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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 Kir6.2deltaC currents with IC(50) of 3.8, 6.1 and 0.7 microM, 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.

Type

Journal article

Journal

Eur J Pharmacol

Publication Date

27/09/2002

Volume

452

Pages

11 - 19

Keywords

ATP-Binding Cassette Transporters, Animals, Cells, Cultured, Electrophysiology, Glucose, Hypoglycemic Agents, Imidazoles, Insulin, KATP Channels, Mice, Naphthalenes, Potassium Channel Blockers, Potassium Channels, Potassium Channels, Inwardly Rectifying, Recombinant Proteins