Faculty Opinions recommendation of The impacts of age and frailty on heart rate and sinoatrial node function.

Sympathetic activation increases heart rate (HR) and reduces atrioventricular interval (AVI), whereas atrial pacing alone increases AVI. We sought to differentiate the direct effects of sympathetic activation on atrioventricular (AV) conduction time from the indirect changes associated with concurrent alterations in HR. We recorded electrocardiograms, blood pressure (BP), and intracardiac electrograms from chloralose-anesthetized autonomically decentralized dogs. Beat-by-beat HR and AVI data were collected continuously. Sympathetic stimulation (0.25-2.5 Hz; mean 0.81 Hz) resulted in a HR change of +60 beats/min after 60 s. This tachycardia was associated with a mean decrease in AVI of 22 ms. Computer-driven atrial pacing to reproduce the HR associated with control sympathetic stimulation caused a mean AVI increase of 10 ms. Propranolol (200 micrograms) was then administered via the sinoatrial node artery and sympathetic stimulation repeated. Although HR remained constant, AVI decreased by 14.8 ms. The AVIs associated with an identical HR achieved by two different mechanisms (sympathetic stimulation and atrial pacing) were significantly different. Although removal of the contribution of sympathetically induced HR changes on AV conduction might be expected to result in potentiation of neural effects at the AV node, none was evident. Thus sympathetic activity restricted to the AV node is less effective in influencing AV conduction than the response that occurs when HR changes occur concurrently. Therefore, the opposing actions of HR and sympathetic tone on AV conduction may not be predicted by a simple linear relationship.

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β3 Adrenergic Receptors in the Sinoatrial Node for Heart Rate Regulation

European Cardiology Review ◽

10.15420/ecr.2021.16.po2 ◽

2021 ◽

Vol 16 ◽

Author(s):

Shu Nakao ◽

Kazuki Yanagisawa ◽

Tomoe Ueyama ◽

Koji Hasegawa ◽

Teruhisa Kawamura

Keyword(s):

Heart Rate ◽

Adrenergic Receptors ◽

Sinoatrial Node ◽

Rate Regulation ◽

Heart Rate Regulation

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Shenxian-Shengmai Oral Liquid Improves Sinoatrial Node Dysfunction through the PKC/NOX-2 Signaling Pathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2021/5572140 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Heng Zhang ◽

Miao Hao ◽

Lingkang Li ◽

Keyan Chen ◽

Jing Qi ◽

...

Keyword(s):

Heart Rate ◽

Signaling Pathway ◽

Sinoatrial Node ◽

Cardiac Conduction ◽

Potential Mechanism ◽

Cardiac Syncope ◽

Common Causes ◽

Oral Liquid ◽

Masson Staining

Sick sinus syndrome (SSS) is one of the common causes of cardiac syncope and sudden death; the occurrence of SSS is associated with the accumulation of ROS in the sinoatrial node (SAN). Shenxian-shengmai (SXSM) is a traditional Chinese medicine available as oral liquid that causes a significant increase in heart rate. The objective of this study is to observe the improvement of SXSM on SAN function in SSS mice and explore its potential mechanism. In the current study, SSS was simulated in mice by inducing SAN dysfunction using a micro-osmotic pump to inject angiotensin II (Ang II). The mouse model with SSS was used to determine the effect of SXSM on SAN function and to explore its potential mechanism. Furthermore, the HL-1 cell line, derived from mouse atrial myocytes, was used to simulate SAN pacemaker cells. Our results indicated that SXSM significantly increased the heart rate of SSS mice by reducing the AngII-induced accumulation of ROS in the SAN and by inhibiting the expression of HDAC4, thereby reducing the loss of HCN4, a critical component of the cardiac conduction system. MASSON staining revealed a reduction of SAN damage in SSS mice that were treated with SXSM compared with controls. In vitro experiments showed that AngII treatment caused an upregulation of the PKC/NOX-2 signaling pathway in HL-1 cells which could be prevented by pretreatment with SXSM. The protective effect of SXSM was attenuated upon treatment with the PCK agonist PMA. In conclusion, SXSM reduced the AngII-induced accumulation of ROS in the SAN through the PKC/NOX2 signaling pathway, improving the functioning of the SAN and preventing the decrease of heart rate in SSS mice.

