Dynamic‐clamping human and rabbit atrial calcium current: narrowing ICaL window abolishes early afterdepolarisations

Kettlewell, S., Saxena, P., Dempster, J., Colman, M. A., Myles, R. C. , Smith, G. L. and Workman, A. J. (2019) Dynamic‐clamping human and rabbit atrial calcium current: narrowing ICaL window abolishes early afterdepolarisations. Journal of Physiology, 597(14), pp. 3619-3638. (doi: 10.1113/JP277827) (PMID:31093979) (PMCID:PMC6767690)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Smith, Professor Godfrey and Myles, Dr Rachel and Workman, Dr Antony and Saxena, Dr Priyanka
Authors: Kettlewell, S., Saxena, P., Dempster, J., Colman, M. A., Myles, R. C., Smith, G. L., and Workman, A. J.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Journal of Physiology
ISSN (Online):1469-7793
Published Online:15 May 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Journal of Physiology 597(14):3619-3638
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
626321Human atrial action potential alternans and afterdepolarisations: electrophysiological and calcium-cycling mechanisms and effects of myocardial diseaseAntony WorkmanBritish Heart Foundation (BHF)PG/13/31/30156RI CARDIOVASCULAR & MEDICAL SCIENCES