Preferential inhibition of Ih in rat trigeminal ganglion neurons by an organic blocker.
The potency and specificity of a novel organic Ih current blocker DK-AH 268 (DK, Boehringer) was studied in cultured rat trigeminal ganglion neurons using whole-cell patch-clamp recording techniques. In neurons current-clamped at the resting potential, the application of 10 microM 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-clamped neurons, DK caused a reduction of a hyperpolarization-activated current. Current subtraction protocols revealed that the time-dependent, hyperpolarization-activated currents blocked by 10 microM DK or external Cs+ (3 mM) had virtually identical activation properties, suggesting that DK and Cs+ caused blockade of the same current, namely Ih. The block of Ih by DK was dose-dependent. At the intermediate and higher concentrations of DK (10 and 100 microM) a decrease in specificity was observed so that time-independent, inwardly rectifying and noninactivating, voltage-gated outward potassium currents were also reduced by DK but to a much lesser extent than the time-dependent, hyperpolarization-activated currents. Blockade of the time-dependent, hyperpolarization-activated currents by DK appeared to be use-dependent since it required hyperpolarization for the effect to take place. Relief of DK block was also aided by membrane hyperpolarization. Since both the time-dependent current blocked by DK and the Cs+-sensitive time-dependent current behaved as Ih, we conclude that 10 microM DK can preferentially reduce Ih without a major effect on other potassium currents. Thus, DK may be a useful agent in the investigation of the function of Ih in neurons.
Janigro
D
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Department of Physiology and Pharmacology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97201-3098, USA.
Martenson
M E
ME
Baumann
T K
TK
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002478:Cells, Cultured; D002586:Cesium / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D012964:Sodium / Q000378:metabolism; D012668:Trigeminal Ganglion / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*
D001552:Benzazepines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; C087873:DK-AH 268; D002586:Cesium; D012964:Sodium; D011188:Potassium