High concentrations of the neuroleptic remoxipride block voltage-activated Na + channels in central and peripheral nerve membranes

Abstract

The actions of the neuroleptic compounds remoxipride, haloperidol and (−)-sulphiride on Na + and K + ion current flow were examined in rat CNS and frog PNS, using 86Rb + ion flux and voltage-clamp techniques, respectively. By combining veratridine and high K +-evoked 86Rb + efflux, it was determined that remoxipride blocked Na + current flow in a concentration-dependent fashion in tissue pieces from cither cerebral cortex or striatum (IC 50 ∼ 20 μM), leaving K + current flow virtually unaffected. Similarly, haloperidol concentration dependently blocked Na + current flow in both tissues (IC 50 ∼ 50 μM). (−)-Sulpiride did not have a significant effect. Direct actions of the compounds on voltage-gated Na + and K + channels were determined in voltage-clamp experiments. The findings confirmed the results of the ion flux measurements in that remoxipride (K d ∼ 300 μM) and haloperidol (K d ∼ 1.5 μM) reduced mainly the Na + current, having little effect on the K + current, whereas (−)-sulpiride did not have a measurable action. The relatively high concentrations of remoxipride or haloperidol needed to alter the Na + current makes it unlikely that these actions are of importance at clinically relevant doses.