Effects of ZD0947, a novel and potent ATP-sensitive K+channel opener, on smooth muscle-type ATP-sensitive K+channels.
The effects of ZD0947, a novel ATP-sensitive K+channel (KATPchannel) opener, on the activity of reconstituted KATPchannels were investigated using cell-attached recordings. KATPchannels were studied in HEK 293 cells by co-expression of inwardly rectifying-6 family K+channel subunits (Kir6.x: Kir6.1 and Kir6.2) with 3 different types of sulphonylurea receptors (SUR.x: SUR1, SUR2A and SUR2B). ZD0947 (100µM) activated SUR2B/Kir6.2 channels in a concentration-dependent manner, but caused only weak activation of SUR1/Kir6.2 channels and SUR2A/Kir6.2 channels expressed in HEK 293 cells. ZD0947 reversibly suppressed diazoxide-elicited SUR1/Kir6.2 channels activity and pinacidil-elicited SUR2A/Kir6.2 channel activity. However, ZD0947 did not affect SUR2B/Kir6.2 channels fully activated by 100µM pinacidil. ZD0947 had little inhibitory effects on the activity of Kir6.2ΔC26 channels (a truncated isoform of Kir6.2) or its mutant channels (i.e. Kir6.2ΔC26C166A) expressed in HEK 293 cells. ZD0947 also elicited activity in SUR2B/Kir6.1 channels expressed in HEK 293 cells, in a concentration-dependent manner. Therefore, ZD0947 is a relatively effective activator of smooth muscle-type KATPchannels (SUR2B/Kir6.1 and SUR2B/Kir6.2) but is a partial antagonist of pancreatic-type KATPchannels (i.e. SUR1/Kir6.2) and cardiac-type KATPchannels (i.e. SUR2A/Kir6.2). These results suggest that a pharmacological agent can possess either agonist or antagonist actions on the activity of KATPchannels, depending on the subtype of SUR.x.
Department of Pharmacology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Saga University, Saga 849-8501, Japan.
Keisuke
K
Mori
Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Saga University, Saga 849-8501, Japan.
Yoshio
Y
Yamashita
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.
Noriyoshi
N
Teramoto
D004095:Dihydropyridines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D054086:KATP Channels / Q000737:chemistry* / Q000378:metabolism*; D009130:Muscle, Smooth / Q000378:metabolism*; D020110:Pinacidil / Q000494:pharmacology; D064233:Sulfonylurea Receptors / Q000378:metabolism
D004095:Dihydropyridines; D054086:KATP Channels; D064233:Sulfonylurea Receptors; C463119:ZD0947; D020110:Pinacidil
ATP-sensitive K(+) channels; K(+) channel opener; Smooth muscle; ZD0947