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

Abstract

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) 1 subunit. Midaglizole, LY397364 and LY389382 blocked Kir6.2ΔC currents with IC 50 of 3.8, 6.1 and 0.7 μM, 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 β-cell.