Resolving the Reversed Rate Effect of Calcium Channel Blockers on Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes and the Impact on In Vitro Cardiac Safety Evaluation
| Autor: | Jixin Wang, Armando Lagrutta, Frederick Sannajust, Holly Clouse, Haoyu Zeng |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Induced Pluripotent Stem Cells hERG Drug Evaluation Preclinical Action Potentials Tetrodotoxin Pharmacology Toxicology 03 medical and health sciences 0302 clinical medicine Heart Rate medicine Humans Myocytes Cardiac Channel blocker Calcium Signaling Diltiazem Cells Cultured Calcium channel opener Voltage-dependent calcium channel biology Chemistry Calcium channel Calcium Channel Inhibition Calcium Channel Blockers Culture Media 030104 developmental biology Potassium biology.protein Verapamil Calcium Channels 030217 neurology & neurosurgery Sodium Channel Blockers medicine.drug |
| Zdroj: | Toxicological Sciences. 167:573-580 |
| ISSN: | 1096-0929 1096-6080 |
| DOI: | 10.1093/toxsci/kfy264 |
| Popis: | Calcium channel blockers (CCBs), such as diltiazem, nifedipine, and verapamil, cause tachycardia effects on several commercially available human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), when tested in culture media provided by suppliers, rather than bradycardia effects, as seen in vivo. We found that in test conditions where Na+ current of hiPSC-CMs was reduced to certain threshold by either specific Na+ channel blocker tetrodotoxin (TTX), or by voltage-dependent inactivation using elevated extracellular potassium concentrations, CCBs produced bradycardia effects on hiPSC-CMs. However, elevated extracellular potassium concentrations or the presence of TTX did not change other pharmacological responses of hiPSC-CMs, including CCBs' effects on contraction intensity and duration; beating rate change by calcium channel opener FPL64176, HCN blocker ivabradine, and β-adrenergic agonist isoproterenol; and action potential duration prolongation by hERG channel blocker dofetilide. We concluded that action potentials of hiPSC-CMs, with regards to the CCB phenotype, were Na+ current driven. When Na+ channel availability was reduced to a critical level, their action potentials became Ca2+ current driven, and their responses to CCBs correlated well to those seen in vivo. Importantly, the corrected bradycardia effect of calcium channel block with our defined conditions will provide more reliable results in cardiac safety readouts of test compounds that integrate multiple effects including calcium channel inhibition. |
| Databáze: | OpenAIRE |
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