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

Abstract

Aims/hypothesis. Hypoglycaemic sulphonylureas are thought to stimulate insulin release by binding to a sulphonylurea receptor, closing KATP channels and inducing electrical activity. However, the fact that these drugs stimulate insulin release at high glucose concentrations where KATP 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. 86Rb+ efflux was measured using intact islets. Beta cell volume was measured using a video-imaging technique. Results. In the absence of glucose, tolbutamide (100 μmol/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 86Rb+ 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 μmol/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. © Springer-Verlag 2004.