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Article

Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes

1
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan
2
Division of Cardiovascular Medicine, Chi-Mei Medical Center, Tainan 71004, Taiwan
3
Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan 71004, Taiwan
4
Division of Cardiology, Internal Medicine, College of Medicine, National Cheng Kung University Hospital, Tainan 70401, Taiwan
5
Department of Physiology, National Cheng Kung University Medical College, Tainan 70101, Taiwan
6
Division of Oncology, Chi-Mei Medical Center, Tainan 71004, Taiwan
7
Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan 70101, Taiwan
8
Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(5), 1672; https://doi.org/10.3390/ijms21051672
Received: 12 February 2020 / Revised: 25 February 2020 / Accepted: 27 February 2020 / Published: 29 February 2020
(This article belongs to the Special Issue Electrophysiology)
Lapatinib (LAP) and sorafenib (SOR) are multitargeted tyrosine kinase inhibitors (TKIs) with antineoplastic properties. In clinical observations, LAP and SOR may contribute to QTc prolongation, but the detailed mechanism for this has been largely unexplored. In this study, we investigated whether LAP and SOR affect the activities of membrane ion channels. Using a small animal model and primary cardiomyocytes, we studied the impact of LAP and SOR on Na+ and K+ currents. We found that LAP-induced QTc prolongation in mice was reversed by isoproterenol. LAP or SOR suppressed the amplitude of the slowly activating delayed-rectifier K+ current (IK(S)) in H9c2 cells in a time- and concentration-dependent fashion. The LAP-mediated inhibition of IK(S) was reversed by adding isoproterenol or meclofenamic acid, but not by adding diazoxide. The steady-state activation curve of IK(S) during exposure to LAP or SOR was shifted toward a less negative potential, with no change in the gating charge required to activate the current. LAP shortened the recovery from IK(S) deactivation. As rapid repetitive stimuli, the IK(S) amplitude decreased; however; the LAP-induced inhibition of IK(S) remained effective. LAP or SOR alone also suppressed inwardly rectifying K+ and voltage-gated Na+ current in neonatal rat ventricular myocytes. The inhibition of ionic currents during exposure to TKIs could be an important mechanism underlying changes in QTc intervals. View Full-Text
Keywords: Lapatinib; sorafenib; K+ current; action potential; cardiomyocytes Lapatinib; sorafenib; K+ current; action potential; cardiomyocytes
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MDPI and ACS Style

Chang, W.-T.; Liu, P.-Y.; Lee, K.; Feng, Y.-H.; Wu, S.-N. Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes. Int. J. Mol. Sci. 2020, 21, 1672. https://doi.org/10.3390/ijms21051672

AMA Style

Chang W-T, Liu P-Y, Lee K, Feng Y-H, Wu S-N. Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes. International Journal of Molecular Sciences. 2020; 21(5):1672. https://doi.org/10.3390/ijms21051672

Chicago/Turabian Style

Chang, Wei-Ting, Ping-Yen Liu, Kaisen Lee, Yin-Hsun Feng, and Sheng-Nan Wu. 2020. "Differential Inhibitory Actions of Multitargeted Tyrosine Kinase Inhibitors on Different Ionic Current Types in Cardiomyocytes" International Journal of Molecular Sciences 21, no. 5: 1672. https://doi.org/10.3390/ijms21051672

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