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

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, antipsychotics, 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 For the nards terfenadine, sertindole and cisapride that have been withdrawn from the drug market, the IC50 values for HERG block were nanomolar, within the range for block of the primary target, and therefore within the therapeutic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 preclinical predictors of non-cardiac proarrhythmic drugs. (Eur Heart J Supplements 2001; 3 (Suppl K): K23-K30 (C) 2001 The European Society of Cardiology.