Specific blockade of slowly activating I(sK) channels by chromanols -- impact on the role of I(sK) channels in epithelia

Chromanols, which were recently shown to inhibit cAMP-mediated Cl- secretion in colon crypts via a blockade of a cAMP-activated K+ conductance, were analyzed for their effects on distinct cloned K+ channels expressed in Xenopus oocytes. The lead chromanol 293B specifically inhibited I(sK) channels w...

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Bibliographic Details
Published in:FEBS letters 1996-11, Vol.396 (2-3), p.271-275
Main Authors: Suessbrich, H, Bleich, M, Ecke, D, Rizzo, M, Waldegger, S, Lang, F, Szabo, I, Lang, H J, Kunzelmann, K, Greger, R, Busch, A E
Format: Article
Language:English
Subjects:
Animals
Chlorides - metabolism
Chromans - pharmacology
Colforsin - pharmacology
Colon - drug effects
Colon - metabolism
Cyclic AMP - metabolism
Cyclic AMP-Dependent Protein Kinases - metabolism
Epithelium - drug effects
Epithelium - metabolism
Female
Hydantoins
Imidazoles - pharmacology
Imidazolidines
Intestinal Mucosa - drug effects
Intestinal Mucosa - metabolism
Male
Oocytes
Patch-Clamp Techniques
Piperazines - pharmacology
Potassium - metabolism
Potassium Channel Blockers
Potassium Channels - drug effects
Potassium Channels - physiology
Potassium Channels, Voltage-Gated
Rats
Stereoisomerism
Structure-Activity Relationship
Xenopus
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Summary:Chromanols, which were recently shown to inhibit cAMP-mediated Cl- secretion in colon crypts via a blockade of a cAMP-activated K+ conductance, were analyzed for their effects on distinct cloned K+ channels expressed in Xenopus oocytes. The lead chromanol 293B specifically inhibited I(sK) channels with an IC50 of 7 micromol/l without affecting the delayed rectifier Kv1.1 or the inward rectifier Kir2.1. Moreover, several other chromanols displayed the same rank order of potency for I(sK) inhibition as demonstrated in colon crypts. Finally, we tested the effects of the previously described I(sK) blocker azimilide on cAMP mediated Cl- secretion in rat colon crypts. Similar to 293B azimilide inhibited the forskolin induced Cl- secretion. These data suggest that I(sK) protein induced K+ conductances are the targets for the chromanol 293B and its analogues, and azimilide.
ISSN:0014-5793