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Actions of ZD0947, a novel ATP‐sensitive K + channel opener, on membrane currents in human detrusor myocytes
Author(s) -
Aishima M,
Tomoda T,
Yunoki T,
Nakano T,
Seki N,
Yonemitsu Y,
Sueishi K,
Naito S,
Ito Y,
Teramoto N
Publication year - 2006
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.0706893
Subject(s) - diazoxide , glibenclamide , pinacidil , chemistry , carbachol , detrusor muscle , membrane potential , myocyte , potassium channel , biophysics , sulfonylurea receptor , patch clamp , atp sensitive potassium channel , iberiotoxin , muscle contraction , contraction (grammar) , endocrinology , medicine , urinary bladder , receptor , biochemistry , biology , insulin , diabetes mellitus
Background and purpose: ATP‐sensitive K + channels (K ATP channels) play important roles in regulating the resting membrane potential of detrusor smooth muscle. Actions of ZD0947, a novel K ATP channel opener, on both carbachol (CCh)‐induced detrusor contractions and membrane currents in human urinary bladder myocytes were investigated. Experimental approach: Tension measurements and patch‐clamp techniques were utilized to study the effects of ZD0947 in segments of human urinary bladder. Immunohistochemistry was also performed to detect the expression of the sulphonylurea receptor 1 (SUR1) and the SUR2B antigens in human detrusor muscle. Key results: ZD0947 (≥0.1 μM) caused a concentration‐dependent relaxation of the CCh‐induced contraction of human detrusor, which was reversed by glibenclamide. The rank order of the potency to relax the CCh‐induced contraction was pinacidil>ZD0947>diazoxide. In conventional whole‐cell configuration, ZD0947 (≥1 μM) caused a concentration‐dependent inward K + current which was suppressed by glibenclamide at ‐60 mV. When 1 mM ATP was included in the pipette solution, application of pinacidil or ZD0947 caused no inward K + current at ‐60 mV. Gliclazide (≤1 μM), a selective SUR1 blocker, inhibited the ZD0947‐induced currents ( K i =4.0 μM) and the diazoxide‐induced currents (high‐affinity site, K i1 =42.4 nM; low‐affinity site, K i2 =84.5 μM) at ‐60 mV. Immunohistochemical studies indicated the presence of SUR1 and SUR2B proteins, which are constituents of K ATP channels, in the bundles of human detrusor smooth muscle. Conclusions and Implications: These results suggest that ZD0947 caused a glibenclamide‐sensitive detrusor relaxation through activation of glibenclamide‐sensitive K ATP channels in human urinary bladder. British Journal of Pharmacology (2006) 149 , 542–550. doi: 10.1038/sj.bjp.0706893