CHARACTERIZATION OF INHIBITION BY HALOPERIDOL AND CHLORPROMAZINE OF A VOLTAGE-ACTIVATED K+ CURRENT IN RAT PHEOCHROMOCYTOMA CELLS

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 mu M) 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 mu M), an antipsychotic drug, inhibited the K+ current, but pimozide (1 and 10 mu M), another antipsychotic drug did not significantly inhibit the K+ current. Sulpiride (1 or 10 mu M), an antagonist of dopamine D-2 receptors, did not affect the K+ current whereas (+)-SCH-23390 (10 mu M), an antagonist of dopamine D-1 receptors, reduced the K+ current. As for calmodulin antagonists, W-7 (100 mu M), but not calmidazolium (1 mu M), 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 D-2 receptors or calmodulin antagonists.