Key result
Nicardipine dose-dependently inhibited the hERG channel tail current expressed in HEK293 cells with an IC50 of 0.43 μM, acting via direct channel blocking rather than disrupting channel trafficking.
Why the study?
Does nicardipine inhibit hERG channel currents in HEK293 cells and Xenopus oocytes?
Does nicardipine inhibit hERG channel currents in HEK293 cells and Xenopus oocytes?
Nicardipine directly inhibits the hERG channel by short-term channel blocking at the pore region, without affecting channel trafficking, which provides a mechanistic basis for its potential to cause QT prolongation.
Answers are grounded in this paper and cite their sources.
May increase arrhythmia risk with nicardipine; leaves open clinical translation pending human studies.
Drug-induced long QT syndrome is known to be associated with the onset of torsades de pointes (TdP), resulting in a fatal ventricular arrhythmia. QT interval prolongation can result from blocking the human ether-a-go-go-related gene (hERG) channel, which is important for the repolarization of cardiac action potential. Nicardipine, a Ca-channel blocker and antihypertensive agent, has been reported to increase the risk of occasional serious ventricular arrhythmias. We studied the effects of nicardipine on hERG K⁺ channels expressed in HEK293 cells and Xenopus oocytes. The cardiac electrophysiological effect of nicardipine was also investigated in this study. Our results revealed that nicardipine dose-dependently decreased the tail current of the hERG channel expressed in HEK293 cells with an IC₅₀ of 0.43 μM . On the other hand, nicardipine did not affect hERG channel trafficking. Taken together, nicardipine inhibits the hERG channel by the mechanism of short-term channel blocking. Two S6 domain mutations, Y652A and F656A, partially attenuated (Y652A) or abolished (F656A) the hERG current blockade, suggesting that nicardipine blocks the hERG channel at the pore of the channel.
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Chung et al. (2010) studied Drug-induced long QT syndrome. Nicardipine vs. Vehicle control was evaluated on hERG channel tail current inhibition (IC50) (IC50 0.43 μM). Nicardipine dose-dependently inhibited the hERG channel tail current expressed in HEK293 cells with an IC50 of 0.43 μM, acting via direct channel blocking rather than disrupting channel trafficking.
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