Inhibition of glucose-induced electrical activity by 4-hydroxytamoxifen in rat pancreatic beta-cells.

The antioestrogen 4-hydroxytamoxifen (10 or 2 microM) abolished the generation of action potentials and repolarized the membrane potential in rat pancreatic beta-cells stimulated by 16 mM glucose. This effect was slowly reversible upon withdrawal of the drug. In cells stimulated by tolbutamide (100 microM), application of 4-hydroxytamoxifen again inhibited action-potential generation but failed to repolarize the membrane potential. 4-Hydroxytamoxifen inhibited voltage-sensitive calcium currents and activity of the volume-sensitive anion channel. The drug had no effect on net K(+) conductance of the cell. Insulin release stimulated by either glucose or tolbutamide was inhibited by 4-hydroxytamoxifen. It is concluded that 4-hydroxytamoxifen impairs beta-cell electrical and secretory activity by inhibiting calcium and anion channel currents. This effect could contribute towards hyperglycaemia during therapy with tamoxifen, of which 4-hydroxytamoxifen is the major metabolite. This study also reveals differences between the depolarizing actions of glucose and tolbutamide in the beta-cell.