title: Partial restoration of defective chloride conductance in DeltaF508 CF mice by trimethylamine oxide.
abstract: This study was designed to test the in vivo efficacy of the chemical chaperone trimethylamine oxide (TMAO) in correcting the Cl- transport defect in a mouse model of cystic fibrosis (CF). Rectal potential difference (RPD) measurements were done in matched wild-type and DeltaF508 CF mice. Mice were treated by subcutaneous injections of TMAO. Wild-type mice demonstrated a forskolin-stimulated, Cl--dependent hyperpolarization of -6.4 +/- 0.8 mV (n = 11), which was significantly increased to -13.1 +/- 1.4 mV after treatment with TMAO. DeltaF508 CF mice showed no significant responses to forskolin. Treatment with TMAO recovered a forskolin-activated RPD in DeltaF508 CF mice (-1.1 +/- 0.2 mV; n = 17) but not in CFTR null mice. The effects of TMAO were dose dependent, resulting in a slope of -0.4 +/- 0.1 mV x g(-1) x kg(-1) in DeltaF508 CF mice. The forskolin-stimulated RPD in TMAO-treated DeltaF508 CF mice was partially blocked by glibenclamide and further stimulated by apigenin. The total response to forskolin plus apigenin was -2.5 +/- 0.45 mV (n = 6 mice), corresponding to 39% of the response evoked by forskolin only in wild-type mice.
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, California 94609, USA. hfischer@chori.org
authors.forename: H
authors.initials: H
authors.lastname: Fischer
authors.forename: N
authors.initials: N
authors.lastname: Fukuda
authors.forename: P
authors.initials: P
authors.lastname: Barbry
authors.forename: B
authors.initials: B
authors.lastname: Illek
authors.forename: C
authors.initials: C
authors.lastname: Sartori
authors.forename: M A
authors.initials: MA
authors.lastname: Matthay
mesh_terms: D000818:Animals; D047310:Apigenin; D018118:Chloride Channels / Q000187:drug effects* / Q000502:physiology*; D005576:Colforsin / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000235:genetics* / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D004594:Electrophysiology; D005419:Flavonoids / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D008744:Methylamines / Q000494:pharmacology*; D051379:Mice; D016877:Oxidants / Q000494:pharmacology*; D012007:Rectum / Q000187:drug effects / Q000503:physiopathology; D012016:Reference Values
chemical_list: D018118:Chloride Channels; D005419:Flavonoids; D008744:Methylamines; D016877:Oxidants; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; D047310:Apigenin; C005855:trimethyloxamine; D005905:Glyburide