title: Effects of the antifungal antibiotic clotrimazole on human cardiac repolarization potassium currents.
abstract: The antifungal antibiotic clotrimazole (CLT) shows therapeutic effects on cancer, sickle cell disease, malaria, etc. by inhibiting membrane intermediate-conductance Ca2+ -activated K+ channels (IKCa). However, it is unclear whether this drug would affect human cardiac K+ currents. The present study was therefore designed to investigate the effects of CLT on transient outward K+ current (Ito1), and ultra-rapid delayed rectifier K+ current (IKur) in isolated human atrial myocytes, and cloned hERG channel current (IhERG) and recombinant human cardiac KCNQ1/KCNE1 channel current (IKs) expressed in HEK 293 cells. It was found that CLT inhibited Ito1 with an IC50 of 29.5 microM, accelerated Ito1 inactivation, and decreased recovery of Ito1 from inactivation. In addition, CLT inhibited human atrial I(Kur) in a concentration-dependent manner (IC50 = 7.6 microM). CLT substantially suppressed IhERG (IC50 = 3.6 microM), and negatively shifted the activation conductance of IhERG. Moreover, CLT inhibited IKs (IC50 = 15.1 microM), and positively shifted the activation conductance of the current. These results indicate that the antifungal antibiotic CLT substantially inhibits human cardiac repolarization K+ currents including Ito1, IKur, IhERG, and IKs. However, caution is recommended when correlating the observed in vitro effects on cardiac ion currents to the clinical relevance.
authors.affiliation: Department of Medicine and Research Centre of Heart, Brain, Hormone and Healthy Aging, Faculty of Medicine, Pokfulam, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Tian
authors.forename: Ming-Qing
authors.initials: MQ
authors.lastname: Dong
authors.forename: Shui-Wha
authors.initials: SW
authors.lastname: Chiu
authors.forename: Chu-Pak
authors.initials: CP
authors.lastname: Lau
authors.forename: Gui-Rong
authors.initials: GR
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D003022:Clotrimazole / Q000494:pharmacology*; D051668:Delayed Rectifier Potassium Channels / Q000037:antagonists & inhibitors; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006321:Heart / Q000187:drug effects*; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000037:antagonists & inhibitors; D008875:Middle Aged; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors
chemical_list: D000935:Antifungal Agents; D051668:Delayed Rectifier Potassium Channels; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C489622:KCNE1 protein, human; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D003022:Clotrimazole