Glimepiride block of cloned ß-cell, cardiac and smooth muscle KATP channels

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 (IC50 = similar to 400 muM) and a high-affinity site on SUR (IC50 = 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.