Actions of ZD0947, a novel ATP-sensitive K + channel opener, on membrane currents in human detrusor myocytes

M. Aishima, T. Tomoda, T. Yunoki, T. Nakano, N. Seki, Y. Yonemitsu, K. Sueishi, S. Naito, Y. Ito, N. Teramoto

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

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 (≥ 0.1 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.

Original languageEnglish
Pages (from-to)542-550
Number of pages9
JournalBritish Journal of Pharmacology
Volume149
Issue number5
DOIs
Publication statusPublished - Nov 21 2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Pharmacology

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