Contribution of Calcium Waves to the Regulation of Beating Rhythm in Sinoatrial Node Cells

Abstract

The synchronized release of calcium (Ca) from the sarcoplasmic reticulum (SR) can initiate a heart beat. This concordant behavior can be altered and produced by the oscillatory dynamics of intracellular Ca release events (Ca waves) that can modulate membrane depolarization and hence heart rate. In this work, the effect of Ca waves on interbeat intervals (IBIs) was evaluated by using a stochastic simulation of rabbit SA-node cell which integrated a Ca wave model (Maltsev et al., 2011) including 1,350 discrete Ca release units (CRUs) with a classical membrane voltage oscillator (M clock model: Wilders et al., 1993). Each CRU opening produces a release flux equal to 1.0 pA and has a fundamental refractory period (varied from 220 to 300 ms), meant to empirically mimic beta-adrenergic effects on CRU intrinsic firing.In the absence of SR function, the intrinsic IBI (due to membrane currents) is 450 ms. This IBI is reduced when stochastic CRU openings are allowed. As refractory period is reduced from 300 to 220 ms IBI progressively shortens to 431 ms, but this effect is small compared to the abbreviation in intrinsic CRU refractory period. This reflects the dynamic interplay of the Ca clock and membrane current clock, and also the stochastic nature of concerted CRU recruitment among neighboring CRUs that are required to drive sufficient inward Na/Ca exchange current and accelerate the IBI. Thus Ca waves with high rhythmicity pushes the cell into a state that is more “ready to fire”. Detailed parameters and formulations from both individual models will impact the relative impact of Ca waves on IBI.