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

Noriyoshi Teramoto, Takakazu Yunoki, Makoto Takano, Yoshikazu Yonemitsu, Ichiro Masaki, Katsuo Sueishi, Alison F. Brading, Yushi Ito

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

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 (KATP 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 KATP channel which was reversibly suppressed by application of glibenclamide. In contrast, ZD6169 (100 μM) inhibited the activity of the levcromakalim-induced KATP 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 KATP channel; activating at low concentration and inhibiting at higher concentration.

Original languageEnglish
Pages (from-to)154-164
Number of pages11
JournalBritish Journal of Pharmacology
Volume133
Issue number1
DOIs
Publication statusPublished - 2001

All Science Journal Classification (ASJC) codes

  • Pharmacology

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