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 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.
Institute of Physiology, Eberhard-Karls-Universität Tübingen, Germany.
H
H
Suessbrich
M
M
Bleich
D
D
Ecke
M
M
Rizzo
S
S
Waldegger
F
F
Lang
I
I
Szabo
H J
HJ
Lang
K
K
Kunzelmann
R
R
Greger
A E
AE
Busch
D000818:Animals; D002712:Chlorides / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006827:Hydantoins; D007093:Imidazoles / Q000494:pharmacology; D048289:Imidazolidines; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009865:Oocytes; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014981:Xenopus
D002712:Chlorides; D002839:Chromans; D006827:Hydantoins; D007093:Imidazoles; D048289:Imidazolidines; D010879:Piperazines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C059983:potassium channel protein I(sk); D005576:Colforsin; C086123:azimilide; C029141:2,2,5,7,8-pentamethyl-1-hydroxychroman; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011188:Potassium