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Regional acidosis locally inhibits but remotely stimulates Ca(2+) waves in ventricular myocytes

AIMS: Spontaneous Ca(2+) waves in cardiomyocytes are potentially arrhythmogenic. A powerful controller of Ca(2+) waves is the cytoplasmic H(+) concentration ([H(+)](i)), which fluctuates spatially and temporally in conditions such as myocardial ischaemia/reperfusion. H(+)-control of Ca(2+) waves is...

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Autores principales: Ford, Kerrie L., Moorhouse, Emma L., Bortolozzi, Mario, Richards, Mark A., Swietach, Pawel, Vaughan-Jones, Richard D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852542/
https://www.ncbi.nlm.nih.gov/pubmed/28339694
http://dx.doi.org/10.1093/cvr/cvx033
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author Ford, Kerrie L.
Moorhouse, Emma L.
Bortolozzi, Mario
Richards, Mark A.
Swietach, Pawel
Vaughan-Jones, Richard D.
author_facet Ford, Kerrie L.
Moorhouse, Emma L.
Bortolozzi, Mario
Richards, Mark A.
Swietach, Pawel
Vaughan-Jones, Richard D.
author_sort Ford, Kerrie L.
collection PubMed
description AIMS: Spontaneous Ca(2+) waves in cardiomyocytes are potentially arrhythmogenic. A powerful controller of Ca(2+) waves is the cytoplasmic H(+) concentration ([H(+)](i)), which fluctuates spatially and temporally in conditions such as myocardial ischaemia/reperfusion. H(+)-control of Ca(2+) waves is poorly understood. We have therefore investigated how [H(+)](i) co-ordinates their initiation and frequency. METHODS AND RESULTS: Spontaneous Ca(2+) waves were imaged (fluo-3) in rat isolated ventricular myocytes, subjected to modest Ca(2+)-overload. Whole-cell intracellular acidosis (induced by acetate-superfusion) stimulated wave frequency. Pharmacologically blocking sarcolemmal Na(+)/H(+) exchange (NHE1) prevented this stimulation, unveiling inhibition by H(+). Acidosis also increased Ca(2+) wave velocity. Restricting acidosis to one end of a myocyte, using a microfluidic device, inhibited Ca(2+) waves in the acidic zone (consistent with ryanodine receptor inhibition), but stimulated wave emergence elsewhere in the cell. This remote stimulation was absent when NHE1 was selectively inhibited in the acidic zone. Remote stimulation depended on a locally evoked, NHE1-driven rise of [Na(+)](i) that spread rapidly downstream. CONCLUSION: Acidosis influences Ca(2+) waves via inhibitory [Formula: see text] and stimulatory [Formula: see text] signals (the latter facilitating intracellular Ca(2+)-loading through modulation of sarcolemmal Na(+)/Ca(2+) exchange activity). During spatial [H(+)](i)-heterogeneity, [Formula: see text]-inhibition dominates in acidic regions, while rapid [Formula: see text] diffusion stimulates waves in downstream, non-acidic regions. Local acidosis thus simultaneously inhibits and stimulates arrhythmogenic Ca(2+)-signalling in the same myocyte. If the principle of remote H(+)-stimulation of Ca(2+) waves also applies in multicellular myocardium, it raises the possibility of electrical disturbances being driven remotely by adjacent ischaemic areas, which are known to be intensely acidic.
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spelling pubmed-58525422018-03-23 Regional acidosis locally inhibits but remotely stimulates Ca(2+) waves in ventricular myocytes Ford, Kerrie L. Moorhouse, Emma L. Bortolozzi, Mario Richards, Mark A. Swietach, Pawel Vaughan-Jones, Richard D. Cardiovasc Res Original Articles AIMS: Spontaneous Ca(2+) waves in cardiomyocytes are potentially arrhythmogenic. A powerful controller of Ca(2+) waves is the cytoplasmic H(+) concentration ([H(+)](i)), which fluctuates spatially and temporally in conditions such as myocardial ischaemia/reperfusion. H(+)-control of Ca(2+) waves is poorly understood. We have therefore investigated how [H(+)](i) co-ordinates their initiation and frequency. METHODS AND RESULTS: Spontaneous Ca(2+) waves were imaged (fluo-3) in rat isolated ventricular myocytes, subjected to modest Ca(2+)-overload. Whole-cell intracellular acidosis (induced by acetate-superfusion) stimulated wave frequency. Pharmacologically blocking sarcolemmal Na(+)/H(+) exchange (NHE1) prevented this stimulation, unveiling inhibition by H(+). Acidosis also increased Ca(2+) wave velocity. Restricting acidosis to one end of a myocyte, using a microfluidic device, inhibited Ca(2+) waves in the acidic zone (consistent with ryanodine receptor inhibition), but stimulated wave emergence elsewhere in the cell. This remote stimulation was absent when NHE1 was selectively inhibited in the acidic zone. Remote stimulation depended on a locally evoked, NHE1-driven rise of [Na(+)](i) that spread rapidly downstream. CONCLUSION: Acidosis influences Ca(2+) waves via inhibitory [Formula: see text] and stimulatory [Formula: see text] signals (the latter facilitating intracellular Ca(2+)-loading through modulation of sarcolemmal Na(+)/Ca(2+) exchange activity). During spatial [H(+)](i)-heterogeneity, [Formula: see text]-inhibition dominates in acidic regions, while rapid [Formula: see text] diffusion stimulates waves in downstream, non-acidic regions. Local acidosis thus simultaneously inhibits and stimulates arrhythmogenic Ca(2+)-signalling in the same myocyte. If the principle of remote H(+)-stimulation of Ca(2+) waves also applies in multicellular myocardium, it raises the possibility of electrical disturbances being driven remotely by adjacent ischaemic areas, which are known to be intensely acidic. Oxford University Press 2017-07 2017-02-21 /pmc/articles/PMC5852542/ /pubmed/28339694 http://dx.doi.org/10.1093/cvr/cvx033 Text en © The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Ford, Kerrie L.
Moorhouse, Emma L.
Bortolozzi, Mario
Richards, Mark A.
Swietach, Pawel
Vaughan-Jones, Richard D.
Regional acidosis locally inhibits but remotely stimulates Ca(2+) waves in ventricular myocytes
title Regional acidosis locally inhibits but remotely stimulates Ca(2+) waves in ventricular myocytes
title_full Regional acidosis locally inhibits but remotely stimulates Ca(2+) waves in ventricular myocytes
title_fullStr Regional acidosis locally inhibits but remotely stimulates Ca(2+) waves in ventricular myocytes
title_full_unstemmed Regional acidosis locally inhibits but remotely stimulates Ca(2+) waves in ventricular myocytes
title_short Regional acidosis locally inhibits but remotely stimulates Ca(2+) waves in ventricular myocytes
title_sort regional acidosis locally inhibits but remotely stimulates ca(2+) waves in ventricular myocytes
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852542/
https://www.ncbi.nlm.nih.gov/pubmed/28339694
http://dx.doi.org/10.1093/cvr/cvx033
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