Dual action of ZD6169, a novel K⁺ channel opener, on ATP-sensitive K⁺ channels in pig urethral myocytes

1. The effects of ZD6169, a novel K⁺ channel opener, on both membrane and unitary currents in pig urethra were investigated using patch-clamp techniques. Its effect was also examined on currents in inside-out patches of COS7 cells expressing carboxy terminus truncated inwardly rectifying K⁺ channel (Kir6.2) subunits (Kir6.2ΔC36) which form ATP-sensitive K⁺ channels (K_ATP channels). 2. In current-clamp mode, ZD6169 (≤ 10 μM) induced a concentration-dependent membrane hyperpolarization. Higher concentrations (≥ 30 μM) caused a transient membrane hyperpolarization, followed by a gradual membrane depolarization. On removal of ZD6169, an after hyperpolarization was observed. 3. In conventional voltage-clamp configuration, at -50 mV in symmetrical 140 mM K⁺ conditions, ZD6169 (100 μM) caused a transient inward current which gradually decayed. Removal of ZD6169 evoked a much larger amplitude K⁺ current with a similar time course. 4. ZD6169 produced an inward glibenclamide-sensitive K⁺ current, demonstrating a bell-shaped concentration-response relationship. 5. In cell-attached configuration in symmetrical 140 mM K⁺ conditions, ZD6169 (≤ 30 μM) activated an K_ATP channel which was reversibly suppressed by application of glibenclamide. In contrast, ZD6169 (100 μM) inhibited the activity of the levcromakalim-induced K_ATP channels. 6. ZD6169 (100 μM) had no significant effect on the channel activity of Kir6.2ΔC36 in inside-out configuration, although cibenzoline greatly suppressed the channel activity. 7. These results demonstrate that ZD6169 possesses a dual effect on the activity of the K_ATP channel; activating at low concentration and inhibiting at higher concentration.