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Phosphorylation and modulation of hyperpolarization-activated HCN4 channels by protein kinase A in the mouse sinoatrial node

The Journal of General Physiology ◽

10.1085/jgp.201010488 ◽

2010 ◽

Vol 136 (3) ◽

pp. 247-258 ◽

Cited By ~ 56

Author(s):

Zhandi Liao ◽

Dean Lockhead ◽

Eric D. Larson ◽

Catherine Proenza

Keyword(s):

Heart Rate ◽

Protein Kinase ◽

Cyclic Nucleotide ◽

Sinoatrial Node ◽

Voltage Dependence ◽

C Terminus ◽

Sympathetic Regulation ◽

Direct Binding ◽

End Effectors

The sympathetic nervous system increases heart rate by activating β adrenergic receptors and increasing cAMP levels in myocytes in the sinoatrial node. The molecular basis for this response is not well understood; however, the cardiac funny current (If) is thought to be among the end effectors for cAMP signaling in sinoatrial myocytes. If is produced by hyperpolarization-activated cyclic nucleotide–sensitive (HCN4) channels, which can be potentiated by direct binding of cAMP to a conserved cyclic nucleotide binding domain in the C terminus of the channels. β adrenergic regulation of If in the sinoatrial node is thought to occur via this direct binding mechanism, independent of phosphorylation. Here, we have investigated whether the cAMP-activated protein kinase (PKA) can also regulate sinoatrial HCN4 channels. We found that inhibition of PKA significantly reduced the ability of β adrenergic agonists to shift the voltage dependence of If in isolated sinoatrial myocytes from mice. PKA also shifted the voltage dependence of activation to more positive potentials for heterologously expressed HCN4 channels. In vitro phosphorylation assays and mass spectrometry revealed that PKA can directly phosphorylate at least 13 sites on HCN4, including at least three residues in the N terminus and at least 10 in the C terminus. Functional analysis of truncated and alanine-substituted HCN4 channels identified a PKA regulatory site in the distal C terminus of HCN4, which is required for PKA modulation of If. Collectively, these data show that native and expressed HCN4 channels can be regulated by PKA, and raise the possibility that this mechanism could contribute to sympathetic regulation of heart rate.

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RGS4 Regulates Parasympathetic Signaling and Heart Rate Control in the Sinoatrial Node

Circulation Research ◽

10.1161/circresaha.108.180984 ◽

2008 ◽

Vol 103 (5) ◽

pp. 527-535 ◽

Cited By ~ 82

Author(s):

Carlo Cifelli ◽

Robert A. Rose ◽

Hangjun Zhang ◽

Julia Voigtlaender-Bolz ◽

Steffen-Sebastian Bolz ◽

...

Keyword(s):

Heart Rate ◽

Rate Control ◽

Sinoatrial Node ◽

Heart Rate Control

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Chronic heart rate reduction remodels ion channel transcripts in the mouse sinoatrial node but not in the ventricle

Physiological Genomics ◽

10.1152/physiolgenomics.00161.2005 ◽

2006 ◽

Vol 24 (1) ◽

pp. 4-12 ◽

Cited By ~ 30

Author(s):

Anne-Laure Leoni ◽

Céline Marionneau ◽

Sophie Demolombe ◽

Sabrina Le Bouter ◽

Matteo E. Mangoni ◽

...

Keyword(s):

