The effects of flecainide on ATP-sensitive K(+) channels in pig urethral myocytes.
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. Kir6.2DeltaC36) which form ATP-sensitive K(+) channels (K(ATP) channels). In current-clamp mode, application of flecainide (> or =100 microM) caused a significant depolarization after the membrane potential had been hyperpolarized by levcromakalim. In voltage-clamp experiments, the levcromakalim-induced outward current was suppressed by 300 microM flecainide in quasi-physiological K(+) conditions (K(i)=51 microM). In contrast, approximately 20% of the levcromakalim-induced inward current still remained even after application of 300 microM flecainide in symmetrical 140 mM K(+) conditions (K(i)=51 microM). In contrast, approximately 20% of the levcromakalim-induced inwar=126 microM). In cell-attached configuration, the channel activity of the levcromakalim-induced K(ATP) channels was reversibly inhibited by flecainide (> or =30 microM) at -50 mV. Their activity was also suppressed by either disopyramide or cibenzoline. Flecainide reversibly inhibited the channel activity of Kir6.2DeltaC36 expressed in COS7 cells using inside-out configuration. 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. These results suggest that flecainide inhibits channel activity through blocking the pore site of the K(ATP) channel in pig urethra.
Yunoki
T
T
Department of Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
Teramoto
N
N
Naito
S
S
Ito
Y
Y
D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D019556:COS Cells; D019806:Cromakalim / Q000494:pharmacology; D004206:Disopyramide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005424:Flecainide / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D008564:Membrane Potentials / Q000187:drug effects; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009154:Mutation; D015221:Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D013552:Swine; D014521:Urethra / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D015221:Potassium Channels; D014665:Vasodilator Agents; D019806:Cromakalim; D000255:Adenosine Triphosphate; D004206:Disopyramide; D005424:Flecainide