Flecainide block of Na(+) current (I(Na)) was investigated in wild-type (WT) or the long QT syndrome 3 (LQT3) sodium channel alpha subunit mutation with three amino acids deleted (DeltaKPQ) 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, DeltaKPQ 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 IC(50) value of peak and late I(Na) for WT was 127 +/- 6 and 44 +/- 2 microM (n = 20) and for DeltaKPQ was 80 +/- 9 and 19 +/- 2 microM (n = 31) respectively. UDB of peak I(Na) was greater and developed more slowly during pulse trains for DeltaKPQ than for WT. The IC(50) value for UDB of peak I(Na) for WT was 29 +/- 4 microM (n = 20) and for DeltaKPQ was 11 +/- 1 microM (n = 26). For DeltaKPQ, UDB of late I(Na) was greater than for peak I(Na). Recovery from block was slower for DeltaKPQ than for WT. We conclude that DeltaKPQ 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.