Rationale Voltage-dependent changes in hERG inhibitor-induced functional inhibition of the hERG potassium (K+) channel can potentially be ascribed not only to state-dependent changes in affinity of the inhibitor for its binding site but also to allosteric modulation of hERG's gating kinetics and to two-step inhibition processes incorporating an initial non-inhibiting inhibitor–channel encounter complex.1 In kinetics modulation models and in encounter complex models the inhibitor–channel interaction involves constant residency, while voltage-dependent changes in affinity will manifest rapid equilibrium of the inhibitor–channel complex in some protocols.2

Methods Patch clamp of hERG-transfected cells in the ‘voltage clamp’ mode was performed with a range of protocols involving washing a range of hERG inhibitors on or off during the protocol.

Results The behaviours of both selected inhibitors with positive voltage- and frequency-dependence and of an inverse voltage-dependent inhibitor (BeKm-1) are indicative of apparent changes in channel inhibition concordant with rapid equilibrium.

Conclusion This rapid equilibrium, if fast enough, will affect the predicted net effect on a cardiac hERG channel undergoing voltage cycling.