Synergistic dual automaticity in sinoatrial node cell and tissue models

Background: The mechanism of sinoatrial node (SAN) automaticity is traditionally attributed to membrane ion currents. Recent evidence indicates spontaneous sarcoplasmic reticulum (SR) Ca²⁺ cycling also plays an important role. Methods and Results: A computer simulation on SAN cell and 1D tissue model was performed. In the SAN cells, SR Ca²⁺ cycling broadly modulated the sinus rate from 1.74 Hz to 3.87 Hz. Shortening of the junctional SR refilling time and increase of SR Ca²⁺ release were responsible for sinus rate acceleration. However, under the fast SR Ca²⁺ cycling, decreased L-type Ca²⁺ current (ICaL) resulted in irregular firing. When Ca²⁺ cycling was suppressed, If and ICaT both acted to stabilize the pacemaker rhythm, but ICaT had less effect than If. At the 1D level, the electrical coupling between neighboring cells had little effect on the earliest pacemaker location. The leading pacemaking site always colocalized with the site with the highest SR Ca²⁺ cycling rate, but shifted to the site with less inhibited ICaL. Conclusions: The rate of SR Ca²⁺ cycling can effectively and broadly modulate the sinus rate. If, ICaL and ICaT play integral roles to guarantee SAN cell rhythmic firing. The leading pacemaker site is determined by intracellular Ca²⁺ dynamics and membrane currents, indicating the synergistic dual automaticity not only exists in single SAN cells, but also at the tissue level.