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

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.