Blockade of K+ and Ca2+ channels by azole antifungal agents in neonatal rat ventricular myocytes.

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Sung DJ, Kim JG, Won KJ, Kim B, Shin HC, Park JY, Bae YM

Blockade of K+ and Ca2+ channels by azole antifungal agents in neonatal rat ventricular myocytes.

Biol Pharm Bull. 2012;35(9):1469-75. doi: 10.1248/bpb.b12-00002.

PubMed ID

22975497 [ View in PubMed

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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 microM, respectively. The IC50 values of ketoconazole for IKdr, IKir and ICaL inhibition were 3.2, 20.8, and 3.5 microM, 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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Miconazole	Inward rectifier potassium channel (Protein Group)	Protein group	Humans	Unknown	Inhibitor	Details
Miconazole	Voltage gated L-type calcium channel (Protein Group)	Protein group	Humans	Unknown	Inhibitor	Details
Miconazole	Voltage-gated Potassium Channels (Protein Group)	Protein group		Unknown	Inhibitor	Details