Interplay between SERCA and sarcolemmal Ca 2+ efflux pathways controls spontaneous release of Ca 2+ 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 Ca 2+ ‐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 Ca 2+ concentration to 4 m m . Application of 100 μ m TBQ decreased the frequency of waves. This was associated with increases of resting [Ca 2+ ] i , the time constant of decay of [Ca 2+ ] i and the integral of the accompanying Na + –Ca 2+ exchange current. There was also a decrease in propagation velocity of the waves. There was an increase of the calculated Ca 2+ efflux per wave. The SR Ca 2+ content when a wave was about to propagate decreased to 91.7 ± 3.2%. The period between waves increased in direct proportion to the Ca 2+ efflux per wave meaning that TBQ had no effect on the Ca 2+ efflux per unit time. We conclude that (i) decreased wave frequency is not a direct consequence of decreased Ca 2+ pumping by SERCA between waves but, rather, to more Ca 2+ loss on each wave; (ii) inhibiting SERCA increases the chance of spontaneous Ca 2+ release propagating at a given SR content.