Regional acidosis locally inhibits but remotely stimulates Ca2+ waves in ventricular myocytes.
OBJECTIVE
Spontaneous Ca2+ waves in cardiomyocytes are potentially arrhythmogenic. A powerful controller of Ca2+ waves is the cytoplasmic H+ concentration ([H+]i), which fluctuates spatially and temporally in conditions such as myocardial ischaemia/reperfusion. H+-control of Ca2+ waves is poorly understood. We have therefore investigated how [H+]i co-ordinates their initiation and frequency.


RESULTS
Spontaneous Ca2+ waves were imaged (fluo-3) in rat isolated ventricular myocytes, subjected to modest Ca2+-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 Ca2+ wave velocity. Restricting acidosis to one end of a myocyte, using a microfluidic device, inhibited Ca2+ 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.


CONCLUSIONS
Acidosis influences Ca2+ waves via inhibitory Hi+ and stimulatory Nai+ signals (the latter facilitating intracellular Ca2+-loading through modulation of sarcolemmal Na+/Ca2+ exchange activity). During spatial [H+]i-heterogeneity, Hi+-inhibition dominates in acidic regions, while rapid Nai+ diffusion stimulates waves in downstream, non-acidic regions. Local acidosis thus simultaneously inhibits and stimulates arrhythmogenic Ca2+-signalling in the same myocyte. If the principle of remote H+-stimulation of Ca2+ 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.
Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, Oxford, OX1 3PT, UK.
Kerrie L
KL
Ford
Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, Oxford, OX1 3PT, UK.
Emma L
EL
Moorhouse
Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, Oxford, OX1 3PT, UK.|Department of Physics and Astronomy "G. Galilei", University of Padua, 35121 Padua, Italy.
Mario
M
Bortolozzi
Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, Oxford, OX1 3PT, UK.
Mark A
MA
Richards
Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, Oxford, OX1 3PT, UK.
Pawel
P
Swietach
Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and Genetics, Oxford, OX1 3PT, UK.
Richard D
RD
Vaughan-Jones
D000138:Acidosis / Q000139:chemically induced*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002413:Cations, Divalent; D006352:Heart Ventricles / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology; D017202:Myocardial Ischemia / Q000378:metabolism*; D015425:Myocardial Reperfusion / Q000379:methods; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism
D002413:Cations, Divalent; D012964:Sodium; D002118:Calcium
Calcium cycling; Cell signalling; Intracellular pH; Intracellular sodium; Membrane transport