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

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‐à‐go‐go‐related 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.

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