Kettlewell, S, Saxena, P, Dempster, J et al. (4 more authors) (2019) Dynamic‐clamping human and rabbit atrial calcium current: narrowing ICaL window abolishes early afterdepolarisations. Journal of Physiology, 597 (14). pp. 3619-3638. ISSN 0022-3751
Abstract
Background: Atrial early‐afterdepolarisations (EADs) may contribute to atrial fibrillation (AF), perhaps involving reactivation of L‐type Ca2+ current (ICaL) in its window‐region voltage range.
Aims: Validate the dynamic‐clamp technique for modifying ICaL contribution to atrial action potential (AP) waveform; investigate effects of widening window‐ICaL on EAD‐propensity; test whether EADs from increased ICaL and AP duration are supressed by narrowing window‐ICaL.
Methods and Results: ICaL and APs were recorded from rabbit and human atrial myocytes by whole‐cell‐patch‐clamp. During AP‐recording, ICaL was inhibited (3 μM nifedipine) and replaced by a dynamic‐clamp model‐current, ICaL,D‐C (tuned to native ICaL characteristics), computed in real‐time (every 50 μs) based on myocyte membrane potential. ICaL,D‐C‐injection restored the nifedipine‐suppressed AP plateau. Widening window‐ICaL,D‐C, symmetrically by step‐wise simultaneous equal shifts of half‐voltages (V0.5) of ICaL,D‐C activation (negatively) and inactivation (positively), generated EADs (single, multiple, or preceding repolarisation‐failure) in a window‐width‐dependent manner, and AP‐alternans. A stronger EAD‐generating effect resulted from independently shifting activation V0.5 (asymmetrical‐widening) than inactivation V0.5; e.g. a 15‐mV activation‐shift produced EADs in 9/17 (53%) human atrial myocytes versus 0/18 from inactivation‐shift (P<0.05). In 11 rabbit atrial myocytes in which EADs were generated either by increasing conductance of normal‐window‐width ICaL,D‐C or subsequent 4‐aminopyridine (2 mM), window‐ICaL,D‐C‐narrowing (10 mV) abolished EADs of all types (P<0.05).
Conclusion: We validated the dynamic‐clamp for ICaL, novel in atrial cardiomyocytes, and showed that EADs of various types are generated by widening (particularly asymmetrically) window‐ICaL, and abolished by narrowing it. Window‐ICaL‐narrowing is a potential therapeutic mechanism worth pursuing in the search for improved anti‐AF drugs.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | Dynamic‐clamp; Atrial myocyte; Calcium window current; Afterdepolarisations; Atrial fibrillation |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 04 Jun 2019 14:29 |
Last Modified: | 25 Jun 2023 21:54 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1113/JP277827 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:146907 |