更新于：2024-11-01

β-adrenoceptors x HCN channels

更新于：2024-11-01

基本信息

关联

项与 β-adrenoceptors x HCN channels 相关的药物

Ivabradine Hydrochloride/Metoprolol Tartrate

盐酸伊伐布雷定/酒石酸美托洛尔

靶点

HCN channels x β-adrenoceptors

作用机制

HCN channels阻滞剂 [+1]

在研机构

Les Laboratoires Servier SAS

原研机构

Les Laboratoires Servier SAS

在研适应症

心绞痛

非在研适应症-

最高研发阶段批准上市

首次获批国家/地区

荷兰

首次获批日期2015-01-01

100 项与 β-adrenoceptors x HCN channels 相关的临床结果

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100 项与 β-adrenoceptors x HCN channels 相关的转化医学

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0 项与 β-adrenoceptors x HCN channels 相关的专利（医药）

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项与 β-adrenoceptors x HCN channels 相关的文献（医药）

2024-05-10·Circulation Research

Pacemaker Channels and the Chronotropic Response in Health and Disease

Review

作者: Fenske, Stefanie ; Hennis, Konstantin ; Wahl-Schott, Christian ; Biel, Martin ; Piantoni, Chiara

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 f ) 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.

2023-06-19·Philosophical transactions of the Royal Society of London. Series B, Biological sciences

Non-canonical role of the sympathetic nervous system in the day-night rhythm in heart rate.

Article

作者: Hu, Wei ; Anderson, Cali ; Boyett, Mark R ; Zhang, Henggui ; Forte, Gabriella ; D'Souza, Alicia

Although, for many decades, the day-night rhythm in resting heart rate has been attributed to the parasympathetic branch of the autonomic nervous system (high vagal tone during sleep), recently we have shown that there is a circadian clock in the cardiac pacemaker, the sinus node, and the day-night rhythm in heart rate involves an intrinsic rhythmic transcriptional remodelling of pacemaker ion channels, particularly Hcn4. We have now investigated the role of the sympathetic branch of the autonomic nervous system in this and shown it to have a non-canonical role. In mice, sustained long-term block of cardiac β-adrenergic receptors by propranolol administered in the drinking water abolished the day-night rhythm in pacemaking in the isolated sinus node. Concomitant with this, there was a loss of the normal day-night rhythm in many pacemaker ion channel transcripts. However, there was little or no change in the local circadian clock, indicating that the well-known day-night rhythm in sympathetic nerve activity is directly involved in pacemaker ion channel transcription. The day-night rhythm in pacemaking helps explain the occurrence of clinically significant bradyarrhythmias during sleep, and this study improves our understanding of this pathology. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.

2021-07-13·Proceedings of the National Academy of Sciences1区 · 综合性期刊

Bidirectional flow of the funny current (I _f ) during the pacemaking cycle in murine sinoatrial node myocytes

1区 · 综合性期刊

Article

作者: Morotti, Stefano ; Liu, Pin W. ; Proenza, Catherine ; Peters, Colin H. ; Gantz, Stephanie C. ; Grandi, Eleonora ; Bean, Bruce P.

Significance The funny current (I f ) is critical for spontaneous activity in cardiac pacemaker cells; however, its precise role remains enigmatic because it activates mostly outside the physiological voltage range and its kinetics are slow relative to the cardiac cycle. I f is typically considered as an inward current; however, we show that I f is persistently active in pacemaker cells. Once opened, the small fraction of ion channels that conduct I f do not reclose. Consequently, I f flows both inward and outward and, paradoxically, conducts a large fraction of the net charge movement. These results establish a new conceptual framework for pacemaking in which voltage-dependent gating of I f is minimal and I f contributes to spontaneous pacemaker activity by providing driving force in both directions.