title: Characterization of inhibition by haloperidol and chlorpromazine of a voltage-activated K+ current in rat phaeochromocytoma cells.
abstract: 1. Inhibition by haloperidol and chlorpromazine of a voltage-activated K+ current was characterized in rat phaeochromocytoma PC12 cells by use of whole-cell voltage-clamp techniques. 2. Haloperidol or chlorpromazine (1 and 10 microM) inhibited a K+ current activated by a test potential of +20 mV applied from a holding potential of -60 mV. The K+ current inhibition did not exhibit voltage-dependence when test potentials were changed between -10 and +40 mV or when holding potentials were changed between -120 and -60 mV. 3. Effects of compounds that are related to haloperidol and chlorpromazine in their pharmacological actions were examined. Fluspirilene (1 and 10 microM), an antipsychotic drug, inhibited the K+ current, but pimozide (1 and 10 microM), another antipsychotic drug did not significantly inhibit the K+ current. Sulpiride (1 or 10 microM), an antagonist of dopamine D2 receptors, did not affect the K+ current whereas (+)-SCH-23390 (10 microM), an antagonist of dopamine D1 receptors, reduced the K+ current. As for calmodulin antagonists, W-7 (100 microM), but not calmidazolium (1 microM), reduced the K+ current. 4. The inhibition by haloperidol or chlorpromazine of the K+ current was abolished when GTP in intracellular solution was replaced with GDP beta S. Similarly, the inhibition by pimozide, fluspirilene, (+)-SCH-23390 or W-7 was abolished or attenuated in the presence of intracellular GDP beta S. The inhibition by haloperidol or chlorpromazine was not prevented when cells were pretreated with pertussis toxin or when K-252a, an inhibitor of a variety of protein kinases, was included in the intracellular solution. 5. Haloperidol and chlorpromazine reduced a Ba2+ current permeating through Ca2+ channels. Inhibition by haloperidol or chlorpromazine of the Ba2+ current was not affected by GDP beta S included in the intracellular solution. 6. It is concluded that haloperidol and chlorpromazine inhibit voltage-gated K+ channels in PC12 cells by a mechanism involving GTP-binding proteins. The inhibition may not be related to their activity as antagonists of dopamine D2 receptors or calmodulin antagonists.
authors.affiliation: Division of Pharmacology, National Institute Health Sciences, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Nakazawa
authors.forename: K
authors.initials: K
authors.lastname: Ito
authors.forename: S
authors.initials: S
authors.lastname: Koizumi
authors.forename: Y
authors.initials: Y
authors.lastname: Ohno
authors.forename: K
authors.initials: K
authors.lastname: Inoue
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001464:Barium / Q000378:metabolism / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002746:Chlorpromazine / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D005484:Fluspirilene / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D006220:Haloperidol / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D016716:PC12 Cells; D010868:Pimozide / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism / Q000502:physiology*; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology*; D051381:Rats
chemical_list: D014150:Antipsychotic Agents; D015220:Calcium Channels; D002147:Calmodulin; D065127:Dopamine D2 Receptor Antagonists; D015221:Potassium Channels; D010868:Pimozide; D001464:Barium; D005484:Fluspirilene; D019204:GTP-Binding Proteins; D006220:Haloperidol; D011188:Potassium; D002746:Chlorpromazine