TY - JOUR

T1 - 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

AU - Gromada, J

AU - Dissing, S

AU - Kofod, Hans

AU - Frøkjaer-Jensen, J

PY - 1995/9

Y1 - 1995/9

N2 - 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%).

AB - 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%).

KW - Adenosine Triphosphate

KW - Animals

KW - Animals, Newborn

KW - Calcium

KW - Carbamates

KW - Cell Line

KW - Cells, Cultured

KW - Cytosol

KW - Dose-Response Relationship, Drug

KW - Glyburide

KW - Hypoglycemic Agents

KW - Ion Channel Gating

KW - Islets of Langerhans

KW - Kinetics

KW - Membrane Potentials

KW - Mice

KW - Patch-Clamp Techniques

KW - Piperidines

KW - Potassium Channels

KW - Rats

KW - Serum Albumin

KW - Time Factors

KW - Verapamil

M3 - Journal article

C2 - 8591815

VL - 38

SP - 1025

EP - 1032

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 9

ER -