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

A case of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and lekoencephalopathy) with Notch 3 (Arg169Cys) mutation and typical granular osmiophilic materials in peripheral small arteries]

We report a 64-year-old Japanese woman with recurrent ischemic strokes and progressive dementia without any cardiovascular risk factors. Her first stroke was at 45 years old, and she has a family history of ischemic strokes compatible with an autosomal dominant trait. Marked leukoaraiosis and multiple lacunar infarcts were shown on brain MR images, and no atherosclerotic changes were observed in her extra- and intra-cranial arteries by cervical arterial echography and intracranial MR angiography. Excluded other inherited or metabolic diseases causing leukodystrophy by examination of her blood samples, her disease was diagnosed as CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and lekoencephalopathy). We demonstrated granular osmiophilic materials (GOM) on the wall of small arteries from a biopsied peripheral nerve tissue specimen and detected a mutation Arg169Cys of Notch 3 gene. Many CADASIL patients have been reported and over 28 kinds of mutations of the Notch 3 were identified in western countries, while few CADASIL patients have been reported in Japanese people. Among them, eleven CADASIL families have been reported and only five mutations (Arg133Cys, Cys174Phe, Arg213Lys, Arg90Cys and Arg141Cys) have been determined so far. The mutation of Notch 3 in our patient was determined as Arg169Cys, and this is the first report on a Japanese patient with CADASIL due to this mutation.