Temperature Dependence of the Biophysical Mechanisms Underlying the Inhibition and Enhancement Effect of Amiodarone on hERG Channels.

Abstract

hERG K+ channel is important for controlling the duration of cardiac action potentials. Amiodarone (AMD), a widely prescribed class III antiarrhythmic, could inhibit hERG currents with relatively few tachyarrhythmic adverse events. We use injected Xenopus oocyte with two-electrode voltage clamp techniques to characterize the action of AMD on hERG channels. We found that AMD binds to the resting hERG channel with an apparent dissociation constant of ∼1.4 μM, and inhibits hERG currents at mild and strong depolarization pulses by slowing activation and enhancing inactivation, respectively, at 22°C. The activation kinetics of hERG channel activation are much faster, but inactivation kinetics are slower at 37°C. AMD accordingly has a 15% to 20% weaker and stronger inhibitory effect at mild and strong depolarization (e.g., -60 and +30 mV, 0.3-second pulse), respectively. In the meanwhile, the resurgent hERG tail currents are dose-dependently inhibited by AMD without altering the kinetics of current decay at both 22°C and 37°C, indicating facilitation of recovery from inactivation via the silent route. Most importantly, AMD no longer inhibits but enhances hERG currents at a mild pulse shortly after a prepulse at 37°C, but not so much at 22°C. We conclude that AMD is an effective hERG channel-gating modifier capable of lengthening the plateau phase of cardiac action potential (without increasing the chance of afterdepolarization). AMD, however, should be used with caution in hypothermia or the other scenarios that slow hERG channel activation. SIGNIFICANCE STATEMENT: It is known that amiodarone (AMD) acts on hERG K+ channels to treat cardiac arrhythmias with relatively little arrhythmogenicity. We found that AMD enhances hERG channel inactivation but slows activation as well as recovery from inactivation, and thus has a differential inhibition and enhancement effect on hERG currents at different phases of membrane voltage changes, especially at 37°C, but not so much at 22°C. AMD is therefore a relatively ideal agent against tachyarrhythmia at 37°C, but should be more cautiously used at lower temperatures or relevant pathophysiological/pharmacological scenarios associated with slower hERG channel activation because of the increased chances of adverse events.