Ablation of a Ca2+-activated K+channel (SK2 channel) results in action potential prolongation in atrial myocytes and atrial fibrillation

Relaxin produces positive inotropic and chronotropic effects in rat hearts. The effect of relaxin on the action potential duration (APD) of single quiescent rat atrial cells was investigated with a whole cell patch clamp. Relaxin induced a significant, dose-dependent prolongation of the APD. This effect was maximal at 200 ng/ml (nominal concentration of 33.6 nM), which caused, on average, a 57% increase in the time taken to reach 90% repolarization. The effect of relaxin was blocked by the protein kinase A inhibitor 5-24 amide, indicating that its effect is mediated by an adenosine 3',5'-cyclic monophosphate-dependent mechanism. The increased APD induced by relaxin caused an enhanced entrance of calcium, with the charge carried through voltage-activated calcium channels increased by approximately 25%. This increase was not due to a direct modulation of calcium currents (20); rather, it was a consequence of the longer period of cellular depolarization. Our findings that relaxin increased the APD and therefore increased the calcium influx in atrial myocytes could explain the positive inotropic effects induced by relaxin in atrial preparations.

Download Full-text

Developmental Changes in Action Potential Prolongation by K+-Channel Blockers in Chick Myocardium

Journal of Pharmacological Sciences ◽

10.1254/jphs.10205sc ◽

2011 ◽

Vol 115 (2) ◽

pp. 235-238 ◽

Cited By ~ 1

Author(s):

Hideaki Nouchi ◽

Naoaki Kiryu ◽

Mikio Kimata ◽

Yayoi Tsuneoka ◽

Shogo Hamaguchi ◽

...

Keyword(s):

Action Potential ◽

Developmental Changes ◽

K Channel ◽

Channel Blockers ◽

Action Potential Prolongation

Download Full-text

Elimination of the transient outward current and action potential prolongation in mouse atrial myocytes expressing a dominant negative Kv4 α subunit

The Journal of Physiology ◽

10.1111/j.1469-7793.1999.0011o.x ◽

1999 ◽

Vol 519 (1) ◽

pp. 11-21 ◽

Cited By ~ 70

Author(s):

Haodong Xu ◽

Huilin Li ◽

Jeanne M. Nerbonne

Keyword(s):

Action Potential ◽

Outward Current ◽

Dominant Negative ◽

Transient Outward Current ◽

Atrial Myocytes ◽

Α Subunit ◽

Action Potential Prolongation

Download Full-text

Atrial fibrillation and electrophysiology in transgenic mice with cardiac-restricted overexpression of FKBP12

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00486.2018 ◽

2019 ◽

Vol 316 (2) ◽

pp. H371-H379 ◽

Cited By ~ 1

Author(s):

Zhenwei Pan ◽

Tomohiko Ai ◽

Po-Cheng Chang ◽

Ying Liu ◽

Jijia Liu ◽

...

Keyword(s):

Atrial Fibrillation ◽

Action Potential ◽

Conduction Velocity ◽

Action Potential Duration ◽

Binding Protein ◽

Expression Level ◽

Atrial Myocytes ◽

Patch Clamp Technique ◽

Inactivation Curve ◽

Fk506 Binding Protein

Cardiomyocyte-restricted overexpression of FK506-binding protein 12 transgenic (αMyHC-FKBP12) mice develop spontaneous atrial fibrillation (AF). The aim of the present study is to explore the mechanisms underlying the occurrence of AF in αMyHC-FKBP12 mice. Spontaneous AF was documented by telemetry in vivo and Langendorff-perfused hearts of αMyHC-FKBP12 and littermate control mice in vitro. Atrial conduction velocity was evaluated by optical mapping. The patch-clamp technique was applied to determine the potentially altered electrophysiology in atrial myocytes. Channel protein expression levels were evaluated by Western blot analyses. Spontaneous AF was recorded in four of seven αMyHC-FKBP12 mice but in none of eight nontransgenic (NTG) controls. Atrial conduction velocity was significantly reduced in αMyHC-FKBP12 hearts compared with NTG hearts. Interestingly, the mean action potential duration at 50% but not 90% was significantly prolonged in αMyHC-FKBP12 atrial myocytes compared with their NTG counterparts. Consistent with decreased conduction velocity, average peak Na+ current ( INa) density was dramatically reduced and the INa inactivation curve was shifted by approximately +7 mV in αMyHC-FKBP12 atrial myocytes, whereas the activation and recovery curves were unaltered. The Nav1.5 expression level was significantly reduced in αMyHC-FKBP12 atria. Furthermore, we found increases in atrial Cav1.2 protein levels and peak L-type Ca2+ current density and increased levels of fibrosis in αMyHC-FKBP12 atria. In summary, cardiomyocyte-restricted overexpression of FKBP12 reduces the atrial Nav1.5 expression level and mean peak INa, which is associated with increased peak L-type Ca2+ current and interstitial fibrosis in atria. The combined electrophysiological and structural changes facilitated the development of local conduction block and altered action potential duration and spontaneous AF. NEW & NOTEWORTHY This study addresses a long-standing riddle regarding the role of FK506-binding protein 12 in cardiac physiology. The work provides further evidence that FK506-binding protein 12 is a critical component for regulating voltage-gated sodium current and in so doing has an important role in arrhythmogenic physiology, such as atrial fibrillation.

