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Pharmacology of the short QT syndrome N588K-hERG K+ channel mutation: differential impact on selected class I and class III antiarrhythmic drugs

By M J McPate, R S Duncan, J C Hancox and H J Witchel

Abstract

Background and purpose: The short QT syndrome (SQTS) is associated with cardiac arrhythmias and sudden death. The SQT1 form of SQTS results from an inactivation-attenuated, gain-of-function mutation (N588K) to the human ether-a-go-gorelated gene (hERG) potassium channel. Pharmacological blockade of this mutated hERG channel may have therapeutic value. However, hERG-blocking potencies of canonical inhibitors such as E-4031 and D-sotalol are significantly reduced for N588K-hERG. Here, five hERG-blocking drugs were compared to determine their relative potencies for inhibiting N588K channels, and two other inactivation-attenuated mutant channels were tested to investigate the association between impaired inactivation and altered drug potency. Experimental approach: Whole-cell patch clamp measurements of hERG current (I-hERG) mediated by wild-type and mutant (N588K, S631A and N588K/S631A) channels were made at 37 degrees C CHO cells. Key results: The N588K mutation attenuated I-hERG inhibition in the following order: E-40314 amiodarone > quinidine > propafenone > disopyramide. Comparing the three inactivation mutants, the two single mutations, although occurring in different modules of the channel, attenuated inactivation to a nearly identical degree, whereas the double mutant caused considerably greater attenuation, permitting the titration of inactivation. Attenuation of channel inhibition was similar between the single mutants for each drug, and was significantly greater with the double mutant. Conclusions and implications: The degree of drug inhibition of hERG channels may vary based on the level of channel inactivation. Drugs previously identified as useful for treating SQT1 have the least dependence on hERG inactivation. In addition, our findings indicate that amiodarone may warrant further investigation as a potential treatment for SQT

Topics: RM, RS
Publisher: Nature Publishing Group
Year: 2008
OAI identifier: oai:sro.sussex.ac.uk:7293
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