Analysis of changes in the action potential morphology of the mouse sinoatrial node true pacemaker cells during ontogenetic development in vitro and in silico

Abstract

Background

Maturation of the mouse is accompanied by the increase in heart rate. However, the mechanisms underlying this process remain unclear. We performed an action potentials (APs) recordings in mouse sinoatrial node (SAN) true pacemaker cells and in silico analysis to clarify the mechanisms underlying pre–postnatal period heart rate changes.

Results

The APs of true pacemaker cells at different stages had similar configurations and dV/dt_max values. The cycle length, action potential duration (APD₉₀), maximal diastolic potential (MDP), and AP amplitude decreased, meanwhile the velocity of diastolic depolarization (DDR) increased from E12.5 stage to adult. Using a pharmacological approach we found that in SAN true pacemaker cells ivabradine reduces the DDR and the cycle length significantly stronger in E12.5 than in newborn and adult mice, whereas the effects of Ni²⁺ and nifedipine were significantly stronger in adult mice. Computer simulations further suggested that the density of the hyperpolarization–activated pacemaker сurrent (I_f) decreased during development, whereas transmembrane and intracellular Ca²⁺ flows increased.

Conclusions

The ontogenetic decrease in I_K1 density from E12.5 to adult leads to depolarization of MDP to the voltage range in which calcium currents are activated, thereby shifting the balance from the “membrane-clock” to the “calcium-clock.”