Adrenoceptor sub-type involvement in Ca2+ current stimulation by noradrenaline in human and rabbit atrial myocytes

Saxena, P., Myles, R. C. , Smith, G. L. and Workman, A. J. (2022) Adrenoceptor sub-type involvement in Ca2+ current stimulation by noradrenaline in human and rabbit atrial myocytes. Pflügers Archiv European Journal of Physiology, 474(12), pp. 1311-1321. (doi: 10.1007/s00424-022-02746-z) (PMID:36131146) (PMCID:PMC9663393)

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Atrial fibrillation (AF) from elevated adrenergic activity may involve increased atrial L-type Ca2+ current (ICaL) by noradrenaline (NA). However, the contribution of the adrenoceptor (AR) sub-types to such ICaL-increase is poorly understood, particularly in human. We therefore investigated effects of various broad-action and sub-type-specific α- and β-AR antagonists on NA-stimulated atrial ICaL. ICaL was recorded by whole-cell-patch clamp at 37 °C in myocytes isolated enzymatically from atrial tissues from consenting patients undergoing elective cardiac surgery and from rabbits. NA markedly increased human atrial ICaL, maximally by ~ 2.5-fold, with EC75 310 nM. Propranolol (β1 + β2-AR antagonist, 0.2 microM) substantially decreased NA (310 nM)-stimulated ICaL, in human and rabbit. Phentolamine (α1 + α2-AR antagonist, 1 microM) also decreased NA-stimulated ICaL. CGP20712A (β1-AR antagonist, 0.3 microM) and prazosin (α1-AR antagonist, 0.5 microM) each decreased NA-stimulated ICaL in both species. ICI118551 (β2-AR antagonist, 0.1 microM), in the presence of NA + CGP20712A, had no significant effect on ICaL in human atrial myocytes, but increased it in rabbit. Yohimbine (α2-AR antagonist, 10 microM), with NA + prazosin, had no significant effect on human or rabbit ICaL. Stimulation of atrial ICaL by NA is mediated, based on AR sub-type antagonist responses, mainly by activating β1- and α1-ARs in both human and rabbit, with a β2-inhibitory contribution evident in rabbit, and negligible α2 involvement in either species. This improved understanding of AR sub-type contributions to noradrenergic activation of atrial ICaL could help inform future potential optimisation of pharmacological AR-antagonism strategies for inhibiting adrenergic AF.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Workman, Dr Antony and Myles, Dr Rachel and Smith, Professor Godfrey and Saxena, Dr Priyanka
Authors: Saxena, P., 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:Pflügers Archiv European Journal of Physiology
ISSN (Online):1432-2013
Published Online:22 September 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Pflügers Archiv European Journal of Physiology 474(12): 1311-1321
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173444Adrenoceptor-subtype antagonism profiles with anti-arrhythmic potential in human atrial myocytesAntony WorkmanBritish Heart Foundation (BHF)PG/16/42/32142Institute of Cardiovascular & Medical Sciences