New channel blocker BIIA388CL blocks delayed rectifier, but not A-type potassium current in central neurons

Abstract

A new substance (R,S)-(3,4-dihydro-6,7-dimethoxyisoquinoline-1-yl)-2-cyclohexyl-N-(3,3-diphenylpropyl)-acetamide hydrochloride (BIIA388Cl), which demonstrates neuroprotective properties in animal models, was examined for its action on K + currents in acutely isolated rat hippocampal neurons using the patch–clamp/concentration clamp techniques in the whole-cell configuration. The delayed rectifier K +-current ( I DR) was strongly inhibited by externally applied BIIA388Cl, while the transient A-current ( I A) remained virtually unaffected. Block of I DR by the pre-applied BIIA388Cl was revealed as a rapid decay of the current indicating direct interaction of the drug with the open state of the channel. The removal of the block upon repolarization was also rapid ( τ=22 ms). The dose–response relationship for the blocking action of BIIA388Cl revealed an IC 50 value of 300 nM for the peak I DR, whereas the IC 50 value for I DR measured 300 ms after the onset of depolarization was 120 nM. The blocking action of BIIA388Cl on I A was at least 200 times less potent. These data allow us to conclude that BIIA388Cl is an effective and selective blocker of I DR. This current is the main pathway for the loss of intracellular potassium by depolarized neurons. Selective obstruction of this pathway could be useful for neuroprotection.