Activation of Ca2+- and cAMP-sensitive K+ channels in murine colonic epithelia by 1-ethyl-2-benzimidazolone

1-Ethyl-2-benzimidazolone (EBIO) caused a sustained increase in electrogeni c Cl- secretion in isolated mouse colon mucosae, an effect, reduced by bloc king basolateral K+ channels. The Ca2+-sensitive K+ channel blocker charybd otoxin (ChTX) and the cAMP-sensitive K+ channel blocker 293B were more effe ctive when the other had been added first, suggesting that both types of K channel were activated. EBIO did not cause Cl- secretion in cystic fibrosi s (CF) colonic epithelia. In apically permeabilized colonic mucosae, EBIO i ncreased the K+ current when a concentration gradient was imposed, an effec t that was completely sensitive to ChTX. No current sensitive to trans-6-cy ano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane (293B) was found in this condition. However, the presence of basolateral cAMP-sen sitive K+ channels was demonstrated by the development of a 293B-sensitive K+ current after cAMP application in permeabilized mucosae. In isolated col onic crypts EBIO increased cAMP content but had no effect on intracellular Ca2+. It is concluded that EBIO stimulates Cl- secretion by activating Ca2-sensitive and cAMP-sensitive K+ channels, thereby hyperpolarizing the apic al membrane, which increases the electrical gradient for Cl- efflux through the CF transmembrane conductance regulator (CFTR). CFTR is also activated by the accumulation of cAMP as well as by direct activation.