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 beta-cell selective and reversible. Glimepiride, 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.
Gribble
Fiona M
FM
Department of Clinical Biochemistry, University of Cambridge, Addenbrookes Hospital, Box 232, Hills Road, CB2 2QR, Cambridge, UK.
Reimann
Frank
F
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004347:Drug Interactions; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D015640:Ion Channel Gating; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D009928:Organ Specificity; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying; D011487:Protein Conformation; D021122:Protein Subunits; D011955:Receptors, Drug / Q000187:drug effects / Q000502:physiology*; D013453:Sulfonylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D064233:Sulfonylurea Receptors; D014981:Xenopus
C577507:ABCC8 protein, human; C577510:ABCC9 protein, human; D018528:ATP-Binding Cassette Transporters; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D021122:Protein Subunits; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; D000255:Adenosine Triphosphate