Tolbutamide potentiates the volume-regulated anion channel current in rat pancreatic beta cells.
OBJECTIVE
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. (86)Rb(+) efflux was measured using intact islets. Beta cell volume was measured using a video-imaging technique.


RESULTS
In the absence of glucose, tolbutamide (100 micromol/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 (86)Rb(+) 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 EC(50) of 85 micromol/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
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.
Best
L
L
Department of Medicine, University of Manchester, UK. Len.Best@cmmc.nhs.uk
Davies
S
S
Brown
P D
PD
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000818:Animals; D048429:Cell Size / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D018272:Porins / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014044:Tolbutamide / Q000494:pharmacology*; D050994:Voltage-Dependent Anion Channels
D007473:Ion Channels; D018272:Porins; D050994:Voltage-Dependent Anion Channels; D014044:Tolbutamide; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid