title: ZD0947, a sulphonylurea receptor modulator, detects functional sulphonylurea receptor subunits in murine vascular smooth muscle ATP-sensitive K+channels.
abstract: In order to identify functional sulphonylurea receptor (SUR.x) subunits of native ATP-sensitive K+channels (KATPchannels) in mouse portal vein, the effects of ZD0947, a SUR.x modulator, were investigated on spontaneous portal vein contractions, macroscopic membrane currents and unitary currents recorded (using patch-clamp techniques) in freshly dispersed mouse portal vein myocytes. Spontaneous contractions in mouse portal vein were reversibly reduced by ZD0947 in a concentration-dependent manner (Ki=293nM). The relaxation elicited by 3µM ZD0947 was antagonized by the additional application of glibenclamide (300nM), but not gliclazide (100-300nM). In the conventional whole-cell configuration, 100µM ZD0947 elicited inward glibenclamide-sensitive currents at a holding potential of -60mV that demonstrated selectivity for K+(i.e. KATPcurrents). The peak amplitude of the membrane current elicited by 30µM or 100µM ZD0947 was smaller than that elicited by 100µM pinacidil at -60mV. In the cell-attached mode, 100µM ZD0947 activated glibenclamide-sensitive K+channels with a conductance (35 pS) similar to that of recombinant Kir6.1/SUR2B channels that were expressed in HEK293 cells and activated by 100µM ZD0947. These results demonstrate that ZD0947 caused a significant vascular relaxation through the activation of KATPchannels and that SUR2B may be the major functional subunit of SUR.x in mouse portal vein KATPchannels, based on its pharmacological selectivity.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Saga University, Saga 849-8501, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Saga University, Saga 849-8501, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Takahara
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Saga University, Saga 849-8501, Japan.
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Uchida
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; Laboratory of Biomedical Engineering, Graduate School of Biomedical Engineering, Tohoku University, Sendai 980-8575, Japan. Electronic address: noritera@cc.saga-u.ac.jp.
authors.forename: Noriyoshi
authors.initials: N
authors.lastname: Teramoto
mesh_terms: D000818:Animals; D004095:Dihydropyridines / Q000494:pharmacology*; D055724:Electrophysiological Phenomena / Q000187:drug effects; D054086:KATP Channels / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D011169:Portal Vein / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits / Q000378:metabolism*; D064233:Sulfonylurea Receptors / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D004095:Dihydropyridines; D054086:KATP Channels; D021122:Protein Subunits; D064233:Sulfonylurea Receptors; C463119:ZD0947
keywords: ATP-sensitive K(+) channels; Kir6.1; SUR2B; Vascular smooth muscle; ZD0947