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

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 (KATP channels). 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. 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. ZD6169 produced an inward glibenclamide‐sensitive K+ current, demonstrating a bell‐shaped concentration‐response relationship. In cell‐attached configuration in symmetrical 140 mM K+ conditions, ZD6169 (30 μM) activated an KATP channel which was reversibly suppressed by application of glibenclamide. In contrast, ZD6169 (100 μM) inhibited the activity of the levcromakalim‐induced KATP channels. 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. These results demonstrate that ZD6169 possesses a dual effect on the activity of the KATP channel; activating at low concentration and inhibiting at higher concentration. British Journal of Pharmacology (2001) 133, 154–164; doi:10.1038/sj.bjp.0704042