Institute of Cardiovascular Physiology and Pathophysiology, Biomedical Center Munich, Walter Brendel Centre of Experimental Medicine, Faculty of Medicine (K.H., C.P., C.W.-S.), Ludwig-Maximilians-Universität München, Germany.
Department of Pharmacy, Center for Drug Research (M.B., S.F.), Ludwig-Maximilians-Universität München, Germany.
Circ Res. 2024 May 10;134(10):1348-1378. doi: 10.1161/CIRCRESAHA.123.323250. Epub 2024 May 9.
Loss or dysregulation of the normally precise control of heart rate via the autonomic nervous system plays a critical role during the development and progression of cardiovascular disease-including ischemic heart disease, heart failure, and arrhythmias. While the clinical significance of regulating changes in heart rate, known as the chronotropic effect, is undeniable, the mechanisms controlling these changes remain not fully understood. Heart rate acceleration and deceleration are mediated by increasing or decreasing the spontaneous firing rate of pacemaker cells in the sinoatrial node. During the transition from rest to activity, sympathetic neurons stimulate these cells by activating β-adrenergic receptors and increasing intracellular cyclic adenosine monophosphate. The same signal transduction pathway is targeted by positive chronotropic drugs such as norepinephrine and dobutamine, which are used in the treatment of cardiogenic shock and severe heart failure. The cyclic adenosine monophosphate-sensitive hyperpolarization-activated current (I) in pacemaker cells is passed by hyperpolarization-activated cyclic nucleotide-gated cation channels and is critical for generating the autonomous heartbeat. In addition, this current has been suggested to play a central role in the chronotropic effect. Recent studies demonstrate that cyclic adenosine monophosphate-dependent regulation of HCN4 (hyperpolarization-activated cyclic nucleotide-gated cation channel isoform 4) acts to stabilize the heart rate, particularly during rapid rate transitions induced by the autonomic nervous system. The mechanism is based on creating a balance between firing and recently discovered nonfiring pacemaker cells in the sinoatrial node. In this way, hyperpolarization-activated cyclic nucleotide-gated cation channels may protect the heart from sinoatrial node dysfunction, secondary arrhythmia of the atria, and potentially fatal tachyarrhythmia of the ventricles. Here, we review the latest findings on sinoatrial node automaticity and discuss the physiological and pathophysiological role of HCN pacemaker channels in the chronotropic response and beyond.
心率通过自主神经系统的正常精确控制的丧失或失调在心血管疾病的发展和进展中起着关键作用，包括缺血性心脏病、心力衰竭和心律失常。虽然调节心率变化（称为变时作用）的临床意义是不可否认的，但控制这些变化的机制仍不完全清楚。心率的加速和减速是通过增加或减少窦房结起搏细胞的自发发放率来介导的。在从休息到活动的过渡期间，交感神经元通过激活β肾上腺素能受体和增加细胞内环磷酸腺苷来刺激这些细胞。相同的信号转导途径被正性变时药物如去甲肾上腺素和多巴酚丁胺靶向，这些药物用于治疗心源性休克和严重心力衰竭。起搏细胞中的环磷酸腺苷敏感超极化激活电流（I）通过超极化激活环核苷酸门控阳离子通道传递，对于产生自主心跳至关重要。此外，该电流被认为在变时作用中起核心作用。最近的研究表明，环磷酸腺苷依赖性调节 HCN4（超极化激活环核苷酸门控阳离子通道同工型 4）作用是稳定心率，特别是在自主神经系统诱导的快速率转换期间。该机制基于在窦房结中创建放电和最近发现的非放电起搏细胞之间的平衡。通过这种方式，超极化激活环核苷酸门控阳离子通道可以保护心脏免受窦房结功能障碍、心房的继发心律失常以及潜在致命的心室心动过速的影响。在这里，我们回顾了窦房结自动性的最新发现，并讨论了 HCN 起搏通道在变时反应中的生理和病理生理作用以及其他作用。
