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Depolarization-induced automaticity in rat ventricular cardiomyocytes is based on the gating properties of L-type calcium and slow Kv channels

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Abstract

Depolarization-induced automaticity (DIA) of cardiomyocytes is the property of those cells to generate pacemaker cell-like spontaneous electrical activity when subjected to a depolarizing current. This property provides a candidate mechanism for generation of pathogenic ectopy in cardiac tissue. The purpose of this study was to determine the biophysical mechanism of DIA in terms of the ion conductance properties of the cardiomyocyte membrane. First, we determined, by use of the conventional whole-cell patch-clamp technique, the membrane conductance and DIA properties of ventricular cardiomyocytes isolated from adult rat heart. Second, we reproduced and analysed DIA properties by using an adapted version of the experimentally based mathematical cardiomyocyte model of Pandit et al. (Biophys J 81:3029–3051 2001, Biophys J 84:832–841 2003) and Padmala and Demir (J Cardiovasc Electrophysiol 14:990–995 2003). DIA in 23 rat cardiomyocytes was a damped membrane potential oscillation with a variable number of action potentials and/or waves, depending on the strength of the depolarizing current and the particular cell. The adapted model was used to reconstruct the DIA properties of a particular cardiomyocyte from its whole-cell voltage-clamp currents. The main currents involved in DIA were an L-type calcium current (I CaL) and a slowly activating and inactivating Kv current (I ss), with linear (I B) and inward rectifier (I K1) currents acting as background currents and I Na and I t as modulators. Essential for DIA is a sufficiently large window current of a slowly inactivating I CaL combined with a critically sized repolarizing current I ss. Slow inactivation of I ss makes DIA transient. In conclusion, we established a membrane mechanism of DIA primarily based on I CaL, I ss and inward rectifier properties; this may be helpful in understanding cardiac ectopy and its treatment.

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Abbreviations

AP:

Action potential

APD:

Action potential duration at half height

CC:

Current clamp

DIA:

Depolarization-induced automaticity

EAD:

Early afterdepolarization

LVMC:

Left ventricular cardiomyocyte

P model:

Model of Pandit et al. (2001, 2003)

PP model:

P model upgraded by Padmala and Demir (2003)

PPYM model:

PP model upgraded by Ypey and van Meerwijk

RMP:

Resting membrane potential

RVMC:

Right ventricular cardiomyocyte

VC:

Voltage clamp

V m :

Membrane potential

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Acknowledgments

We thank Dr Pandit (University of Michigan, USA) for his kind help in correcting a few misprints in the published model equations (2001). We acknowledge Dr A. Baartscheer (University of Amsterdam) for his advice on rat cardiomyocyte dissociation procedure.

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Author notes

  1. Soban Umar

    Present address: Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, University of California Los Angeles, 650 Charles Young Drive, Los Angeles, CA, 90095-7115, USA

Authors and Affiliations

  1. Department of Cardiology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands

    Dirk L. Ypey, Wilbert P. M. van Meerwijk, Soban Umar, Daniel A. Pijnappels, Martin J. Schalij & Arnoud van der Laarse

Authors
  1. Dirk L. Ypey
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  2. Wilbert P. M. van Meerwijk
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Corresponding author

Correspondence to Arnoud van der Laarse.

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Ypey, D.L., van Meerwijk, W.P.M., Umar, S. et al. Depolarization-induced automaticity in rat ventricular cardiomyocytes is based on the gating properties of L-type calcium and slow Kv channels. Eur Biophys J 42, 241–255 (2013). https://doi.org/10.1007/s00249-012-0866-9

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  • DOI: https://doi.org/10.1007/s00249-012-0866-9

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