ro-6-4563 and gliquidone

The ATP-sensitive K+ channel, an octameric complex of two structurally unrelated types of subunits, SUR1 and Kir6.2, plays a central role in the physiological regulation of insulin secretion. The sulfonylurea glibenclamide, which trigger insulin secretion by blocking the ATP-sensitive K+ channel, interacts with both high and low affinity binding sites present on beta-cells. The high affinity binding site has been localized on SUR1 but the molecular nature of the low affinity site is still uncertain. In this study, we analyzed the pharmacology of glibenclamide in a transformed COS-7 cell line expressing the rat Kir6.2 cDNA and compared with that of the MIN6 beta cell line expressing natively both the Kir6.2 and the SUR1 subunits. Binding studies and Scatchard analysis revealed the presence of a single class of low affinity binding sites for glibenclamide on the COS/Kir6.2 cells with characteristics similar to that observed for the low affinity site of the MIN6 beta cells.

Topics: Animals; ATP-Binding Cassette Transporters; Binding Sites; Blotting, Northern; Cell Line; Cell Membrane; COS Cells; Gliclazide; Glipizide; Glyburide; Islets of Langerhans; Kinetics; Organelles; Phentolamine; Potassium Channels; Potassium Channels, Inwardly Rectifying; Rats; Receptors, Drug; Recombinant Fusion Proteins; Sulfonylurea Compounds; Sulfonylurea Receptors; Tolbutamide; Transfection

The sulphonamide-derived oral antidiabetic drugs carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide, glipizide, gliquidone, glisoxepide, glymidine, tolazamide and tolbutamide were investigated for photohemolytic properties in vitro. Irradiation with a SOL 3 apparatus (solar simulating irradiation) revealed hemolysis in the presence of chlorpropamide, glipizide, gliquidone, glymidine and tolbutamide (all in the concentration 10(-3) mol/l). Except for glymidine, which exerted photohemolysis in the concentration 10(-4) mol/l, no hemolytic effects were seen in the concentration of 10(-4) mol/l or 10(-5) mol/l. Irradiation with TL 12 light bulbs (UVB), a UVASUN 5000 apparatus (UVA) or an experimental lamp (visible light) did not induce phototoxic hemolysis with either of the test substances. Addition of the antioxidants ascorbic acid, alpha-tocopherol or superoxide dismutase significantly inhibited the phototoxic hemolysis. Investigations carried out in a nitrogen-rich atmosphere reduced the hemolysis as well. These findings indicate an involvement of reactive oxygen species in the mechanism of action of the hemolytic process in the presence of oral antidiabetic drugs.

Topics: Antioxidants; Ascorbic Acid; Carbutamide; Chlorpropamide; Dose-Response Relationship, Drug; Gliclazide; Glipizide; Glyburide; Hemolysis; Humans; Hypoglycemic Agents; Nitrogen; Radiation-Sensitizing Agents; Reactive Oxygen Species; Sulfonamides; Sulfonylurea Compounds; Superoxide Dismutase; Tolazamide; Tolbutamide; Ultraviolet Rays; Vitamin E