Characterization of human iPS cell-derived cardiomyocyte sheets as a model to detect drug-induced conduction disturbance.
In order to characterize human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) sheets as a model for detecting drug-induced conduction disturbance, we examined their electrophysiological and electropharmacological properties by using the multi-electrode array system with a programmed electrical stimulation protocol. At pre-drug control, the conduction speed, effective refractory period and field potential duration were 0.14 ± 0.01 m/sec, 453 ± 10 msec and 361 ± 9 msec, respectively at a cycle length of 1,000 msec (n = 18). Shortening the pacing cycle length from 1,000 to 600 msec decreased the conduction speed and field potential duration, but prolonged the effective refractory period. Disopyramide, lidocaine and flecainide decreased the conduction speed but prolonged the effective refractory period and field potential duration, whereas the reverse was true for verapamil. Thus, conduction properties of the cell sheet may largely depend on the extent of Na+channel availability as is the case in the human ventricle. Importantly, there was no relationship between the conduction delay and 1stspike amplitude reduction after the treatment of Na+channel blockers. These findings may provide crucial guide on future application of this new technology for early phase safety pharmacological screening of new chemical entities.
Department of Pharmacology, Faculty of Medicine, Toho University.
Hiroko
H
Izumi-Nakaseko
Yuji
Y
Nakamura
Takeshi
T
Wada
Kentaro
K
Ando
Yasunari
Y
Kanda
Yuko
Y
Sekino
Atsushi
A
Sugiyama
D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D018929:Cell Culture Techniques; D004558:Electric Stimulation; D006339:Heart Rate; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D026941:Sodium Channel Blockers / Q000494:pharmacology
D002121:Calcium Channel Blockers; D026941:Sodium Channel Blockers