Phenanthrolines - a new class of CFTR chloride channel openers

1 A number of phenanthrolines and benzoquinolines were examined for their a bility to activate epithelial chloride secretion by measuring short circuit current (SCC) using the mouse colon epithelium. 1,10 phenanthroline stimul ated electrogenic chloride secretion with an EC50 of 612 +/- 10 muM and a H ill slope of 4.9 +/- 0.3. A similar pharmacology was demonstrated by both 1 ,7 and 4,7 phenanthrolines, 7,8 benzoquinoline and phenanthridine. 2 Evidence that the increase in SCC caused by 1,10 phenanthroline was due t o chloride secretion is based upon (a) inhibition of the current by furosem ide, (b) failure of cystic fibrosis (CF) colons to respond and (c) an assoc iated net flux of Cl-36(-). 3 1,10 Phenanthroline affected neither the generation of cyclic AMP or the concentration of intracellular Ca2+ in colonic epithelial cells. 4 1,10 phenanthroline affected the chloride conductance of the apical membr ane, as shown by an increase in chloride current in 'apical membrane only' preparations in the presence of an apical to basolateral chloride gradient. The increase in chloride current was inhibited by 5-nitro-2-(3-phenylpropy lamino) benzoic acid (NPPB) and was not present in CF colons. 5 Additionally, 1,10 phenanthroline activated basolateral K+ channels, both Ca2+- and cyclic AMP-sensitive channels, as shown by inhibitor studies wit h charybdotoxin (ChTX) and XE991, and after the apical membrane was permeab ilized with nystatin. 6 The phenanthrolines and benzoquinolines described here, with dual actions affecting CFTR and basolateral K+ channels, may constitute useful lead com pounds for adjunct therapy in CF.