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 (K-ATP channel) opener, on the activity of reconstituted KATP channels were investigated using cell-attached recordings. KATP channels 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 (100 mu M) 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 100 mu M pinacidil. ZD0947 had little inhibitory effects on the activity of Kir6.2 Delta C26 channels (a truncated isoform of Kir6.2) or its mutant channels (i.e. Kir6.2 Delta C26C166A) 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 KATP channels (SUR2B/Kir6.1 and SUR2B/Kir6.2) but is a partial antagonist of pancreatic-type KATP channels (i.e. SUR1/Kir6.2) and cardiac-type KATP channels (i.e. SUR2A/Kir6.2). These results suggest that a pharmacological agent can possess either agonist or antagonist actions on the activity of KATP channels, depending on the subtype of SUR.x.