Effect of glipizide on dopamine synthesis, release and metabolism in PC12 cells.
Sulfonylureas block ATP-dependent K(+) channels (K/ATP channels) in pancreatic beta cells and brain gamma-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.
Lamensdorf
I
I
Clinical Neuroscience Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA. lamensdo@helix.nih.gov
He
L
L
Nechushtan
A
A
Harvey-White
J
J
Eisenhofer
G
G
Milan
R
R
Rojas
E
E
Kopin
I J
IJ
D018528:ATP-Binding Cassette Transporters; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism; D004298:Dopamine / Q000096:biosynthesis / Q000378:metabolism*; D005913:Glipizide / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D054086:KATP Channels; D008564:Membrane Potentials / Q000187:drug effects; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D016716:PC12 Cells; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013453:Sulfonylurea Compounds / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D002395:Catecholamines; D007004:Hypoglycemic Agents; D054086:KATP Channels; D008996:Monoamine Oxidase Inhibitors; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D013453:Sulfonylurea Compounds; C092520:uK-ATP-1 potassium channel; D014446:Tyrosine 3-Monooxygenase; D002118:Calcium; D004298:Dopamine; D005913:Glipizide