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-cells
Departments of 1 Metabolism and Clinical Nutrition and of 2 Internal Medicine, Faculty of Medicine, and 3 Faculty of Integrated Human Studies, Kyoto University, Kyoto 606, Japan
The effect of
metabolic inhibition on the blocking of 
-cell ATP-sensitive
K+ channels
(KATP channels) by glibenclamide
was investigated using a patch-clamp technique. Inhibition of
KATP channels by glibenclamide was
attenuated in the cell-attached mode under metabolic inhibition induced
by 2,4-dinitrophenol. Under a low concentration (0.1 µM) of ATP
applied in the inside-out mode,
KATP channel activity was not
fully abolished, even when a high dose of glibenclamide was applied, in
contrast to the dose-dependent and complete
KATP channel inhibition under 10 µM ATP. On the other hand, cibenzoline, a class Ia antiarrhythmic
agent, inhibits KATP 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, KATP
channel inhibition by glibenclamide is impaired under the condition of
decreased intracellular ATP in pancreatic -cells, probably because
of a defect in signal transmission between SUR1 and Kir6.2 downstream of the site of sulfonylurea binding to SUR1.
sulfonylurea receptor; glibenclamide; intracellular metabolism
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