PREFERENTIAL INHIBITION OF I-H IN RAT TRIGEMINAL GANGLION NEURONS BY AN ORGANIC BLOCKER

The potency and specificity of a novel organic I-h current blocker DK- AH 268 (DK, Boehringer) was studied in cultured rat trigeminal ganglio n neurons using whole-cell patch-clamp recording techniques. In neuron s current-clamped at the resting potential, the application of 10 mu M DK caused a slight hyperpolarization of the membrane potential and a small increase in the threshold for action potential discharge without any major change in the shape of the action potential. In voltage-cla mped neurons, DK caused a reduction of a hyperpolarization-activated c urrent. Current subtraction protocols revealed that the time-dependent , hyperpolarization-activated currents blocked by 10 mu M DK or extern al Cs+ (3 mM) had virtually identical activation properties, suggestin g that DK and Cs+ caused blockade of the same current, namely I-h. The block of I-h by DK was dose-dependent. At the intermediate and higher concentrations of DK (10 and 100 mu M) a decrease in specificity was observed so that time-independent, inwardly rectifying and noninactiva ting, voltage-gated outward potassium currents were also reduced by DK but to a much lesser extent than the time-dependent, hyperpolarizatio n-activated currents. Blockade of the time-dependent, hyperpolarizatio n-activated currents by DK appeared to be use-dependent since it requi red hyperpolarization for the effect to take place. Relief of DK block was also aided by membrane hyperpolarization. Since both the time-dep endent current blocked by DK and the Cs+-sensitive time-dependent curr ent behaved as I-h, we conclude that 10 mu M DK can preferentially red uce I-h without a major effect on other potassium currents. Thus, DK m ay be useful agent in the investigation of the function of I-h in neur ons.