%0 Journal Article %A Toshihisa Nagatomo %A Craig T. January %A Jonathan C. Makielski %T Preferential Block of Late Sodium Current in the LQT3 ΔKPQ Mutant by the Class IC Antiarrhythmic Flecainide %D 2000 %J Molecular Pharmacology %P 101-107 %V 57 %N 1 %X Flecainide block of Na+ current (INa) 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 INa in a concentration-dependent manner. Compared with WT, ΔKPQ 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 and 44 ± 2 μM (n = 20) and for ΔKPQ was 80 ± 9 and 19 ± 2 μM (n = 31) respectively. UDB of peak INawas greater and developed more slowly during pulse trains for ΔKPQ than for WT. The IC50 value for UDB of peak INafor WT was 29 ± 4 μM (n = 20) and for ΔKPQ was 11 ± 1 μM (n = 26). For ΔKPQ, UDB of late INa was greater than for peak INa. 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 INa. 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. The American Society for Pharmacology and Experimental Therapeutics %U https://molpharm.aspetjournals.org/content/molpharm/57/1/101.full.pdf