Block of pancreatic ATP-sensitive K~+ channels and insulinotrophic action by the antiarrhythmic agent, cibenzoline

摘要

1 We investigated the effect of cibenzoline (a class Ia antiarrhythmic drug) on basal insulin secretory activity of rat pancreatic islets and ATP-sensitive K~+ channels (K_(ATP)) in single pancreatic β cells of the same species, using radioimmunoassay and patch clamp techniques. 2 Micromolar cibenzoline had a dose-dependent insulinotrophic action with an EC_(50) of 94.2 ± 46.4 μM. The compound inhibited the activity of the K_(ATP) channel recorded from a single β-cell in a concentration-dependent manner. The IC_(50) was 0.4 μM in the inside-out mode and 5.2 μM in the cell-attached mode, at pH 7.4. 3 In the cell-attached mode, alkalinization of extracellular solution increased the inhibitory action of cibenzoline and the IC_(50) was reduced from 26.8 μM at pH 6.2 to 0.9 μM at pH 8.4. On the other hand, the action of cibenzoline in the excised inside-out mode was acute in onset with a small IC_(50), indicating that the drug attains its binding site from the cytoplasmic side of the cell membrane. 4 In the inside-out mode, micromolar ADP reactivated the cibenzoline-blocked K_(ATP) channels in a manner similar to that by which ADP restored ATP-dependent block of the channel. 5 The binding of [~3H]-glibenclamide to pancreatic islets was inhibited by glibenclamide but not by 3 cibenzoline. In contrast, the [~3H]-cibenzoline binding was displaced by unlabelled cibenzoline but not by glibenclamide. It is concluded that cibenzoline blocks pancreatic K_(ATP) channels via a binding site distinct from the sulphonylurea receptor.