Hyperthermia Influences the Effects of Sodium Channel Blocking Drugs in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
BACKGROUND
Fever can increase the susceptibility to supraventricular and ventricular arrhythmias, in which sodium channel dysfunction has been implicated. Whether fever influences the efficacy of sodium channel blocking drugs is unknown. The current study was designed to investigate the temperature dependent effects of distinct sodium channel blocking drugs on the sodium currents in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).


RESULTS
hiPSC-CMs were generated from human skin fibroblasts of a healthy donor. The peak and late sodium currents (INa), steady-state activation, inactivation and recovery from inactivation of INa in hiPSC-CMs were analyzed using the whole-cell patch clamp technique. The effects of different concentrations of the antiarrhythmic drugs flecainide, lidocaine, ajmaline and the antianginal drug ranolazine on INa were tested at 36°C and 40°C. Increasing the temperature of the bath solution from 36°C to 40°C enhanced the inhibition of peak INa but reduced the inhibition of late INa by flecainide and lidocaine. By contrast, increasing the temperature reduced the effect of ajmaline and ranolazine on the peak INa but not late INa. None of the tested drugs showed temperature-dependent effects on the steady-state activation and inactivation as well as on the recovery from inactivation of INa in hiPSC-CMs.


CONCLUSIONS
Temperature variation from the physiological to the febrile range apparently influences the effects of sodium channel blockers on the sodium currents. This may influence their antiarrhythmic efficacy in patients suffering from fever.
First Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.|DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen, Germany.
Ibrahim
I
El-Battrawy
First Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.|DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen, Germany.
Siegfried
S
Lang
First Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Zhihan
Z
Zhao
First Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.|DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen, Germany.
Ibrahim
I
Akin
First Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.|DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen, Germany.
Gökhan
G
Yücel
First Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Sophie
S
Meister
First Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.|DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen, Germany.
Bence
B
Patocskai
First Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.|DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen, Germany.
Michael
M
Behnes
First Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.|DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen, Germany.
Boris
B
Rudic
First Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.|DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen, Germany.
Erol
E
Tülümen
First Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Volker
V
Liebe
DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen, Germany.|Institute of Pharmacology and Toxicology, University of Göttingen, Göttingen, Germany.
Malte
M
Tiburcy
DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen, Germany.|Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.
Jennifer
J
Dworacek
DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen, Germany.|Institute of Pharmacology and Toxicology, University of Göttingen, Göttingen, Germany.
Wolfram-Hubertus
WH
Zimmermann
DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen, Germany.|Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.
Jochen
J
Utikal
DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen, Germany.|Institute of Experimental and Clinical Pharmacology and Toxicology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Thomas
T
Wieland
First Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.|DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen, Germany.
Martin
M
Borggrefe
First Department of Medicine, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.|DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen, Germany.|Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China.
Xiao-Bo
XB
Zhou
D000404:Ajmaline / Q000494:pharmacology; D005424:Flecainide / Q000494:pharmacology; D006358:Hot Temperature / Q000009:adverse effects*; D006801:Humans; D008012:Lidocaine / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D039904:Pluripotent Stem Cells / Q000187:drug effects*; D016133:Polymerase Chain Reaction; D000069458:Ranolazine / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology
D026941:Sodium Channel Blockers; D015222:Sodium Channels; D000404:Ajmaline; D008012:Lidocaine; D000069458:Ranolazine; D005424:Flecainide