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.
Best
Leonard
L
Department of Medicine, University of Manchester, Oxford Road, Manchester M13 9WL, UK. lbest@central.cmht.nwest.nhs.uk
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D015220:Calcium Channels / Q000502:physiology; D002478:Cells, Cultured; D004553:Electric Conductivity; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005947:Glucose / Q000037:antagonists & inhibitors*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007473:Ion Channels / Q000502:physiology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D007700:Kinetics; D018408:Patch-Clamp Techniques; D051381:Rats; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014044:Tolbutamide / Q000494:pharmacology
D015220:Calcium Channels; D004965:Estrogen Antagonists; D007004:Hypoglycemic Agents; D007328:Insulin; D007473:Ion Channels; D013629:Tamoxifen; C016601:afimoxifene; D014044:Tolbutamide; D005947:Glucose