title: Effects of the hypoglycaemic drugs repaglinide and glibenclamide on ATP-sensitive potassium-channels and cytosolic calcium levels in beta TC3 cells and rat pancreatic beta cells.
abstract: The present study demonstrates the action of the hypoglycaemic drugs repaglinide and glibenclamide in cultured newborn rat islet cells and mouse beta TC3 cells. In cell-attached membrane patches of newborn rat islet cells repaglinide (10 nmol/l) and glibenclamide (20 nmol/l) decrease the open probability of single ATP-sensitive K(+)-channels to approximately 10% of the activity prior to addition of the drugs in short-term experiments (< 5 min). The influence of repaglinide and glibenclamide on the ATP-sensitive K+ current was studied using the whole-cell patch clamp configuration. A half-maximal steady-state inhibition of the ATP-sensitive K+ currents is observed at 89 pmol/l repaglinide and at 47 pmol/l glibenclamide in whole-cell experiments of longer duration (30 min). Applying digital Ca2+ imaging on single beta TC3 cells we found that repaglinide and glibenclamide induced a concentration-dependent increase in intracellular free Ca2+ concentration ([Ca2+]i) with a half-maximal effect at 0.5 nmol/l for both drugs in long-term experiments (30 min). The rise in [Ca2+]i results from Ca2+ entry through voltage-dependent L-type Ca(2+)-channels since it is inhibited by verapamil (10 mumol/l). The effect of repaglinide and glibenclamide is partly reversible (approximately 80%).
authors.affiliation: Diabetes Discovery, Novo Nordisk A/S, Bagsvaerd, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Gromada
authors.forename: S
authors.initials: S
authors.lastname: Dissing
authors.forename: H
authors.initials: H
authors.lastname: Kofod
authors.forename: J
authors.initials: J
authors.lastname: Frøkjaer-Jensen
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D012709:Serum Albumin / Q000494:pharmacology; D013997:Time Factors; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002219:Carbamates; D007004:Hypoglycemic Agents; D010880:Piperidines; D015221:Potassium Channels; D012709:Serum Albumin; C072379:repaglinide; D000255:Adenosine Triphosphate; D014700:Verapamil; D005905:Glyburide; D002118:Calcium