INHIBITION OF THE HUMAN CARDIAC POTASSIUM CHANNEL, HERG, BY SOTALOL HYDROCHLORIDE.
B D Walker, H Tie, C B Singleton, J A Bursill, K R Wyse, M R Qiu, S M Valenzuela, S N Breit, T J Campbell.
Department of Medicine, Victor Chang Cardiac Research Institute and Centre for Immunology, St Vincent's Hospital, Darlinghurst, NSW
Background: Class III antiarrhythmic drugs and non-cardiac drugs which cause QT prolongation (eg. cisapride, terfenadine) commonly inhibit the rapidly activating delayed rectifier potassium channel (Ikr), which is encoded by the human ether-a-go-go-related gene (HERG). There is surprisingly limited information regarding the effects of sotalol on the biophysics of Ikr, or HERG currents at a single cell level.
Methods and results: Whole cell voltage-clamp technology was used to study the current produced in Chinese hamster ovary (CHO-K1) cells stable transfected with HERG. D,L-solatol is a relatively weak inhibitor of HERG tail currents (IC50 198 mM, 95%CI 122 - 321 mM), in contrast to the sotalol analog, E-4031, which inhibited the channel with 1000-fold greater potency (IC50 134 nM, 95%CI 113 - 160 nM). Inhibition by D,L-solatol 300 mM exhibited reverse use-dependence (22 + 6% block after 40 pulses at 0.5 Hz vs 70 + 5% block at 0.1 Hz, p < 0.05), which has not previously been described at the single cell level. Channel block occurred both in the resting state and after channel opening (tblock = 4 min, 0.1 Hz stimulation), with washout also occurring slowly (~ 80% complete at 30 min). The time course of channel deactivation was significantly prolonged in the presence of D,L-solatol (tfast 677 + 64 ms in control, 1328 + 160 ms sotalol, p < 0.05) suggestive of unbinding from open channels during cell repolarization. D,L-solatol had no effect on the time course or the voltage dependence of channel activation or inactivation.
Conclusions: D,L-solatol weakly inhibits HERG (human therapeutic plasma concentration: 2 - 6 mM), suggesting that the drug may have a greater effect on another repolarizing current. Channel blockade develops slowly with greatest affinity for a closed (resting) state.
