scholarly journals cAMP-dependent regulation of HCN4 controls the tonic entrainment process in sinoatrial node pacemaker cells

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Stefanie Fenske ◽  
Konstantin Hennis ◽  
René D. Rötzer ◽  
Verena F. Brox ◽  
Elvir Becirovic ◽  
...  
Keyword(s):  
Heart Rate ◽  
Sinoatrial Node ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Mouse Line ◽  
Pacemaker Cells ◽  
Heart Rate Regulation ◽  
Cardiac Phenotype ◽  
Pacemaker Channel ◽  
Central Pacemaker

Abstract It is highly debated how cyclic adenosine monophosphate-dependent regulation (CDR) of the major pacemaker channel HCN4 in the sinoatrial node (SAN) is involved in heart rate regulation by the autonomic nervous system. We addressed this question using a knockin mouse line expressing cyclic adenosine monophosphate-insensitive HCN4 channels. This mouse line displayed a complex cardiac phenotype characterized by sinus dysrhythmia, severe sinus bradycardia, sinus pauses and chronotropic incompetence. Furthermore, the absence of CDR leads to inappropriately enhanced heart rate responses of the SAN to vagal nerve activity in vivo. The mechanism underlying these symptoms can be explained by the presence of nonfiring pacemaker cells. We provide evidence that a tonic and mutual interaction process (tonic entrainment) between firing and nonfiring cells slows down the overall rhythm of the SAN. Most importantly, we show that the proportion of firing cells can be increased by CDR of HCN4 to efficiently oppose enhanced responses to vagal activity. In conclusion, we provide evidence for a novel role of CDR of HCN4 for the central pacemaker process in the sinoatrial node.

scholarly journals β3 Adrenergic Receptors in the Sinoatrial Node for Heart Rate Regulation

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

Ivabradine augments high-frequency dynamic gain of the heart rate response to low- and moderate-intensity vagal nerve stimulation under beta-blockade

2021 ◽  
Author(s):  
Toru Kawada ◽  
Hiromi Yamamoto ◽  
Kazunori Uemura ◽  
Yohsuke Hayama ◽  
Takuya Nishikawa ◽  
...  
Keyword(s):  
Heart Rate ◽  
Nerve Stimulation ◽  
High Frequency ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Vagal Nerve ◽  
Vagal Nerve Stimulation ◽  
Moderate Intensity ◽  
Beta Blockade ◽  
Hcn Channels

Our previous study indicated that intravenously administered ivabradine (IVA) augmented the dynamic heart rate (HR) response to moderate-intensity vagal nerve stimulation (VNS). Considering an accentuated antagonism, the results were somewhat paradoxical; i.e., the accentuated antagonism indicates that an activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels via the accumulation of intracellular cyclic adenosine monophosphate (cAMP) augments the HR response to VNS, whereas the inhibition of HCN channels by IVA also augmented the HR response to VNS. To remove the possible influence from the accentuated antagonism, we examined the effects of IVA on the dynamic vagal control of HR under beta-blockade. In anesthetized rats (n = 7), the right vagal nerve was stimulated for 10 min according to binary white noise signals between 0 and 10 Hz (V0-10), between 0 and 20 Hz (V0-20), and between 0 and 40 Hz (V0-40). The transfer function from VNS to HR was estimated. Under beta-blockade (propranolol, 2 mg/kg, i.v.), IVA (2 mg/kg, i.v.) did not augment the asymptotic low-frequency gain but increased the asymptotic high-frequency gain in V0-10 (0.53 ± 0.10 vs. 1.74 ± 0.40 beats·min−1·Hz−1, P < 0.01) and V0-20 (0.79 ± 0.14 vs. 2.06 ± 0.47 beats·min−1·Hz−1, P < 0.001). These changes, which were observed under a minimal influence from sympathetic background tone, may reflect an increased contribution of the acetylcholine-sensitive potassium channel (IK,ACh) pathway after IVA, because the HR control via the IK,ACh pathway is faster and acts in the frequency range higher than the cAMP-mediated pathway.

