K_(ATP) channel pharmacology in the pancreas and the cardiovascular system

摘要

ATP-sensitive K (K_(ATP)) channels are the targets for a number of therapeutic drugs, including the sulphonylureas used to treat type 2 diabetes, and K_(ATP) channel openers used to treat hypertension and angina. The tissue selectivity of agents that modulate K_(ATP) channels is due to the differential expression of sulphonylurea receptor (SUR) subunits (SUR1 in pancreatic ?-cells, SUR2A in cardiac and skeletal muscles, and SUR2B in smooth muscle). Simple sulphonylureas such as tolbutamide and gliclazide block channels containing SUR1, but not those containing SUR2, with high affinity Glibenclamide, glimepiride and repaglinide, by contrast, inhibit both SUR1- and SUR2-containing channels. Differences in drug selectivity and reversibility have provided insight into the nature of the drug binding pocket on the sulphonylurea receptor subunits. This will be the basis for the development of more tissue-specific drags, reducing the risk of unwanted side-effects.