Inhibition of ATP-sensitive K+ channels in pancreatic beta-cells by nonsulfonylurea drug linogliride.
Linogliride is a nonsulfonylurea drug that lowers blood glucose levels in nondiabetic and diabetic humans and animals. Linogliride also stimulates insulin release in vitro. In the perfused pancreas, pretreatment with tolbutamide desensitizes beta-cells to the action of linogliride. We tested the hypothesis that linogliride, like tolbutamide, affects the activity of ATP-sensitive K+ channels, which are thought to control insulin release. We used the whole-cell voltage-clamping technique to measure the K+ current through ATP-sensitive K+ channels in the plasma membrane of single rat beta-cells, which were dialyzed with 30 microM ATP. Linogliride (10-300 microM) inhibited the K+ current; half-maximal inhibition was observed at 6-25 microM, depending on how much time was allowed for equilibration of the drug. Reversal of the inhibition was slow (t1/2 approximately 4 min). In summary, linogliride leads to a decrease in the activity of ATP-sensitive K+ channels.
Ronner
P
P
Department of Biochemistry and Biophysics, School of Medicine, University of Pennsylvania, Philadelphia 19104.
Higgins
T J
TJ
Kimmich
G A
GA
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology / Q000379:methods; D005947:Glucose / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D015394:Molecular Structure; D010477:Perfusion; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D011759:Pyrrolidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D014044:Tolbutamide / Q000494:pharmacology
D000596:Amino Acids; D007004:Hypoglycemic Agents; D015221:Potassium Channels; D011759:Pyrrolidines; C044425:linogliride; D000255:Adenosine Triphosphate; D014044:Tolbutamide; D005947:Glucose