The influence of melatonin on the heart rhythm – An in vitro simulation with murine embryonic stem cell derived cardiomyocytes

Abstract

Background: In healthy individuals, a major factor influencing the heart rate variability (HRV) is the circadian rhythm. The role of melatonin as an essential component of the circadian rhythm in the adult human organism and the beneficial effects of a treatment with melatonin during the fetal period is well described. Toxic effects of melatonin are discussed less frequently.Since pharmacological studies cannot be carried out on pregnant women, the establishment of an equivalent in vitro model is important. We therefore tested whether melatonin can influence the beat rate variability (BRV) of spontaneously beating cardiomyocytes derived from murine embryonic stem cells (mESCs) and whether melatonin exhibits toxic effects in this in vitro model. Methods: Microelectrode Arrays recorded extracellular field potentials of spontaneously beating cardiomyocytes. Melatonin was applied in a concentration range from 10−11 M to 10–5 M. The analysis of the BRV focused on time domain methods. Results: In line with clinical observations, melatonin decreased the beating frequency and increased the BRV. The effect of melatonin up to a concentration of 10−6 M was reversible, whereas the application of higher concentrations induced an irreversible effect. Conclusion: The study underlines the potential of this in vitro model to help explore the development of circadian rhythms and their modulation by melatonin in the embryonic phase. The results imply that melatonin influences the heart rhythm as early as during the embryonic heart development. Furthermore, the results indicate a potentially toxic effect of melatonin that has not been described in detail before.

Keywords

• Beat rate variability
• Melatonin
• Microelectrode array
• Murine embryonic stem cells
• Cardiomyocytes
• Circadian rhythm