Interplay between SERCA and sarcolemmal Ca2+ efflux pathways controls spontaneous release of Ca2+ from the sarcoplasmic reticulum in rat ventricular myocytes

Waves of calcium‐induced calcium release occur in a variety of cell types and have been implicated in the origin of cardiac arrhythmias. We have investigated the effects of inhibiting the SR Ca2+‐ATPase (SERCA) with the reversible inhibitor 2′,5′‐di(tert‐butyl)‐1,4‐benzohydroquinone (TBQ) on the properties of these waves. Cardiac myocytes were voltage clamped at a constant potential between −65 and −40 mV and spontaneous waves evoked by increasing external Ca2+ concentration to 4 mm. Application of 100 μm TBQ decreased the frequency of waves. This was associated with increases of resting [Ca2+]i, the time constant of decay of [Ca2+]i and the integral of the accompanying Na+–Ca2+ exchange current. There was also a decrease in propagation velocity of the waves. There was an increase of the calculated Ca2+ efflux per wave. The SR Ca2+ content when a wave was about to propagate decreased to 91.7 ± 3.2%. The period between waves increased in direct proportion to the Ca2+ efflux per wave meaning that TBQ had no effect on the Ca2+ efflux per unit time. We conclude that (i) decreased wave frequency is not a direct consequence of decreased Ca2+ pumping by SERCA between waves but, rather, to more Ca2+ loss on each wave; (ii) inhibiting SERCA increases the chance of spontaneous Ca2+ release propagating at a given SR content