TY - JOUR T1 - 10 Voltage-dependent affinity of some compounds that inhibit hERG: rapid dissociation and reassociation? JF - Heart JO - Heart SP - e3 LP - e3 DO - 10.1136/hrt.2010.213496.10 VL - 97 IS - 1 AU - J T Milnes AU - M McPate AU - C E Dempsey AU - R S Duncan AU - J L Leaney AU - D J Leishman AU - J C Hancox AU - H J Witchel Y1 - 2011/01/01 UR - http://heart.bmj.com/content/97/1/e3.2.abstract N2 - 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.2Methods 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. ER -