Abstract 16515: Differential Functions of HCN1 and HCN4 Pacemaker Channels Within the Sinoatrial Node for the Stable and Precise Beating of the Heart

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Stefanie Fenske ◽  
Vanessa Marks ◽  
Stefanie Koenigsbauer ◽  
Sami I Hassan ◽  
Tilman Ziegler ◽  
...  
Keyword(s):  
Heart Rate ◽  
Mouse Models ◽  
Sinoatrial Node ◽  
Critical Role ◽  
Functional Characterization ◽  
Heart Beat ◽  
Fine Tuning ◽  
Hcn Channels ◽  
Pacemaker Cells

The heart beat is initiated by the generation of spontaneous action potentials in pacemaker cells of the sinoatrial node (SAN) region. The maintenance of a stable heart beat requires mechanisms which protect the SAN pacemaker cells from potential perturbing influences which arise from inside and outside the sinoatrial network. Our previous work suggests that the hyperpolarization-activated cyclic nucleotide gated channel subtype 1 (HCN1) protects against such perturbations and thereby increases the stability, the precision and the safety of the sinoatrial network. Here, we investigate the role of HCN4 channels within this context. Using genetic mouse models deficient for HCN channels as well as mouse models expressing engineered HCN channels, we performed a detailed functional characterization of pacemaker mechanisms in single isolated sinoatrial node cells, explanted beating sinoatrial node preparations, with telemetric in vivo electrocardiography, echocardiography, and in vivo electrophysiology. We provide evidence that HCN4 has a critical role in counteracting and balancing potentially destabilizing effects of the autonomic nervous system on the regulation of the heart rate. Specifically, HCN4 channels smooth the transition of the heart rate to a new equilibrium. Furthermore, we provide evidence that the cAMP- dependent fine tuning of HCN4 channel activity could provide the exact dosage of current to balance and counteract overshooting responses of the heart rate to autonomic regulation. In the absence of such a protecting effect, mice display a brady- tachy syndrome.

Heart rate regulation by G proteins acting on the cardiac pacemaker channel

Science ◽  
1990 ◽  
Vol 249 (4973) ◽  
pp. 1163-1166 ◽  
Author(s):  
A Yatani ◽  
K Okabe ◽  
J Codina ◽  
L Birnbaumer ◽  
A. Brown
Keyword(s):  
Heart Rate ◽  
G Proteins ◽  
Cardiac Pacemaker ◽  
Rate Regulation ◽  
Heart Rate Regulation ◽  
Pacemaker Channel

scholarly journals RGS4 attenuates parasympathetic signaling in the sinoatrial node: implications for heart rate regulation

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Carlo Cifelli ◽  
Hangjun Zhang ◽  
Robert Alan Rose ◽  
Peter Backx ◽  
Scott Heximer
Keyword(s):  
Heart Rate ◽  
Sinoatrial Node ◽  
Rate Regulation ◽  
Heart Rate Regulation

scholarly journals Bi-directional flow of the funny current (If) during the pacemaking cycle in murine sinoatrial node myocytes

2021 ◽  
Author(s):  
Colin H. Peters ◽  
Pin W. Liu ◽  
Stefano Morotti ◽  
Stephanie C. Gantz ◽  
Eleonora Grandi ◽  
...  
Keyword(s):  
Heart Rate ◽  
Conceptual Framework ◽  
Sinoatrial Node ◽  
Cardiac Pacemaker ◽  
Charge Movement ◽  
Firing Cycle ◽  
Pacemaker Cells ◽  
Net Charge ◽  
Precise Role

AbstractSinoatrial node myocytes (SAMs) act as cardiac pacemaker cells by firing spontaneous action potentials (APs) that initiate each heartbeat. The funny current, If, is critical for the generation of these spontaneous APs; however, its precise role during the pacemaking cycle remains unresolved. We used the AP-clamp technique to quantify If during the cardiac cycle in mouse SAMs. We found that If is persistently active throughout the sinoatrial AP, with surprisingly little voltage-dependent gating. As a consequence, it carries both inward and outward current around its reversal potential of -30 mV. Despite operating at only 2-5% of its maximal conductance, If carries a substantial fraction of both depolarizing and repolarizing net charge movement during the firing cycle. We also show that β-adrenergic receptor stimulation increases the percentage of net depolarizing charge moved by If, consistent with a contribution of If to the fight-or-flight increase in heart rate. These properties were confirmed by heterologously-expressed HCN4 channels and by mathematical models of If. Modelling further suggested that the slow activation and deactivation of the HCN4 isoform underlie the persistent activity of If during the sinoatrial AP. These results establish a new conceptual framework for the role of If in pacemaking, in which it operates at a very small fraction of maximal activation but nevertheless drives membrane potential oscillations in SAMs by providing substantial driving force in both inward and outward directions.Significance StatementCardiac pacemaker cells trigger each heartbeat by virtue of spontaneous oscillations in their membrane voltage. Although the funny current (If) is critical for these oscillations and for setting heart rate, its precise role remains an enigma because it activates mostly outside of the physiological voltage range and quite slowly relative to the pacemaker cycle. Here we show that If is persistently active in pacemaker cells; once opened, the small fraction of ion channels that conduct If do not re-close. Consequently, If flows both inward and outward to help propel the voltage oscillations and it paradoxically conducts a large fraction of the net charge movement. These results establish a new conceptual framework for the role of If in driving cardiac pacemaking.

