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- sec retion in colon crypts via a blockade of a cAMP-activated K+ conductan ce, were analyzed for their effects on distinct cloned K+ channels exp ressed in Xenopus oocytes, The lead chromanol 293B specifically inhibi ted I-sK channels with an IC50 of 7 mu mol/l without affecting the del ayed rectifier Kv1.1 or the inward rectifier Kir2.1. Moreover, several other chromanols displayed the same rank order of potency for I-sK in hibition as demonstrated in colon crypts, Finally, we tested the effec ts of the previously described I-sK blocker azimilide on cAMP mediated Cl- secretion in rat colon crypts. Similar to 293B azimilide inhibite d the forskolin induced Cl- secretion, These data suggest that I-sK pr otein induced K+ conductances are the targets for the chromanol 293B a nd its analogues, and azimilide.