Effect of glipizide on dopamine synthesis, release and metabolism in PC12 cells

• Published in: European journal of pharmacology 2000-01, Vol.388 (2), p.147-154
• Main Authors: Lamensdorf, Itschak, He, Le-Ping, Nechushtan, Amotz, Harvey-White, Judith, Eisenhofer, Graeme, Milan, Rusnak, Rojas, Eduardo, Kopin, Irwin J
• Format: Article
• Language: English
• Subjects: Animals; ATP-Binding Cassette Transporters; Biological and medical sciences; Calcium - metabolism; Catecholamines - metabolism; DOPAC (3,4-dihydroxyphenylacetic acid); Dopamine; Dopamine - biosynthesis; Dopamine - metabolism; General and cellular metabolism. Vitamins; Glipizide; Glipizide - pharmacology; HVA (homovalinic acid); Hypoglycemic Agents - pharmacology; KATP Channels; Medical sciences; Membrane Potentials - drug effects; Monoamine Oxidase Inhibitors - pharmacology; Patch-Clamp Techniques; PC12 Cells; Pharmacology. Drug treatments; Potassium Channels - drug effects; Potassium Channels - genetics; Potassium Channels - metabolism; Potassium Channels, Inwardly Rectifying; Rats; Reverse Transcriptase Polymerase Chain Reaction; Sulfonylurea; Sulfonylurea Compounds - pharmacology; Tyrosine 3-Monooxygenase - antagonists & inhibitors; Tyrosine 3-Monooxygenase - metabolism; Tyrosine hydroxylase
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/S0014-2999(99)00839-0

Sulfonylureas block ATP-dependent K + channels (K/ATP channels) in pancreatic β cells and brain γ-aminobutyric acid (GABA) containing neurons causing depolarization-evoked insulin or GABA release. In high concentrations, sulfonylureas also inhibit catecholamine release from bovine adrenal chromaffin cells and isolated guinea pig aorta. In this study, we examined the effect of glipizide, a sulfonylurea, on dopamine release from PC12 cells and found that neither basal nor K +-stimulated dopamine release was affected. Although PC12 cells expressed mRNA for the K/ATP channel, functional K/ATP channels could not be demonstrated electrophysiologically, consistent with the lack of effect of glipizide on dopamine release. Glipizide did, however, increase cytoplasmic retention of the acidic dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), indicating blockade of their outward transport. The cellular accumulation of DOPAC was accompanied by reduced tyrosine hydroxylase activity and reduced formation of dopamine and its metabolites presumably by a negative feedback effect of the increased cytoplasmic concentrations of DOPAC.