Abstract

Flecainide block of Na⁺ current (I_Na) was investigated in wild-type (WT) or the long QT syndrome 3 (LQT3) sodium channel α subunit mutation with three amino acids deleted (ΔKPQ) stably transfected into human embryonic kidney 293 cells using whole-cell, patch-clamp recordings. Flecainide (1–300 mM) caused tonic and use-dependent block (UDB) of I_Na in a concentration-dependent manner. Compared with WT, ΔKPQ I_Na was more sensitive to flecainide, and flecainide preferentially inhibited late I_Na (mean current between 20 and 23.5 ms after depolarization) compared with peak I_Na. The IC₅₀ value of peak and late I_Na for WT was 127 ± 6 and 44 ± 2 μM (n = 20) and for ΔKPQ was 80 ± 9 and 19 ± 2 μM (n = 31) respectively. UDB of peak I_Nawas greater and developed more slowly during pulse trains for ΔKPQ than for WT. The IC₅₀ value for UDB of peak I_Nafor WT was 29 ± 4 μM (n = 20) and for ΔKPQ was 11 ± 1 μM (n = 26). For ΔKPQ, UDB of late I_Na was greater than for peak I_Na. Recovery from block was slower for ΔKPQ than for WT. We conclude that ΔKPQ interacts differently with flecainide than with WT, leading to increased block and slowed recovery, especially for late I_Na. These data provide insights into mechanisms for flecainide block and provide a rationale at the cellular and molecular level that open channel block may be a useful pharmacological property for treatment of LQT3.