Regional differences in effects of E-4031 within the sinoatrial node

1999 ◽  
Vol 276 (3) ◽  
pp. H793-H802 ◽  
Author(s):  
I. Kodama ◽  
M. R. Boyett ◽  
M. R. Nikmaram ◽  
M. Yamamoto ◽  
H. Honjo ◽  
...  
Keyword(s):  
Action Potential ◽  
Electrical Activity ◽  
Spontaneous Activity ◽  
Regional Differences ◽  
Sinoatrial Node ◽  
Peripheral Tissue ◽  
Delayed Rectifier ◽  
Small Ball ◽  
Rabbit Sinoatrial Node ◽  
Diastolic Potential

Effects of block of the rapid delayed rectifier K+current ( I K,r) by E-4031 on the electrical activity of small ball-like tissue preparations from different regions of the rabbit sinoatrial node were measured. The effects of partial block of I K,r by 0.1 μM E-4031 varied in different regions of the node. In tissue from the center of the node spontaneous activity was generally abolished, whereas in tissue from the periphery spontaneous activity persisted, although the action potential was prolonged, the maximum diastolic potential was decreased, and the spontaneous activity slowed. After partial block of I K,r, the electrical activity of peripheral tissue was more like that of central tissue under normal conditions. One possible explanation of these findings is that the density of I K,r is greater in the periphery of the node; this would explain the greater resistance of peripheral tissue to I K,r block and help explain why, under normal conditions, the maximum diastolic potential is more negative, the action potential is shorter, and pacemaking is faster in the periphery.

Regional differences in effects of 4-aminopyridine within the sinoatrial node

1998 ◽  
Vol 275 (4) ◽  
pp. H1158-H1168 ◽  
Author(s):  
M. R. Boyett ◽  
H. Honjo ◽  
M. Yamamoto ◽  
M. R. Nikmaram ◽  
R. Niwa ◽  
...  
Keyword(s):  
Action Potential ◽  
Regional Differences ◽  
Sinoatrial Node ◽  
Outward Current ◽  
Peripheral Tissue ◽  
Transient Outward Current ◽  
Pacemaker Activity ◽  
Small Ball ◽  
Tissue Differences ◽  
Rabbit Sinoatrial Node

4-Aminopyridine (4-AP)-sensitive transient outward current ( I to) has been observed in the sinoatrial node, but its role is unknown. The effect of block of I to by 5 mM 4-AP on small ball-like tissue preparations (diameter ∼0.3–0.4 mm) from different regions of the rabbit sinoatrial node has been investigated. 4-AP elevated the plateau, prolonged the action potential, and decreased the maximum diastolic potential. Effects were greater in tissue from the periphery of the node than from the center. In peripheral tissue, 4-AP abolished the action potential notch, if present. 4-AP slowed pacemaker activity of peripheral tissue but accelerated that of central tissue. Differences in the response to 4-AP were also observed between tissue from more superior and inferior regions of the node. In the intact sinoatrial node, 4-AP resulted in a shift of the leading pacemaker site consistent with the regional differences in the response to 4-AP. It is concluded that 4-AP-sensitive outward current plays a major role in action potential repolarization and pacemaker activity in the sinoatrial node and that its role varies regionally.

Role of rapidly activating delayed rectifier K+ current in sinoatrial node pacemaker activity

1995 ◽  
Vol 269 (2) ◽  
pp. H453-H462 ◽  
Author(s):  
K. Ono ◽  
H. Ito
Keyword(s):  
Action Potential ◽  
Maximum Rate ◽  
Sinoatrial Node ◽  
Cell Voltage ◽  
Delayed Rectifier ◽  
Pacemaker Activity ◽  
Amplitude Maximum ◽  
K Current ◽  
Sinoatrial Node Cells ◽  
Diastolic Potential

A rapidly activating component of delayed rectifier K+ current (IK,r) was dissected using a selective blocker, E-4031, during the action potential clamp (AP clamp) in rabbit sinoatrial node cells. Application of E-4031 induced a large compensation current, of which amplitude was similar to or larger than the net current during repolarization and was maximum (2.2 +/- 0.2 pA/pF) at -46.0 +/- 1.8 mV (n = 13). During the slow diastolic depolarization, the compensation current gradually decayed and then abruptly decreased at the peak of action potential. The time-dependent change of IK,r was calculated using a mathematical model, in which independent gates of activation and inactivation were assumed based on the whole cell voltage-clamp experiments. The reconstructed IK,r corresponded well with the E-4031-sensitive current measured by the AP clamp method. Partial block of IK,r by E-4031 in spontaneously beating cells decreased the action potential amplitude, maximum rate of rise, and maximum rate of repolarization and induced a positive shift of the maximum diastolic potential. Complete block of IK,r terminated the spontaneous action potential at -37.4 +/- 2.9 mV (n = 3). It is concluded that IK,r plays an essential role in determining the maximum diastolic potential and ensures the firing of the following action potential in sinoatrial node cells.

