Tissue-specific effects of sulfonylureas lessons from studies of cloned K-ATP channels

Sulfonylureas stimulate insulin secretion in type-2 diabetic patients by bl ocking ATP-sensitive (K-ATP) potassium channels in the pancreatic beta-cell membrane. This effect is mediated by the binding of the drug to the sulfon ylurea receptor (SUR) subunit of the channel. K-ATP channels are also prese nt in other tissues, but often contain different types of SUR subunits (e.g ., SUR1 in beta-cells, SUR2A in heart, SUR2B in smooth muscle). The sensiti vity of these different types of K-ATP channels to sulfonylureas is variabl e: gliclazide and tolbutamide block the beta-cell, but not the cardiac or s mooth muscle, types of K-ATP channel. In contrast, glibenclamide blocks all three types of channel with similar affinity. The reversibility of the dru gs also varies, with tolbutamide and gliclazide being reversible on all thr ee types of K-ATP channel, while glibenclamide is reversible on cardiac, bu t not beta-cell, K-ATP channels. This review summarizes current knowledge o f how sulfonylureas act on the different types of K-ATP channel found in be ta-cells and in extrapancreatic tissues, and discusses the implications of these findings for their use as therapeutic agents. (C) 2000 Elsevier Scien ce Inc. All rights reserved.