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本公众号每天分享一篇最新一期Anesthesia & Analgesia等SCI杂志的摘要翻译，敬请关注并提出宝贵意见 HCN4 pacemaker channels attenuate the parasympathetic response and stabilize the spontaneous firing of the sinoatrial node. 背景与目的 心率由交感神经和副交感神经系统动态控制，这些系统调节窦房结(SAN)。HCN 4起搏器通道是先天性病态窦房结综合征的著名致病分子.虽然HCN4通道被cAMP激活，但HCN 4基因缺失突变患者仍保留SAN的交感神经反应。 方 法 为了阐明HCN4通道在SAN自主神经调节中的作用，我们研制了一种新型的功能获得性突变小鼠，利用四环素反式激活剂和四环素应答元件，HCN4通道的表达水平可可逆地从野生型小鼠的零变为3倍。我们的遥感心电图记录自由活动的清醒小鼠的心率变异性并分析。我们还评估了SAN对颈迷走神经刺激(CVNS)的反应。 结 果 HCN4的条件性过表达并不能诱发心动过速，但可降低心率变异性。HCN4过表达还可减轻由CVN仅在β-肾上腺素能刺激时引起的心动过缓。相反，HCN4的敲除导致窦性心律失常，并增强副交感神经反应；由CVNS诱导的完全性窦性停顿。在体外，我们比较了乙酰胆碱对单个起搏器细胞自发动作电位的影响，发现在β-肾上腺素能刺激和没有β-肾上腺素能刺激的情况下，HCN 4基因的表达都会引起类似的表型变化。 结 论 我们的研究表明，HCN4通道可以减弱SAN的迷走神经反应，从而稳定了SAN的自发放电。 原始文献摘要 Kozasa Y, Nakashima N, Ito M,et.al. HCN4 pacemaker channels attenuate the parasympathetic response and stabilize the spontaneous firing of the sinoatrial node. J Physiol. 2018 Jan 9. doi: 10.1113/JP275303. ABSTRACT: The heart rate is dynamically controlled by the sympathetic and parasympathetic nervous systems that regulate the sinoatrial node (SAN). HCN4 pacemaker channels are the well-known causative molecule of congenital sick sinus syndrome. Although HCN4 channels are activated by cAMP, the sympathetic response of the SAN was preserved in patients carrying loss-of-function mutations of the HCN4 gene. In order to clarify the contribution of HCN4 channels in the autonomic regulation of the SAN, we developed novel gain-of-function mutant mice in which the expression level of HCN4 channels could be reversibly changed from zero to ∼3 times that in wild-type mice, using tetracycline transactivator and the tetracycline responsive element. We recorded telemetric ECGs in freely moving conscious mice and analysed the heart rate variability. We also evaluated the response of the SAN to cervical vagus nerve stimulation (CVNS). The conditional overexpression of HCN4 did not induce tachycardia, but reduced heart rate variability. The HCN4 overexpression also attenuated bradycardia induced by the CVNS only during the β-adrenergic stimulation. In contrast, the knockdown of HCN4 gave rise to sinus arrhythmia, and enhanced the parasympathetic response; complete sinus pause was induced by the CVNS. In vitro, we compared the effects of acetylcholine on the spontaneous action potentials of single pacemaker cells, and found that similar phenotypic changes were induced by genetic manipulation of HCN4 expression both in the presence and absence of β-adrenergic stimulation. Our study suggests that HCN4 channels attenuate the vagal response of the SAN, and thereby stabilize the spontaneous firing of the SAN. 麻醉学文献进展分享 联系我们 |
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