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 (Kir6.2C36) which form ATP-sensitive K(+) channels (K(ATP) channels). 2. In current-clamp mode, ZD6169 (< or = 10 microM) induced a concentration-dependent membrane hyperpolarization. Higher concentrations (> or = 30 microM) 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 microM) 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 (< or = 30 microM) activated an K(ATP) channel which was reversibly suppressed by application of glibenclamide. In contrast, ZD6169 (100 microM) inhibited the activity of the levcromakalim-induced K(ATP) channels. 6. ZD6169 (100 microM) had no significant effect on the channel activity of Kir6.2C36 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.
Teramoto
N
N
Department of Pharmacology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan. noritera@linne.med.kyushu-u.ac.jp
Yunoki
T
T
Takano
M
M
Yonemitsu
Y
Y
Masaki
I
I
Sueishi
K
K
Brading
A F
AF
Ito
Y
Y
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001577:Benzophenones / Q000494:pharmacology*; D019556:COS Cells; D002478:Cells, Cultured; D019806:Cromakalim / Q000494:pharmacology; D004553:Electric Conductivity; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects*; D008564:Membrane Potentials / Q000187:drug effects; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying; D013552:Swine; D013997:Time Factors; D014521:Urethra / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
D000577:Amides; D000889:Anti-Arrhythmia Agents; D001577:Benzophenones; D007004:Hypoglycemic Agents; D007093:Imidazoles; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D014665:Vasodilator Agents; C095007:Zeneca ZD 6169; D019806:Cromakalim; D000255:Adenosine Triphosphate; D005905:Glyburide; C032151:cifenline