Abstract
AimsSpontaneous 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.Methods and resultsSpontaneous 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.ConclusionAcidosis influences Ca2+ waves via inhibitory and stimulatory signals (the latter facilitating intracellular Ca2+-loading through modulation of sarcolemmal Na+/Ca2+ exchange activity). During spatial [H+]i-heterogeneity, -inhibition dominates in acidic regions, while rapid 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.
Highlights
An aberrant form of Ca2þ signalling is the Ca2þ wave, commonly observed in ventricular myocytes during periods of Ca2þ-overload.[1]
The increase was attributable to an Hþi -dependent stimulation of NHE1 activity, as it was abolished in the presence of 5-(N,N-dimethyl) amiloride (DMA, 30 lM), a high-affinity NHE1 inhibitor
Spontaneous Ca2þ wave initiation depends on a balance between the stimulatory effects of Hþ-activated Naþ influx via pHi regulatory transporters such as NHE1, and the inhibitory effects of Hþ ions on Ca2þ handling proteins, notably ryanodine receptor (RyR)
Summary
An aberrant form of Ca2þ signalling is the Ca2þ wave, commonly observed in ventricular myocytes during periods of Ca2þ-overload.[1] Ca2þ waves can occur spontaneously, initiated by a localised SR Ca2þ release that propagates spatially, via a ‘fire-diffuse-fire’ form of Ca2þinduced Ca2þ release from the SR2. Ca2þ waves are believed to facilitate triggered arrhythmias, by driving delayed after-depolarizations (DADs) that may transition to ectopic action potentials.[3,4] Spontaneous Ca2þ waves are common events during clinical conditions such as myocardial ischaemia. We have investigated the mechanisms coupling Ca2þ waves to changes of pHi
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