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

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 (IK_ir), voltage-gated L-type Ca²⁺ currents (ICa_L), and delayed rectifier K⁺ currents (IK _dr) in rat neonate ventricular myocytes. Strikingly, miconazole and ketoconazole strongly inhibited IK_ir, IK_dr, and ICa _L at clinically relevant concentrations. The IC₅₀ values of miconazole for IK_dr, IK_ir, and ICa_L inhibition were 2.5, 10.4, and 3.0 μM, respectively. The IC₅₀ values of ketoconazole for IK_dr, IK_ir and ICa_L 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.