Comparison of block among cloned cardiac potassium channels by non-antiarrhythmic drugs

Abstract

Aims A major problem in contemporary therapeutics is to predict those non-antiarrhythmic drugs (nards) which might prolong the QT interval. Block of repolarizing cardiac K⁺ current is the most likely cause of drug-induced QT prolongation. In this paper we compared six members from four important classes of nards, antihistamines, anti-psychotics, antibiotics and prokinetics, for their block of the major repolarizing cardiac potassium currents I_Kr, I_Ks, I_To and I_Kur. The currents were produced by heterologous expression of HERG (KCNH2), MinK/KvLQT1 (KCNE1/ KCNQ1), Kv4·3 (KCND3) and Kv1·5 (KCNA5) respectively. To evaluate the effects of different cellular backgrounds HERG was expressed stably in HEK 293 and mouse L cells, and transiently in Xenopus laevis oocytes. Methods and Results We measured currents with whole cell patch clamp and calculated IC₅₀ values from dose-response curves at room and body temperatures. In all six cases HERG was the most sensitive target among the cloned K⁺ channels. HERG channels expressed in different mammalian cell lines had similar IC₅₀ values. IC₅₀ values were five to one hundred times larger when HERG was expressed transiently in Xenopus oocytes. Block was temperature-dependent but the effects were small and variable. For the nards terfenadine, sertindole and cisapride that have been withdrawn from the drug market, the IC₅₀ values for HERG block were nanomolar, within the range for block of the primary target, and therefore within the therapeutic range. Conclusion Cloned ion channel assays are robust pre-clinical predictors of non-cardiac proarrhythmic drugs.