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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2017
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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 |
Sumario: | 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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