Structural basis for the interference between nicorandil and sulfonylurea action

Nicorandil is a new antianginal agent that potentially may be used to treat the cardiovascular side effects of diabetes. It is both a nitric oxide don or and an opener of ATP-sensitive K+ (K-ATP) channels in muscle and thereby causes vasodilation of the coronary vasculature. The aim of this study was to investigate the domains of the K-ATP channel involved in nicorandil act ivity and to determine whether nicorandil interacts with hypoglycemic sulfo nylureas that target K-ATP channels in pancreatic beta -cells. K-ATP channe ls in muscle and beta -cells share a common pore-forming subunit, Kir6.2, b ut possess alternative sulfonylurea receptors (SURs; SUR1 in beta -cells, S UR2A in cardiac muscle, and SUR2B in smooth muscle). We expressed recombina nt K-ATP channels in Xenopus oocytes and measured the effects of drugs and nucleotides by recording macroscopic currents in excised membrane patches. Nicorandil activated Kir6.2/SUR2A and Kir6.2/SUR2B but not Kir6.2/SUR1 curr ents, consistent with its specificity for cardiac and smooth muscle K-ATP c hannels. Drug activity depended on the presence of intracellular nucleotide s and was impaired when the Walker A lysine residues were mutated in either nucleotide-binding domain of SUR2. Chimeric studies showed that the COOH-t erminal group of transmembrane helices (TMs), especially TM 17, is responsi ble for the specificity of nicorandil for channels containing SUR2. The spl ice variation between SUR2A and SUR2B altered the off-rate of the nicorandi l response. Finally, we showed. that nicorandil activity was unaffected by gliclazide.. which specifically blocks SUR1-type K-ATP channels, but; was s everely impaired by glibenclamide and glimepiride, which target both SUR1 a nd SUR2-type K-ATP channels.