Preferential block of late sodium currents in the LQT3 deltaKPQ mutant by the class I(c) antiarrhythmic flecainide

Flecainide block of Na1 current (INa) was investigated in wild-type (WT) or the long QT syndrome 3 (LQT3) sodium channel a subunit mutation with three amino acids deleted (DKPQ) 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 INa in a con-centration-dependent manner. Compared with WT, DKPQ INa was more sensitive to flecainide, and flecainide preferentially inhibited late INa (mean current between 20 and 23.5 ms after depolarization) compared with peak INa. The IC50 value of peak and late INa for WT was 127 6 6 and 44 6 2 mM (n 5 20) and for DKPQ was 80 6 9 and 19 6 2 mM (n 5 31) respectively. UDB of peak INa was greater and developed more slowly during pulse trains for DKPQ than for WT. The IC50 value for UDB of peak INa for WT was 29 6 4 mM (n 5 20) and for DKPQ was 11 6 1 mM (n 5 26). For DKPQ, UDB of late INa was greater than for peak INa. Recovery from block was slower for DKPQ than for WT. We conclude that DKPQ interacts differently with flecainide than with WT, leading to increased block and slowed recovery, especially for late INa. These data provide insights into mech-anisms for flecainide block and provide a rationale at the cel-lular and molecular level that open channel block may be a useful pharmacological property for treatment of LQT3. The congenital long QT syndrome (LQT) is an inherited cardiac disorder that causes ventricular arrhythmias, result-ing in syncope and sudden death. One form of the disease, LQT3, is caused by mutations in SCN5A, the gene that encodes the voltage-dependent cardiac Na1 channel a sub