Sulfonylurea sensitivity of adenosine triphosphate-sensitive potassium channels from beta cells and extrapancreatic tissues

Sulfonylureas are widely used to stimulate insulin secretion in type 2 diab etic patients because they close adenosine triphosphate-sensitive potassium (K-ATP) channels in the pancreatic beta-cell membrane. This action is medi ated by binding of the drug to the sulfonylurea receptor (SUR1) subunit of the channel. K-ATP channels are also present in a range of extrapancreatic tissues, but many of these contain an alternative type of SUR subunit (SUR2 A in heart and SUR2B in smooth muscle). The sulfonylurea-sensitivity of K-A TP channels containing the different types of SUR is variable: gliclazide a nd tolbutamide block the beta cell, but not the cardiac or smooth muscle ty pes of K-ATP channels with high affinity. Glibenclamide and glimepiride, on the other hand, block channels containing SUR1 and SUR2 with similar affin ity. The reversibility of the different sulfonylureas also varies. Tolbutam ide and gliclazide produce a reversible inhibition of Kir6.2/SUR1 and Kir6. 2/SUR2 channels, whereas glibenclamide has a reversible effect on cardiac, but not beta-cell, K-ATP channels. In this article, we summarize current kn owledge of how sulfonylureas act on K-ATP channels containing the different types of sulfonylurea receptor, and discuss the implications of these find ings for the use of sulfonylureas in the treatment of diabetes mellitus, Co pyright (C) 2000 by W.B. Saunders Company.