Heart Rate ◽

Ion Channel ◽

Clustering Analysis ◽

Connexin 43 ◽

Sinoatrial Node ◽

Rt Pcr ◽

Cardiac Electrical Activity ◽

Channel Expression ◽

Freely Moving ◽

Α Subunits

We investigated the effects of chronic and moderate heart rate (HR) reduction on ion channel expression in the mouse sinoatrial node (SAN) and ventricle. Ten-week-old male C57BL/6 mice were treated twice daily with either vehicle or ivabradine at 5 mg/kg given orally during 3 wk. The effects of HR reduction on cardiac electrical activity were investigated in anesthetized mice with serial ECGs and in freely moving mice with telemetric recordings. With the use of high-throughput real-time RT-PCR, the expression of 68 ion channel subunits was evaluated in the SAN and ventricle at the end of the treatment period. In conscious mice, ivabradine induced a mean 16% HR reduction over a 24-h period that was sustained over the 3-wk administration. Other ECG parameters were not modified. Two-way hierarchical clustering analysis of gene expression revealed a separation of ventricles from SANs but no discrimination between treated and untreated ventricles, indicating that HR reduction per se induced limited remodeling in this tissue. In contrast, SAN samples clustered in two groups depending on the treatment. In the SAN from ivabradine-treated mice, the expression of nine ion channel subunits, including Navβ1 (−25%), Cav3.1 (−29%), Kir6.1 (−28%), Kvβ2 (−41%), and Kvβ3 (−30%), was significantly decreased. Eight genes were significantly upregulated, including K+ channel α-subunits (Kv1.1, +30%; Kir2.1, +29%; Kir3.1, +41%), hyperpolarization-activated cation channels (HCN2, +24%; HCN4, +52%), and connexin 43 (+26%). We conclude that reducing HR induces a complex remodeling of ion channel expression in the SAN but has little impact on ion channel transcripts in the ventricle.

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Novel Pathways for Regulation of Sinoatrial Node Plasticity and Heart Rate

Circulation Research ◽

10.1161/circresaha.117.311922 ◽

2017 ◽

Vol 121 (9) ◽

pp. 1027-1028 ◽

Cited By ~ 1

Author(s):

Peter J. Mohler ◽

Thomas J. Hund

Keyword(s):

Heart Rate ◽

Sinoatrial Node

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The impacts of frailty on heart rate variability in aging mice: roles of the autonomic nervous system and sinoatrial node

Heart Rhythm ◽

10.1016/j.hrthm.2021.07.069 ◽

2021 ◽

Author(s):

Tristan W. Dorey ◽

Hailey J. Jansen ◽

Motahareh Moghtadaei ◽

K. Lockhart Jamieson ◽

Robert A. Rose

Keyword(s):

Heart Rate ◽

Heart Rate Variability ◽

Nervous System ◽

Autonomic Nervous System ◽

Sinoatrial Node ◽

Autonomic Nervous

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STIM1–Ca2+ signaling modulates automaticity of the mouse sinoatrial node

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1503847112 ◽

2015 ◽

Vol 112 (41) ◽

pp. E5618-E5627 ◽

Cited By ~ 28

Author(s):

Hengtao Zhang ◽

Albert Y. Sun ◽

Jong J. Kim ◽

Victoria Graham ◽

Elizabeth A. Finch ◽

...

Keyword(s):

Heart Rate ◽

Sinoatrial Node ◽

Membrane Surface ◽

Surface Membrane ◽

Autonomic Response ◽

Sinus Arrest ◽

Cholinergic Signaling ◽

Ionic Fluxes ◽

Cardiac Pacemaking ◽

Specific Deletion

Cardiac pacemaking is governed by specialized cardiomyocytes located in the sinoatrial node (SAN). SAN cells (SANCs) integrate voltage-gated currents from channels on the membrane surface (membrane clock) with rhythmic Ca2+ release from internal Ca2+ stores (Ca2+ clock) to adjust heart rate to meet hemodynamic demand. Here, we report that stromal interaction molecule 1 (STIM1) and Orai1 channels, key components of store-operated Ca2+ entry, are selectively expressed in SANCs. Cardiac-specific deletion of STIM1 in mice resulted in depletion of sarcoplasmic reticulum (SR) Ca2+ stores of SANCs and led to SAN dysfunction, as was evident by a reduction in heart rate, sinus arrest, and an exaggerated autonomic response to cholinergic signaling. Moreover, STIM1 influenced SAN function by regulating ionic fluxes in SANCs, including activation of a store-operated Ca2+ current, a reduction in L-type Ca2+ current, and enhancing the activities of Na+/Ca2+ exchanger. In conclusion, these studies reveal that STIM1 is a multifunctional regulator of Ca2+ dynamics in SANCs that links SR Ca2+ store content with electrical events occurring in the plasma membrane, thereby contributing to automaticity of the SAN.

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