Characterization of inhibition by haloperidol and chlorpromazine of a voltage‐activated K⁺ current in rat phaeochromocytoma cells

. 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. . Haloperidol or chlorpromazine (1 and 10 μm) 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 +40mV or when holding potentials were changed between —120 and —60 mV. . Effects of compounds that are related to haloperidol and chlorpromazine in their pharmacological actions were examined. Fluspirilene (1 and 10 μm), an antipsychotic drug, inhibited the K⁺ current, but pimozide (1 and 10 μm), another antipsychotic drug did not significantly inhibit the K⁺ current. Sulpiride (1 or 10 μm), an antagonist of dopamine D₂ receptors, did not affect the K⁺ current whereas (+)‐SCH‐23390 (10 μm), an antagonist of dopamine D₁ receptors, reduced the K⁺ current. As for calmodulin antagonists, W‐7 (100 μm), but not calmidazolium (1 μm), reduced the K⁺ current. . The inhibition by haloperidol or chlorpromazine of the K⁺ current was abolished when GTP in intracellular solution was replaced with GDPβS. Similarly, the inhibition by pimozide, fluspirilene, (+)‐SCH‐23390 or W‐7 was abolished or attenuated in the presence of intracellular GDPβS. 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. . Haloperidol and chlorpromazine reduced a Ba²⁺ current permeating through Ca²⁺ channels. Inhibition by haloperidol or chlorpromazine of the Ba²⁺ current was not affected by GDPβS included in the intracellular solution. . It is concluded that haloperidol and chlorpromazine inhibit voltage‐gated K⁺ channels in PC 12 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. 1995 British Pharmacological Society