title: Blockade of K+ and Ca2+ channels by azole antifungal agents in neonatal rat ventricular myocytes.
abstract: Some azole antifungal agents induce long QT syndrome and arrhythmias. Although composite functions of ion channels in cardiomyocytes contribute to the shaping of action potentials, information on the effects of azole antifungal agents on ion currents, except human-ether-a-go-go-related gene (HERG) K+ currents, is largely lacking. Using the whole cell patch-clamp technique, we investigated the effects of four azole agents (miconazole, ketoconazole, fluconazole, and itraconazole) on inward rectifying K+ currents (IKir), voltage-gated L-type Ca2+ currents (ICaL), and delayed rectifier K+ currents (IKdr) in rat neonate ventricular myocytes. Strikingly, miconazole and ketoconazole strongly inhibited IKir, IKdr, and ICaL at clinically relevant concentrations. The IC50 values of miconazole for IKdr, IKir, and ICaL inhibition were 2.5, 10.4, and 3.0 µM, respectively. The IC50 values of ketoconazole for IKdr, IKir and ICaL inhibition were 3.2, 20.8, and 3.5 µM, respectively. Fluconazole and itraconazole had relatively little effect on ion currents. These findings indicate that miconazole and ketoconazole are multiple ion channel inhibitors in cardiomyocytes. We suggest that it is necessary to consider this inhibition of ion channels by azole agents when assessing cardiovascular side effects.
authors.affiliation: Department of Physiology, Institute of Functional Genomics, Research Institute of Medical Science, School of Medicine, Konkuk University, Choongju, Korea.
authors.forename: Dong-Jun
authors.initials: DJ
authors.lastname: Sung
authors.forename: Jae-Gon
authors.initials: JG
authors.lastname: Kim
authors.forename: Kyung Jong
authors.initials: KJ
authors.lastname: Won
authors.forename: Bokyung
authors.initials: B
authors.lastname: Kim
authors.forename: Ho Chul
authors.initials: HC
authors.lastname: Shin
authors.forename: Jae-Yong
authors.initials: JY
authors.lastname: Park
authors.forename: Young Min
authors.initials: YM
authors.lastname: Bae
mesh_terms: D000200:Action Potentials; D000818:Animals; D000831:Animals, Newborn; D000935:Antifungal Agents / Q000009:adverse effects*; D001393:Azoles / Q000009:adverse effects*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000009:adverse effects; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007654:Ketoconazole / Q000009:adverse effects; D008825:Miconazole / Q000009:adverse effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000009:adverse effects; D015221:Potassium Channels / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000935:Antifungal Agents; D001393:Azoles; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D008825:Miconazole; D007654:Ketoconazole; D011188:Potassium; D002118:Calcium