Metabolic inhibition impairs atp-sensitive k+ channel block by
sulfonylurea in pancreatic b cells.
Mukai, Eri, Hitoshi Ishida, Seika Kato, Yoshiyuki Tsuura, Shimpei
Fujimoto, Ayako Ishida-Takahashi, Minoru Horie, Kinsuke Tsuda, and
Yutaka Seino.
Department of Metabolism and Clinical Nutrition, and Department of
Internal Medicine, Faculty of Medicine, and [tilde]nFaculty of
Integrated Human Studies, Kyoto University, Kyoto 606, Japan
APStracts 4:0211E, 1997.
The effect of metabolic inhibition on the blocking of b cell ATP
-sensitive K+ channels (KATP channels) by glibenclamide was
investigated using 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 M) 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 M 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 b cells, probably due to a
defect in signal transmission between SUR1 and Kir6.2 downstream of
the site of sulfonylurea binding to SUR1.
Received 15 May 1997; accepted in final form 18 September 1997.
APS Manuscript Number E221-7.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 7 October 1997