clock system regulates normal cardiac pacemaker cell automaticity. Thus, IVA-induced bradycardia includes a suppression of both clocks within this system.
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影响因子：
39.3
作者：
Heusch, Gerd;Skyschally, Andreas;Schulz, Rainer
通讯作者：
Schulz, Rainer
影响因子：
3.8
作者：
Bucchi, Annalisa;Baruscotti, Mirko;DiFrancesco, Dario
通讯作者：
DiFrancesco, Dario
影响因子：
1.9
作者：
Busseuil, David;Shi, Yanfen;Tardif, Jean-Claude
通讯作者：
Tardif, Jean-Claude
影响因子：
5.5
作者：
Honjo, H;Boyett, MR;Toyama, J
通讯作者：
Toyama, J
影响因子：
20.1
作者：
Lyashkov, Alexey E.;Juhaszova, Magdalena;Lakatta, Edward G.
通讯作者：
Lakatta, Edward G.