Mechanisms of Beat-to-Beat Regulation of Cardiac Pacemaker Cell Function by Ca2+ Cycling Dynamics

Whether intracellular Ca2+ cycling dynamics regulate cardiac pacemaker cell function on a beat-to-beat basis remains unknown. Here we show that under physiological conditions, application of low concentrations of caffeine (2–4 mM) to isolated single rabbit sinoatrial node cells acutely reduces their spontaneous action potential cycle length (CL) and increases Ca2+ transient amplitude for several cycles. Numerical simulations, using a modified Maltsev-Lakatta coupled-clock model, faithfully reproduced these effects, and also the effects of CL prolongation and dysrhythmic spontaneous beating (produced by cytosolic Ca2+ buffering) and an acute CL reduction (produced by flash-induced Ca2+ release from a caged Ca2+ buffer), which we had reported previously. Three contemporary numerical models (including the original Maltsev-Lakatta model) failed to reproduce the experimental results. In our proposed new model, Ca2+ releases acutely change the CL via activation of the Na+/Ca2+ exchanger current. Time-dependent CL reductions after flash-induced Ca2+ releases (the memory effect) are linked to changes in Ca2+ available for pumping into sarcoplasmic reticulum which, in turn, changes the sarcoplasmic reticulum Ca2+ load, diastolic Ca2+ releases, and Na+/Ca2+ exchanger current. These results support the idea that Ca2+ regulates CL in cardiac pacemaker cells on a beat-to-beat basis, and suggest a more realistic numerical mechanism of this regulation.