On the Adverse Effects of Glibenclamide Administration

Glibenclamide (glyburide) is a sulfonylurea derivative, N-p[2-(5-Chloro-2-methoxybenzamido) ethyl] benzene sulfonylN′-cyclohexylurea (C23H28ClN3O5S), which is widely used as a blocker of ATP-sensitive potassium channels (KATP channels) ubiquitously present in plasma membranes and mitochondria. KATP channel is an octameric multiprotein complex that comprises four pore-forming Kir subunits, which are inwardrectifier K+ channels, and four sulfonylurea receptors (SUR) [1]. Molecular composition of mitochondrial KATP channel (mKATP) channel remains yet undisclosed and the most part of the notions on the properties of mKATP channel was obtained from the studies on plasmalemmal KATP channels. It is known that glibenclamide binds to SUR subunits to block KATP channel [1,2]. SUR subunit of KATP channel belongs to ATP binding cassette proteins that bind ATP upon its hydrolysis [1-3]. MgATPase activity of SUR subunits is thought to be required for KATP channel functioning, its activation by KATP channels openers and the channel blockage by glibenclamide [3]. The same mechanism is supposed to underlie KATP channel blockage in mitochondria. Generally, no blockage of KATP channels was observed either in the absence of MgATP, or in the presence of Mg2+ or ATP alone [4,5]. Glibenclamide binds to mKATP channels with high affinity, however values of Ki (~1-6 μM [4]) obtained for mKATP channels were by the order higher than inhibition constants obtained for sKATP channels [1]. This was used by Garlid’s group for semiquantitative estimation of the density of mKATP channels in mitochondria from various tissues with fluorescent glibenclamide derivative [6]. Glibenclamide is a widely applied antidiabetic drug, known to stimulate insulin release by blocking sKATP channels in betacells. However, the application of sulfonylureas (glibenclamide and tolbutamide) produced adverse effects in heart and brain, such as increased cardiovascular mortality in patients with diabetes [7], and increased neurodegeneration after hypoxic brain injury [8]. In our work we observed one of the adverse effects of glibenclamide application in vivo caused by the direct effects of this drug on mitochondrial functions.