Mechanisms of anion secretion in Calu-3 human airway epithelial cells by 7,8-benzoquinoline.

(1) Cultured epithelial monolayers of Calu-3 human airway cells were used to measure anion secretion in response to a number of phenanthrolines and benzoquinolines, using short-circuit current measurements. Calu-3 cells are derived from serous cells of submucosal glands of the airways and are a target for conditions in which muco-ciliary clearance is compromised. (2) Compounds studied were 5,6-benzoquinoline, 5-chloro-1,10-phenanthroline, 7,8-benzoquinoline, 5-nitro-1,10-phenanthroline, benzo[c]cinnoline and 1,10-phenanthroline, which gave EC50 values of 34, 48, 123, 235, 192 and 217 microm, respectively. Of these, 7,8-benzoquinoline was chosen for further detailed study. Concentration-response relationships for all the compounds had Hill slopes greater than 1. (3) Permeabilisation of the apical surface of epithelia with nystatin in the presence of an apical to basolateral potassium ion gradient reduced the EC50 for 7,8-benzoquinoline to 31 microm and altered the Hill slope to close to 1. (4) Using apically permeabilised epithelia it was shown that 7,8-benzoquinoline activates an intermediate-conductance calcium-sensitive potassium channel (KCNN4) and a cAMP-sensitive potassium channel (KCNQ1/KCNE3) in the basolateral epithelial membranes. (5) 7,8-Benzoquinoline was shown to increase chloride conductance of apical epithelial membranes, presumed to be by activation of the cystic fibrosis transmembrane conductance regulator. (6) 7,8-Benzoquinoline had a minor effect on cAMP accumulation in Calu-3 cells, probably by inhibition of phosphodiesterase, which may contribute to its effect on CFTR- and cAMP-sensitive potassium channels. (7) The usefulness of these novel actions in promoting secretion in airway submucosal glands is discussed.