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

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 (tau=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.

[K+]out accelerates inactivation of Shal-channels responsible for A-current in rat CA1 neurons.

Somato-dendritic subthreshold transient potassium current [I(SA)] was measured in acutely isolated rat hippocampal CA1 pyramidal neurons. The inactivation of this current was insensitive to externally applied H2O2 (20 mM) which causes cysteine oxidation. This result suggests that Shal-channels not Shaker Kv1.4 channels underlie the somato-dendritic I(SA) in rat CA1 pyramidal neurons. The kinetics of the I(SA) inactivation was measured at various [K+]out. Increase in [K+]out leads to acceleration of Shal-channel inactivation. Thus, the shift in [K+]out from 1 to 50 mM results in decreased inactivation time constant from 37 to 19 ms. This effect of [K+]out on the I(SA) is opposite to the previously described action of [K+]out on the inactivation of Shaker K+ channels.