Download Full-text

Triggered Ca 2+ Waves Induce Depolarization of Maximum Diastolic Potential and Action Potential Prolongation in Dog Atrial Myocytes

Circulation Arrhythmia and Electrophysiology ◽

10.1161/circep.119.008179 ◽

2020 ◽

Vol 13 (6) ◽

Author(s):

Georg Gussak ◽

William Marszalec ◽

Shin Yoo ◽

Rishi Modi ◽

Caitlin O’Callaghan ◽

...

Keyword(s):

Action Potential ◽

Conduction Block ◽

Atrial Arrhythmias ◽

Atrial Myocytes ◽

Electrophysiological Properties ◽

Recovery From Inactivation ◽

Electrophysiological Responses ◽

Intracellular Ca ◽

Action Potential Prolongation ◽

Diastolic Potential

Background: We have identified a novel form of abnormal Ca 2+ wave activity in normal and failing dog atrial myocytes which occurs during the action potential (AP) and is absent during diastole. The goal of this study was to determine if triggered Ca 2+ waves affect cellular electrophysiological properties. Methods: Simultaneous recordings of intracellular Ca 2+ and APs allowed measurements of maximum diastolic potential and AP duration during triggered calcium waves (TCWs) in isolated dog atrial myocytes. Computer simulations then explored electrophysiological behavior arising from TCWs at the tissue scale. Results: At 3.3 to 5 Hz, TCWs occurred during the AP and often outlasted several AP cycles. Maximum diastolic potential was reduced, and AP duration was significantly prolonged during TCWs. All electrophysiological responses to TCWs were abolished by SEA0400 and ORM10103, indicating that Na-Ca exchange current caused depolarization. The time constant of recovery from inactivation of Ca 2+ current was 40 to 70 ms in atrial myocytes (depending on holding potential) so this current could be responsible for AP activation during depolarization induced by TCWs. Modeling studies demonstrated that the characteristic properties of TCWs are potentially arrhythmogenic by promoting both conduction block and reentry arising from the depolarization induced by TCWs. Conclusions: Triggered Ca 2+ waves activate inward NCX and dramatically reduce atrial maximum diastolic potential and prolong AP duration, establishing the substrate for reentry which could contribute to the initiation and maintenance of atrial arrhythmias.

Download Full-text

Transient outward K+ current can strongly modulate action potential duration and initiate alternans in the human atrium

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00251.2018 ◽

2019 ◽

Vol 316 (3) ◽

pp. H527-H542 ◽

Cited By ~ 8

Author(s):

Haibo Ni ◽

Henggui Zhang ◽

Eleonora Grandi ◽

Sanjiv M. Narayan ◽

Wayne R. Giles

Keyword(s):

Atrial Fibrillation ◽

Action Potential ◽

Initial Slope ◽

K Channel ◽

Pharmacological Management ◽

Electrophysiological Properties ◽

New Approaches ◽

Electrophysiological Recordings ◽

Spatial Differences ◽

K Current

Efforts to identify the mechanisms for the initiation and maintenance of human atrial fibrillation (AF) often focus on changes in specific elements of the atrial “substrate,” i.e., its electrophysiological properties and/or structural components. We used experimentally validated mathematical models of the human atrial myocyte action potential (AP), both at baseline in sinus rhythm (SR) and in the setting of chronic AF, to identify significant contributions of the Ca2+-independent transient outward K+ current ( Ito) to electrophysiological instability and arrhythmia initiation. First, we explored whether changes in the recovery or restitution of the AP duration (APD) and/or its dynamic stability (alternans) can be modulated by Ito. Recent reports have identified disease-dependent spatial differences in expression levels of the specific K+ channel α-subunits that underlie Ito in the left atrium. Therefore, we studied the functional consequences of this by deletion of 50% of native Ito (Kv4.3) and its replacement with Kv1.4. Interestingly, significant changes in the short-term stability of the human atrial AP waveform were revealed. Specifically, this K+ channel isoform switch produced discontinuities in the initial slope of the APD restitution curve and appearance of APD alternans. This pattern of in silico results resembles some of the changes observed in high-resolution clinical electrophysiological recordings. Important insights into mechanisms for these changes emerged from known biophysical properties (reactivation kinetics) of Kv1.4 versus those of Kv4.3. These results suggest new approaches for pharmacological management of AF, based on molecular properties of specific K+ isoforms and their changed expression during progressive disease. NEW & NOTEWORTHY Clinical studies identify oscillations (alternans) in action potential (AP) duration as a predictor for atrial fibrillation (AF). The abbreviated AP in AF also involves changes in K+ currents and early repolarization of the AP. Our simulations illustrate how substitution of Kv1.4 for the native current, Kv4.3, alters the AP waveform and enhances alternans. Knowledge of this “isoform switch” and related dynamics in the AF substrate may guide new approaches for detection and management of AF. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/k-channel-isoforms-regulate-human-atrial-arrhythmogenesis/ .

Download Full-text