The effects of flecainide on ATP-sensitive K+ channels in pig urethral myocytes

1 The effects of the antiarrhythmic drug flecainide on levcromakalim-induced hyperpolarization, macroscopic and unitary K+ currents in pig urethra were investigated using patch-clamp techniques. The effects of flecainide were also examined on currents in inside-out patches of COS7 cells expressing carboxy terminus truncated inwardly rectifying K+ channel (Kir6.2) subunits (i.e. Kir6.2 Delta C36) which form ATP-sensitive K+ channels (K-ATP channels). 2 In current-clamp mode, application of flecainide (greater than or equal to 100 muM) caused a significant depolarization after the membrane potential had been hyperpolarized by levcromakalim. 3 In voltage-clamp experiments, the levcromakalim-induced outward current was suppressed by 300 muM flecainide in quasi-physiological K+ conditions(K-i=51 muM). In contrast, approximately 20% of the levcromakalim-induced inward current still remained even after application of 300 muM flecainide in symmetrical 140 mM K+ conditions (K-i=126 muM). 4 In cell-attached configuration, the channel activity of the levcromakalim-induced K-ATP channels was reversibly inhibited by flecainide (greater than or equal to 30 muM) at -50 mV. Their activity was also suppressed by either disopyramide or cibenzoline. 5 Flecainide reversibly inhibited the channel activity of Kir6.2 Delta C36 expressed in COS7 cells using inside-out configuration. 6 Inhibitory effects of flecainide on the levcromakalim-induced currents became more potent when the value of external pH increased, although this slightly reduced the proportion of drug molecules carrying a positive charge. 7 These results suggest that flecainide inhibits channel activity through blocking the pore site of the K-ATP channel in pig urethra.