Application of human induced pluripotent stem cell-derived cardiomyocytes sheets with microelectrode array system to estimate antiarrhythmic properties of multi-ion channel blockers

J Pharmacol Sci. 2018 Aug;137(4):372-378. doi: 10.1016/j.jphs.2018.07.011. Epub 2018 Aug 4.

Abstract

We examined electrophysiological indices of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) sheets in order to quantitatively estimate Na+, K+ and Ca2+ channel blocking actions of bepridil and amiodarone using microelectrode array system in comparison with that of E-4031. We analyzed the field potential duration, effective refractory period, current threshold and conduction property using a programmed electrical stimulation protocol to obtain the post repolarization refractoriness and coefficient a of the relationship between the pacing cycle length and field potential duration. Electropharmacological profile of each drug was successfully characterized; namely, 1) the changes in the current threshold and conduction property provided basic information of Na+ channel blocking kinetics, 2) the relationship between pacing cycle length and field potential duration reflected drug-induced inhibition of human ether-à-go-go-related gene (hERG) K+ channel, 3) the post repolarization refractoriness indicated the relative contribution of these drugs to Na+ and K+ channel blockade, and 4) L-type Ca2+ channel blocking action was more obvious in the field potential waveform of the hiPSC-CMs sheets than that expected in the electrocardiogram in humans. Thus, this information may help to better utilize the hiPSC-CMs sheets for grasping the properties and net effects of drug-induced Na+, Ca2+ and K+ channel blockade.

Keywords: Antiarrhythmic property; Human induced pluripotent stem cell-derived cardiomyocytes; Multichannel blocker; Post repolarization refractoriness.

Publication types

  • Comparative Study

MeSH terms

  • Action Potentials / drug effects
  • Amiodarone / pharmacology*
  • Anti-Arrhythmia Agents*
  • Bepridil / pharmacology*
  • Calcium Channel Blockers / pharmacology*
  • Cells, Cultured
  • Drug Evaluation, Preclinical / methods*
  • Electrophysiological Phenomena / drug effects
  • Humans
  • Induced Pluripotent Stem Cells*
  • Microelectrodes*
  • Myocytes, Cardiac / physiology*
  • Piperidines / pharmacology
  • Potassium Channel Blockers / pharmacology*
  • Pyridines / pharmacology
  • Sodium Channel Blockers / pharmacology*

Substances

  • Anti-Arrhythmia Agents
  • Calcium Channel Blockers
  • Piperidines
  • Potassium Channel Blockers
  • Pyridines
  • Sodium Channel Blockers
  • E 4031
  • Bepridil
  • Amiodarone