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Modulation of sodium current kinetics by chlorpromazine in freshly‐isolated striatal neurones of the adult guinea‐pig
Author(s) -
Ogata Nobukuni,
Tatebayashi Hideharu
Publication year - 1989
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1989.tb12662.x
Subject(s) - chlorpromazine , chemistry , depolarization , sodium channel , sodium , biophysics , kinetics , time constant , electrophysiology , steady state (chemistry) , guinea pig , endocrinology , medicine , biology , physics , organic chemistry , engineering , quantum mechanics , electrical engineering
1 The neurones of the striatum were freshly dissociated from the adult guinea‐pig brain by enzymatic and mechanical treatments. Sodium channel current kinetics in these neurones were measured using a whole cell variation of the patch‐clamp technique. 2 Chlorpromazine, a neuroleptic, in micromolar concentrations reversibly reduced the amplitude of the sodium currents. Activation and inactivation time constants were not affected. The inhibition followed one‐to‐one binding stoichiometry. 3 The concentration‐response curve shifted to the left when the holding potential was less negative. The EC 50 shifted from 4.8 μ m to 0.9 μ m when the holding potential was changed from −120 mV to −70 mV. 4 The steady‐state activation curve of the sodium current was not affected by chlorpromazine, whereas the steady‐state inactivation curve was shifted in the negative direction. Consequently, the window current which is normally present at a potential range around −50 mV was decreased in the presence of chlorpromazine. 5 Successive sodium currents evoked by a train of depolarizing pulses (30 ms duration) to −10 mV showed a cumulative decrease in size during the application of chlorpromazine. However, such ‘use‐dependent’ block was not observed when the pulse duration was reduced to 1 ms. 6 The recovery from inactivation in the presence of chlorpromazine, was expressed as a second order process. The faster component was similar to the recovery time course of the normal sodium channels. The slower component accounted for the use‐dependent effect of chlorpromazine. 7 The results indicate that chlorpromazine binds to the resting sodium channels producing steady‐state block at a very negative holding potential. When the membrane is depolarized, chlorpromazine binds to the inactivated form of the sodium channels with much higher affinity and stabilizes them in the inactivated state, slowing their kinetics.