Affiliation:
1. Ben Gurion University of Negev Beer Sheva Israel
2. Department of Cardiac Physiology, Institute of Physiology, Komi Science Center Ural Branch of the Russian Academy of Sciences Syktyvkar Russia
Abstract
AbstractBackgroundMaturation 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.ResultsThe APs of true pacemaker cells at different stages had similar configurations and dV/dtmax 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 (If) decreased during development, whereas transmembrane and intracellular Ca2+ flows increased.ConclusionsThe ontogenetic decrease in IK1 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.”