title: Glimepiride block of cloned beta-cell, cardiac and smooth muscle K(ATP) channels.
abstract: 1. We examined the effect of the sulphonylurea glimepiride on three types of recombinant ATP-sensitive potassium (K(ATP)) channels. 2. K(ATP) channels share a common pore-forming subunit, Kir6.2, which associates with different sulphonylurea receptor isoforms (SUR1 in beta-cells, SUR2A in heart and SUR2B in smooth muscle). 3. Kir6.2 was coexpressed with SUR1, SUR2A or SUR2B in Xenopus oocytes and macroscopic K(ATP) currents were recorded from giant inside-out membrane patches. Glimepiride was added to the intracellular membrane surface. 4. Glimepiride inhibited Kir6.2/SUR currents by interaction with two sites: a low-affinity site on Kir6.2 (IC(50)= approximately 400 microM) and a high-affinity site on SUR (IC(50)=3.0 nM for SUR1, 5.4 nM for SUR2A and 7.3 nM for SUR2B). The potency of glimepiride at the high-affinity site is close to that observed for glibenclamide (4 nM for SUR1, 27 nM for SUR2A), which has a similar structure. 5. Glimepiride inhibition of Kir6.2/SUR2A and Kir6.2/SUR2B currents, but not Kir6.2/SUR1 currents, reversed rapidly. 6. Our results indicate that glimepiride is a high-affinity sulphonylurea that does not select between the beta-cell, cardiac and smooth muscle types of recombinant K(ATP) channel, when measured in inside-out patches. High-affinity inhibition is mediated by interaction of the drug with the sulphonylurea receptor subunit of the channel.
authors.affiliation: Department of Physiology, Keimyung University School of Medicine, 194 Dongsan Dong, Choong Gu, Taegu, 700-712 Korea.
authors.forename: D K
authors.initials: DK
authors.lastname: Song
authors.forename: F M
authors.initials: FM
authors.lastname: Ashcroft
mesh_terms: D000818:Animals; D004553:Electric Conductivity; D004594:Electrophysiology; D005260:Female; D020128:Inhibitory Concentration 50; D007515:Islets of Langerhans; D051379:Mice; D009130:Muscle, Smooth; D009206:Myocardium; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013379:Substrate Specificity; D013453:Sulfonylurea Compounds / Q000737:chemistry / Q000494:pharmacology*; D014982:Xenopus laevis
chemical_list: D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011994:Recombinant Proteins; D013453:Sulfonylurea Compounds; C057619:glimepiride