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

Sulfonylureas block ATP-dependent K+ channels (K/ATP channels) in pancreati c beta cells and brain gamma-aminobutyric acid (GABA) containing neurons ca using depolarization-evoked insulin or GABA release. In high concentrations , sulfonylureas also inhibit catecholamine release from bovine adrenal chro maffin cells and isolated guinea pig aorta. In this study, we examined the effect of glipizide, a sulfonylurea, on dopamine release from PC12 cells an d 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, howeve r, increase cytoplasmic retention of the acidic dopamine metabolites, 3,4-d ihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), indicating b lockade 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. (C) 2000 Elsevier Scien ce B.V. All rights reserved.