Metabolic inhibition impairs ATP-sensitive K+ channel block by sulfonylurea in pancreatic β-cells

The effect of metabolic inhibition on the blocking of beta-cell ATP-sensitive K+ channels (K-ATP channels) by glibenclamide was investigated using a patch-clamp technique. Inhibition of K-ATP channels by glibenclamide was attenuated in the cell-attached mode under metabolic inhibition induced by 2,4-dinitrophenol. Under a low concentration (0.1 mu M) of ATP applied in the inside-out mode, K-ATP channel activity was not fully abolished, even when a high dose of glibenclamide was applied, in contrast to the dose-dependent and complete K-ATP channel inhibition under 10 mu M ATP. On the other hand, cibenzoline, a class Ia antiarrhythmic agent, inhibits K-ATP channel activity in a dose-dependent manner and completely blocks it, even under metabolic inhibition. In sulfonylurea receptor (SUR1)- and inward rectifier K+ channel (Kir6.2)-expressed proteins, cibenzoline binds directly to Kir6.2, unlike glibenclamide. Thus, K-ATP channel inhibition by glibenclamide is impaired under the condition of decreased intracellular ATP in pancreatic beta-cells, probably because of a defect in signal transmission between SUR1 and Kir6.2 downstream of the site of sulfonylurea binding to SUR1.