Tolbutamide potentiates the volume-regulated anion channel current in rat pancreatic beta cells

Aims/hypothesis. Hypoglycaemic sulphonylureas are thought to stimulate insulin release by binding to a sulphonylurea receptor, closing K-ATP channels and inducing electrical activity. However, the fact that these drugs stimulate insulin release at high glucose concentrations where K-ATP channels are closed suggests additional ionic actions. The aim of this study was to test the hypothesis that sulphonylureas influence the current of the glucose- and volume-regulated anion channel. Methods. Electrical and ion-channel activity were recorded in isolated rat beta cells using the patch-clamp technique. Rb-86(+) efflux was measured using intact islets. Beta cell volume was measured using a video-imaging technique. Results. In the absence of glucose, tolbutamide (100 mumol/l) transiently depolarised the cells. In the presence of glucose (5 mmol/l), tolbutamide evoked a sustained period of electrical activity, whilst at 10 mmol/l glucose, the drug evoked a pronounced 'silent' depolarisation. In the absence of glucose, tolbutamide inhibited Rb-86(+) efflux. However, at 10 mmol/l glucose, tolbutamide induced a transient stimulation of efflux. Tolbutamide potentiated the whole-cell volume-regulated anion conductance in a glucose-dependent manner with an EC50 of 85 mumol/l. In single channel recordings, tolbutamide increased the channel-open probability. Tolbutamide caused beta cell swelling in the presence of glucose, but not in its absence. Conclusions/interpretation. Tolbutamide can induce beta cell electrical activity by potentiating the glucose- and volume-regulated anion channel current. This effect is probably not due to a direct effect of the drug on the channel, but could be secondary to a metabolic action in the beta cell.