scholarly journals Direct Negative Chronotropic Action of Desflurane on Sinoatrial Node Pacemaker Activity in the Guinea Pig Heart

2014 ◽  
Vol 120 (6) ◽  
pp. 1400-1413 ◽  
Author(s):  
Akiko Kojima ◽  
Yuki Ito ◽  
Hirotoshi Kitagawa ◽  
Hiroshi Matsuura ◽  
Shuichi Nosaka
Keyword(s):  
Heart Rate ◽  
Action Potentials ◽  
Inhibitory Action ◽  
Sinoatrial Node ◽  
Ionic Currents ◽  
Pacemaker Cells ◽  
Chronotropic Action ◽  
Perfused Hearts ◽  
Sinoatrial Node Automaticity

Abstract Background: Desflurane inhalation is associated with sympathetic activation and concomitant increase in heart rate in humans and experimental animals. There is, however, little information concerning the direct effects of desflurane on electrical activity of sinoatrial node pacemaker cells that determines the intrinsic heart rate. Methods: Whole-cell patch-clamp experiments were conducted on guinea pig sinoatrial node pacemaker cells to record spontaneous action potentials and ionic currents contributing to sinoatrial node automaticity, namely, hyperpolarization-activated cation current (If), T-type and L-type Ca2+ currents (ICa,T and ICa,L, respectively), Na+/Ca2+ exchange current (INCX), and rapidly and slowly activating delayed rectifier K+ currents (IKr and IKs, respectively). Electrocardiograms were recorded from ex vivo Langendorff-perfused hearts and in vivo hearts. Results: Desflurane at 6 and 12% decreased spontaneous firing rate of sinoatrial node action potentials by 15.9% (n = 11) and 27.6% (n = 10), respectively, which was associated with 20.4% and 42.5% reductions in diastolic depolarization rate, respectively. Desflurane inhibited If, ICa,T, ICa,L, INCX, and IKs but had little effect on IKr. The negative chronotropic action of desflurane was reasonably well reproduced in sinoatrial node computer model. Desflurane reduced the heart rate in Langendorff-perfused hearts. High concentration (12%) of desflurane inhalation was associated with transient tachycardia, which was totally abolished by pretreatment with the β-adrenergic blocker propranolol. Conclusions: Desflurane has a direct negative chronotropic action on sinoatrial node pacemaking activity, which is mediated by its inhibitory action on multiple ionic currents. This direct inhibitory action of desflurane on sinoatrial node automaticity seems to be counteracted by sympathetic activation associated with desflurane inhalation in vivo.

Contribution of Cardiovascular Reflexes to Differences in β-Adrenoceptor-Mediated Responses in Essential Hypertension

1981 ◽  
Vol 61 (s7) ◽  
pp. 177s-180s ◽  
Author(s):  
G. Jennings ◽  
A. Bobik ◽  
M. Esler ◽  
P. Korner
Keyword(s):  
Heart Rate ◽  
Essential Hypertension ◽  
Dose Range ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Normal Subjects ◽  
Cardiovascular Reflexes ◽  
Similar Dose ◽  
Before And After

1. The responses to stimulation of both cardiac and lymphocyte β-adrenoceptors were studied in 23 normal subjects and 23 with untreated essential hypertension. Lymphocyte cyclic adenosine monophosphate was measured in vitro after incubation with isoprenaline (0.01 μmol/l-10 mmol/l). There were no significant differences between the amount of cyclic adenosine monophosphate generated by lymphocytes in the two groups in the isoprenaline concentration range 0.01 μmol/l-1 mmol/l. 2. In the same subjects we compared cardiac β-adrenoceptor-mediated responses using the change in heart rate after bolus doses of isoprenaline (dose range 0.25–3 μg). In 12 subjects (six normotensive, six hypertensive) we studied the heart rate responses to isoprenaline before and after ‘total’ autonomic block (0.04 mg of atropine/kg and 300 μg of clonidine). The latter permitted assessment of intrinsic cardiac responsiveness after eliminating cardiovascular reflexes. 3. In subjects with reflexes intact the rise in heart rate was significantly greater in normal than in hypertensive subjects at all doses of isoprenaline. Isoprenaline evoked a similar dose-related fall in blood pressure in both groups, which contributed to the reflex drive. After autonomic block the differences in heart rate responses were no longer present. 4. The results indicate that the reduced tachycardia at a given dose of isoprenaline in hypertensive subjects is due to impairment in their baroreceptor—heart rate reflex since this was no longer present after atropine and clonidine. 5. The absence of any intrinsic difference in cardiac β-adrenoceptor responsiveness is in agreement with the results with lymphocytes.

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