A rapidly activating delayed rectifier K+ channel in rabbit sinoatrial node cells

1995 ◽  
Vol 269 (2) ◽  
pp. H443-H452 ◽  
Author(s):  
H. Ito ◽  
K. Ono
Keyword(s):  
Steady State ◽  
Sinoatrial Node ◽  
Single Channel ◽  
Ensemble Average ◽  
Negative Slope ◽  
Delayed Rectifier ◽  
Channel Current ◽  
Single Channel Current ◽  
Sinoatrial Node Cells ◽  
Rabbit Sinoatrial Node

The single-channel current of the delayed rectifier K+ current (IK) was recorded in rabbit sinoatrial node cells. In the cell-attached patch, depolarization from -70 mV to potentials more positive than -50 mV activated the IK channel while repolarization deactivated it. The single-channel conductance was 7.8 pS for the outward current and 10.8 pS for the inward current (n = 6). The steady-state open probability (NPo) was maximum at around -30 mV and markedly decreased at more positive potentials. On repolarization from positive potentials, the channel was initially closed and then rapidly opened. The ensemble average showed an initial rise to a peak followed by the deactivation time course. Because the channel events were completely blocked by E-4031, the drug-sensitive component was examined in the whole cell current. The steady-state current-voltage relation of the drug-sensitive current showed a marked negative slope at potentials more positive than -10 mV. Upon repolarization, the drug-sensitive current initially increased (removal of inactivation) to the peak of the outward tail current, which was in agreement with the ensemble average of the single-channel current. We conclude that IK in the sinoatrial node cells is largely composed of the rapidly activating IK (IK,r) channels and that the inward rectification of IK,r, which is more marked than had been assumed in previous studies, is due to the decrease in NPo.

scholarly journals Isoprenaline: A Potential Contributor in Sick Sinus Syndrome—Insights from a Mathematical Model of the Rabbit Sinoatrial Node

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Xiang Li ◽  
Ji-qian Zhang ◽  
Jian-wei Shuai
Keyword(s):  
Action Potential ◽  
Sinoatrial Node ◽  
Sick Sinus Syndrome ◽  
Surrounding Tissue ◽  
Pacemaker Activity ◽  
Histological Structure ◽  
Cell Models ◽  
Peripheral Cell ◽  
Positive Effects ◽  
Rabbit Sinoatrial Node

The mechanism of isoprenaline exerting its effects on cardiac pacemaking and driving in sick sinus syndrome is controversial and unresolved. In this paper, mathematical models for rabbit sinoatrial node cells were modified by incorporating equations for the known dose-dependent actions of isoprenaline on various ionic channel currents, the intracellular Ca2+transient, andiNachanges induced by SCN5A gene mutations; the cell models were also incorporated into an intact SAN-atrium model of the rabbit heart that is based on both heterogeneities of the SAN electrophysiology and histological structure. Our results show that, in both central and peripheral cell models, isoprenaline could not only shorten the action potential duration, but also increase the amplitude of action potential. The mutation impaired the SAN pacemaking. Simulated vagal nerve activity amplified the bradycardic effects of the mutation. However, in tissue case, the pacemaker activity may show temporal, spatial, or even spatiotemporal cessation caused by the mutation. Addition of isoprenaline could significantly diminish the bradycardic effect of the mutation and the SAN could restart pacing and driving the surrounding tissue. Positive effects of isoprenaline may primarily be attributable to an increase iniNaandiCa,Twhich were reduced by the mutation.

scholarly journals Distinct Effects of Ibrutinib and Acalabrutinib on Mouse Atrial and Sinoatrial Node Electrophysiology and Arrhythmogenesis

2021 ◽  
Author(s):  
Jari M. Tuomi ◽  
Loryn J. Bohne ◽  
Tristan W. Dorey ◽  
Hailey J. Jansen ◽  
Yingjie Liu ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Action Potential ◽  
Sinoatrial Node ◽  
Optical Mapping ◽  
Delayed Rectifier ◽  
Action Potential Firing ◽  
Atrial Electrophysiology ◽  
Potential Firing ◽  
Beating Rate ◽  
Upstroke Velocity

Background Ibrutinib and acalabrutinib are Bruton tyrosine kinase inhibitors used in the treatment of B‐cell lymphoproliferative disorders. Ibrutinib is associated with new‐onset atrial fibrillation. Cases of sinus bradycardia and sinus arrest have also been reported following ibrutinib treatment. Conversely, acalabrutinib is less arrhythmogenic. The basis for these different effects is unclear. Methods and Results The effects of ibrutinib and acalabrutinib on atrial electrophysiology were investigated in anesthetized mice using intracardiac electrophysiology, in isolated atrial preparations using high‐resolution optical mapping, and in isolated atrial and sinoatrial node (SAN) myocytes using patch‐clamping. Acute delivery of acalabrutinib did not affect atrial fibrillation susceptibility or other measures of atrial electrophysiology in mice in vivo. Optical mapping demonstrates that ibrutinib dose‐dependently impaired atrial and SAN conduction and slowed beating rate. Acalabrutinib had no effect on atrial and SAN conduction or beating rate. In isolated atrial myocytes, ibrutinib reduced action potential upstroke velocity and Na + current. In contrast, acalabrutinib had no effects on atrial myocyte upstroke velocity or Na + current. Both drugs increased action potential duration, but these effects were smaller for acalabrutinib compared with ibrutinib and occurred by different mechanisms. In SAN myocytes, ibrutinib impaired spontaneous action potential firing by inhibiting the delayed rectifier K + current, while acalabrutinib had no effects on SAN myocyte action potential firing. Conclusions Ibrutinib and acalabrutinib have distinct effects on atrial electrophysiology and ion channel function that provide insight into the basis for increased atrial fibrillation susceptibility and SAN dysfunction with ibrutinib, but not with acalabrutinib.

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