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Inhibition of a TREK-like K(+) channel current by noradrenaline requires both β(1)- and β(2)-adrenoceptors in rat atrial myocytes
AIMS: Noradrenaline plays an important role in the modulation of atrial electrophysiology. However, the identity of the modulated channels, their mechanisms of modulation, and their role in the action potential remain unclear. This study aimed to investigate the noradrenergic modulation of an atrial...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174890/ https://www.ncbi.nlm.nih.gov/pubmed/25205295 http://dx.doi.org/10.1093/cvr/cvu192 |
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author | Bond, Richard C. Choisy, Stéphanie C.M. Bryant, Simon M. Hancox, Jules C. James, Andrew F. |
author_facet | Bond, Richard C. Choisy, Stéphanie C.M. Bryant, Simon M. Hancox, Jules C. James, Andrew F. |
author_sort | Bond, Richard C. |
collection | PubMed |
description | AIMS: Noradrenaline plays an important role in the modulation of atrial electrophysiology. However, the identity of the modulated channels, their mechanisms of modulation, and their role in the action potential remain unclear. This study aimed to investigate the noradrenergic modulation of an atrial steady-state outward current (I(Kss)). METHODS AND RESULTS: Rat atrial myocyte whole-cell currents were recorded at 36°C. Noradrenaline potently inhibited I(Kss) (IC(50) = 0.90 nM, 42.1 ± 4.3% at 1 µM, n = 7) and potentiated the L-type Ca(2+) current (I(CaL), EC(50) = 136 nM, 205 ± 40% at 1 µM, n = 6). Noradrenaline-sensitive I(Kss) was weakly voltage-dependent, time-independent, and potentiated by the arachidonic acid analogue, 5,8,11,14-eicosatetraynoic acid (EYTA; 10 µM), or by osmotically induced membrane stretch. Noise analysis revealed a unitary conductance of 8.4 ± 0.42 pS (n = 8). The biophysical/pharmacological properties of I(Kss) indicate a TREK-like K(+) channel. The effect of noradrenaline on I(Kss) was abolished by combined β(1)-/β(2)-adrenoceptor antagonism (1 µM propranolol or 10 µM β(1)-selective atenolol and 100 nM β(2)-selective ICI-118,551 in combination), but not by β(1)- or β(2)-antagonist alone. The action of noradrenaline could be mimicked by β(2)-agonists (zinterol and fenoterol) in the presence of β(1)-antagonist. The action of noradrenaline on I(Kss), but not on I(CaL), was abolished by pertussis toxin (PTX) treatment. The action of noradrenaline on I(CaL) was mediated by β(1)-adrenoceptors via a PTX-insensitive pathway. Noradrenaline prolonged APD(30) by 52 ± 19% (n = 5; P < 0.05), and this effect was abolished by combined β(1)-/β(2)-antagonism, but not by atenolol alone. CONCLUSION: Noradrenaline inhibits a rat atrial TREK-like K(+) channel current via a PTX-sensitive mechanism involving co-operativity of β(1)-/β(2)-adrenoceptors that contributes to atrial APD prolongation. |
format | Online Article Text |
id | pubmed-4174890 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-41748902014-10-01 Inhibition of a TREK-like K(+) channel current by noradrenaline requires both β(1)- and β(2)-adrenoceptors in rat atrial myocytes Bond, Richard C. Choisy, Stéphanie C.M. Bryant, Simon M. Hancox, Jules C. James, Andrew F. Cardiovasc Res Original Articles AIMS: Noradrenaline plays an important role in the modulation of atrial electrophysiology. However, the identity of the modulated channels, their mechanisms of modulation, and their role in the action potential remain unclear. This study aimed to investigate the noradrenergic modulation of an atrial steady-state outward current (I(Kss)). METHODS AND RESULTS: Rat atrial myocyte whole-cell currents were recorded at 36°C. Noradrenaline potently inhibited I(Kss) (IC(50) = 0.90 nM, 42.1 ± 4.3% at 1 µM, n = 7) and potentiated the L-type Ca(2+) current (I(CaL), EC(50) = 136 nM, 205 ± 40% at 1 µM, n = 6). Noradrenaline-sensitive I(Kss) was weakly voltage-dependent, time-independent, and potentiated by the arachidonic acid analogue, 5,8,11,14-eicosatetraynoic acid (EYTA; 10 µM), or by osmotically induced membrane stretch. Noise analysis revealed a unitary conductance of 8.4 ± 0.42 pS (n = 8). The biophysical/pharmacological properties of I(Kss) indicate a TREK-like K(+) channel. The effect of noradrenaline on I(Kss) was abolished by combined β(1)-/β(2)-adrenoceptor antagonism (1 µM propranolol or 10 µM β(1)-selective atenolol and 100 nM β(2)-selective ICI-118,551 in combination), but not by β(1)- or β(2)-antagonist alone. The action of noradrenaline could be mimicked by β(2)-agonists (zinterol and fenoterol) in the presence of β(1)-antagonist. The action of noradrenaline on I(Kss), but not on I(CaL), was abolished by pertussis toxin (PTX) treatment. The action of noradrenaline on I(CaL) was mediated by β(1)-adrenoceptors via a PTX-insensitive pathway. Noradrenaline prolonged APD(30) by 52 ± 19% (n = 5; P < 0.05), and this effect was abolished by combined β(1)-/β(2)-antagonism, but not by atenolol alone. CONCLUSION: Noradrenaline inhibits a rat atrial TREK-like K(+) channel current via a PTX-sensitive mechanism involving co-operativity of β(1)-/β(2)-adrenoceptors that contributes to atrial APD prolongation. Oxford University Press 2014-10-01 /pmc/articles/PMC4174890/ /pubmed/25205295 http://dx.doi.org/10.1093/cvr/cvu192 Text en © The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Original Articles Bond, Richard C. Choisy, Stéphanie C.M. Bryant, Simon M. Hancox, Jules C. James, Andrew F. Inhibition of a TREK-like K(+) channel current by noradrenaline requires both β(1)- and β(2)-adrenoceptors in rat atrial myocytes |
title | Inhibition of a TREK-like K(+) channel current by noradrenaline requires both β(1)- and β(2)-adrenoceptors in rat atrial myocytes |
title_full | Inhibition of a TREK-like K(+) channel current by noradrenaline requires both β(1)- and β(2)-adrenoceptors in rat atrial myocytes |
title_fullStr | Inhibition of a TREK-like K(+) channel current by noradrenaline requires both β(1)- and β(2)-adrenoceptors in rat atrial myocytes |
title_full_unstemmed | Inhibition of a TREK-like K(+) channel current by noradrenaline requires both β(1)- and β(2)-adrenoceptors in rat atrial myocytes |
title_short | Inhibition of a TREK-like K(+) channel current by noradrenaline requires both β(1)- and β(2)-adrenoceptors in rat atrial myocytes |
title_sort | inhibition of a trek-like k(+) channel current by noradrenaline requires both β(1)- and β(2)-adrenoceptors in rat atrial myocytes |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174890/ https://www.ncbi.nlm.nih.gov/pubmed/25205295 http://dx.doi.org/10.1093/cvr/cvu192 |
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