Differential selectivity of insulin secretagogues - Mechanisms, clinical implications, and drug interactions

The sulphonylurea receptor (SUR) subunits of K-ATP channels are the targets for several classes of therapeutic drugs. Sulphonylureas close K-ATP channels in pancreatic beta-cells and are used to stimulate insulin release in type 2 diabetes, whereas the K-ATP channel opener nicorandil acts as an antianginal agent by opening K-ATP channels in cardiac and vascular smooth muscle. The predominant type of SUR varies between tissues: SUR1 in beta-cells, SUR2A in cardiac muscle, and SUR2B in smooth muscle. Sulphonylureas and related drugs exhibit differences in tissue specificity, as the drugs interact to varying degrees with different types of SUR. Gliclazide and tolbutamide are P-cell selective and reversible. Glimepirde, glibenclamide, and repaglinide, however, inhibit cardiac and smooth muscle K-ATP channels in addition to those in beta-cells and are only slowly reversible. Similar properties have been observed by recording K-ATP channel activity in intact cells and in Xenopus oocytes expressing cloned K-ATP channel subunits. While K-ATP channels in cardiac and smooth muscle are largely closed under physiological conditions (but open during ischaemia), they are activated by antianginal agents such as nicorandil. Under these conditions, they may be inhibited by sulphonylureas that block SUR2-type K-ATP channels (e.g., glibenclamide). Care should, therefore, be taken when choosing a sulphonylurea if potential interactions with cardiac and smooth muscle K-ATP channels are to be avoided. (C) 2003 Elsevier Science Inc. All rights reserved.