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The involvement of L‐type Ca 2+ channels in the relaxant effects of the ATP‐sensitive K + channel opener ZD6169 on pig urethral smooth muscle
Author(s) -
Teramoto Noriyoshi,
Yunoki Takakazu,
Ikawa Shigeoki,
Takano Naruaki,
Tanaka Kiyoshi,
Seki Narihito,
Naito Seiji,
Ito Yushi
Publication year - 2001
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704408
Subject(s) - bay k8644 , glibenclamide , chemistry , membrane potential , biophysics , nifedipine , depolarization , patch clamp , voltage clamp , muscle relaxation , potassium channel , endocrinology , medicine , biochemistry , calcium , biology , receptor , organic chemistry , diabetes mellitus
The effects of ZD6169, a novel ATP‐sensitive K + channel (K ATP channel) opener, were investigated on membrane currents in isolated myocytes using patch‐clamp techniques. Tension measurement was also performed to study the effects of ZD6169 on the resting tone of pig urethral smooth muscle. Levcromakalim was more potent than ZD6169 in lowering the resting urethral tone. Relaxation induced by low concentrations of ZD6169 (3 μ M ) was completely suppressed by additional application of glibenclamide (1 μ M ). In contrast, glibenclamide (1 – 10 μ M ) only partially inhibited the relaxation induced by higher concentrations of ZD6169 (10 μ M ). Bay K8644 (1 μ M ) reduced the maximum relaxation produced by ZD6169 (10 μ M ). In whole‐cell configuration, ZD6169 suppressed the peak amplitude of voltage‐dependent Ba 2+ currents in a concentration‐ and voltage‐dependent manner, and at 100 μ M , shifted the steady‐state inactivation curve of the voltage‐dependent Ba 2+ currents to the left at a holding potential of −90 mV. In cell‐attached configuration, open probability of unitary voltage‐dependent Ba 2+ channels (27 pS, 90 m M Ba 2+ ) was inhibited by 100 μ M ZD6169 and by 10 μ M nifedipine. Reverse transcriptase‐polymerase chain reaction (RT – PCR) analysis revealed the presence of the transcript of the α 1C subunit of L‐type Ca 2+ channels in pig urethra. These results demonstrate that ZD6169 causes urethral relaxation through two distinct mechanisms, activation of K ATP channels at lower concentrations and inhibition of voltage‐dependent Ca 2+ channels at higher concentrations (about 10 μ M ).British Journal of Pharmacology (2001) 134 , 1505–1515; doi: 10.1038/sj.bjp.0704408