Inhibition of recombinant KATP channels by the antidiabetic agents midaglizole, LY397364 and LY389382

Most imidazolines inhibit ATP-sensitive K+ (K-ATP) channels. Since these drugs are potentially clinically relevant insulin secretagogues, it is important to know whether extrapancreatic K-ATP channels are targeted. We examined the effects of three imidazoline-derived antidiabetic drugs on the cloned K-ATP channel, expressed in Xenopus laevis oocytes, and their specificity for interaction with the pore-forming Kir6.2 or the sulphonylurea receptor (SUR) I subunit. Midaglizole, LY397364 and LY389382 blocked Kir6.2DeltaC currents with IC50 of 3.8, 6.1 and 0.7 muM, respectively. The block of Kir6.2/SUR1 currents by LY397364 and LY389382 was best fit by a two-site model, suggesting that these drugs also interact with SUR1. However, since all three drugs interact with the Kir6.2 subunit, and Kir6.2 forms the pore of extrapancreatic K-ATP channels, these drugs are unlikely to be specific for the beta-cell. (C) 2002 Elsevier Science B.V. All rights reserved.