Stochasticity intrinsic to coupled-clock mechanisms underlies beat-to-beat variability of spontaneous action potential firing in sinoatrial node pacemaker cells

We perturbed the coupled-clock system by directly inhibiting the M clock by ivabradine (IVA) or the Ca2 + clock by cyclopiazonic acid (CPA). When either clock is perturbed by IVA (3, 10 and 30 μM), which has no direct effect on Ca2 + cycling, or CPA (0.5 and 5 μM), which has no direct effect on the M clock ion channels, the clock system failed to achieve the basal AP BI and both AP BI and AP BI variability increased. The changes in average LCR period and its variability in response to perturbations of the coupled-clock system were correlated with changes in AP beating interval and AP beating interval variability. We conclude that the stochasticity within the coupled-clock system affects and is affected by the AP BI firing rate and rhythm via modulation of the effectiveness of clock coupling.