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Phenanthrolines – a new class of CFTR chloride channel openers
Author(s) -
Duszyk Marek,
MacVinish Lesley,
Cuthbert Alan W
Publication year - 2001
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704328
Subject(s) - chloride channel , cystic fibrosis transmembrane conductance regulator , chemistry , apical membrane , biophysics , chloride , epithelial polarity , secretion , ion transporter , membrane potential , patch clamp , charybdotoxin , channel blocker , intracellular , biochemistry , pharmacology , biology , membrane , receptor , calcium , organic chemistry , gene
A number of phenanthrolines and benzoquinolines were examined for their ability to activate epithelial chloride secretion by measuring short circuit current (SCC) using the mouse colon epithelium. 1,10 phenanthroline stimulated electrogenic chloride secretion with an EC 50 of 612±10 μ M and a Hill slope of 4.9±0.3. A similar pharmacology was demonstrated by both 1,7 and 4,7 phenanthrolines, 7,8 benzoquinoline and phenanthridine. Evidence that the increase in SCC caused by 1,10 phenanthroline was due to chloride secretion is based upon (a) inhibition of the current by furosemide, (b) failure of cystic fibrosis (CF) colons to respond and (c) an associated net flux of 36 Cl − . 1,10 Phenanthroline affected neither the generation of cyclic AMP or the concentration of intracellular Ca 2+ in colonic epithelial cells. 1,10 phenanthroline affected the chloride conductance of the apical membrane, 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‐phenylpropylamino) benzoic acid (NPPB) and was not present in CF colons. Additionally, 1,10 phenanthroline activated basolateral K + channels, both Ca 2+ ‐ and cyclic AMP‐sensitive channels, as shown by inhibitor studies with charybdotoxin (ChTX) and XE991, and after the apical membrane was permeabilized with nystatin. The phenanthrolines and benzoquinolines described here, with dual actions affecting CFTR and basolateral K + channels, may constitute useful lead compounds for adjunct therapy in CF.British Journal of Pharmacology (2001) 134 , 853–864; doi: 10.1038/sj.bjp.0704328