Linogliride is a nonsulfonylurea drug that lowers blood glucose levels in nondiabetic and diabetic humans and animals. Linogliride also stimulates insulin release in vitro. In the perfused pancreas, pretreatment with tolbutamide desensitizes β-cells to the action of linogliride. We tested the hypothesis that linogliride, like tolbutamide, affects the activity of ATP-sensitive K+ channels, which are thought to control insulin release. We used the whole-cell voltage-clamping technique to measure the K+ current through ATP-sensitive K+ channels in the plasma membrane of single rat β-cells, which were dialyzed with 30 μM ATP. Linogliride (10–300 μM) inhibited the K+ current; half-maximal inhibition was observed at 6–25 μM, depending on how much time was allowed for equilibration of the drug. Reversal of the inhibition was slow (t½ ∼4 min). In summary, linogliride leads to a decrease in the activity of ATP-sensitive K+ channels.

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