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

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 beta 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 mu M. The compound inhibited the activity of the K-ATP channel recorded from a single beta-cell in a concentration-dependent manner. The IC50 was 0.4 mu M in the inside-out mode and 5.2 mu M 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 IC50 was reduced from 26.8 mu M at pH 6.2 to 0.9 mu M 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 IC50, 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 [H-3]-glibenclamide to pancreatic islets was inhibited by glibenclamide but not by cibenzoline. In contrast, the [H-3]-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.