Phenanthrolines--a new class of CFTR chloride channel openers.
1. 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 microM 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. 2. 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(-). 3. 1,10 Phenanthroline affected neither the generation of cyclic AMP or the concentration of intracellular Ca(2+) in colonic epithelial cells. 4. 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. 5. 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. 6. 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.
Duszyk
M
M
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ.
MacVinish
L
L
Cuthbert
A W
AW
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001464:Barium / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D018999:Charybdotoxin / Q000494:pharmacology; D018118:Chloride Channels / Q000187:drug effects* / Q000502:physiology; D002712:Chlorides / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000502:physiology; D003563:Cyclic CMP / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D010618:Phenanthrolines / Q000737:chemistry / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D011804:Quinolines / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism
C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; D000873:Anthracenes; D001562:Benzimidazoles; D018118:Chloride Channels; D002712:Chlorides; D010618:Phenanthrolines; D015221:Potassium Channels; D011804:Quinolines; D018999:Charybdotoxin; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D001464:Barium; D003563:Cyclic CMP; D000584:Amiloride; C102635:1-ethyl-2-benzimidazolinone; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine