Document Detail


CFTR involvement in nasal potential differences in mice and pigs studied using a thiazolidinone CFTR inhibitor.
MedLine Citation:
PMID:  15246976     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Nasal potential difference (PD) measurements have been used to demonstrate defective CFTR function in cystic fibrosis (CF) and to evaluate potential CF therapies. We used the selective thiazolidinone CFTR inhibitor CFTR(inh)-172 to define the involvement of CFTR in nasal PD changes in mice and pigs. In normal mice infused intranasally with a physiological saline solution containing amiloride, nasal PD was -4.7 +/- 0.7 mV, hyperpolarizing by 15 +/- 1 mV after a low-Cl- solution, and a further 3.9 +/- 0.5 mV after forskolin. CFTR(inh)-172 produced 1.1 +/- 0.9- and 4.3 +/- 0.7-mV depolarizations when added after low Cl- and forskolin, respectively. Systemically administered CFTR(inh)-172 reduced the forskolin-induced hyperpolarization from 4.7 +/- 0.4 to 0.9 +/- 0.1 mV but did not reduce the low Cl(-)-induced hyperpolarization. Nasal PD was -12 +/- 1 mV in CF mice after amiloride, changing by <0.5 mV after low Cl- or forskolin. In pigs, nasal PD was -14 +/- 3 mV after amiloride, hyperpolarizing by 13 +/- 2 mV after low Cl- and a further 9 +/- 1 mV after forskolin. CFTR(inh)-172 and glibenclamide did not affect nasal PD in pigs. Our results suggest that cAMP-dependent nasal PDs in mice primarily involve CFTR-mediated Cl- conductance, whereas cAMP-independent PDs are produced by a different, but CFTR-dependent, Cl- channel. In pigs, CFTR may not be responsible for Cl- channel-dependent nasal PDs. These results have important implications for interpreting nasal PDs in terms of CFTR function in animal models of CFTR activation and inhibition.
Authors:
Danieli B Salinas; Nicoletta Pedemonte; Chatchai Muanprasat; Walter F Finkbeiner; Dennis W Nielson; A S Verkman
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2004-07-09
Journal Detail:
Title:  American journal of physiology. Lung cellular and molecular physiology     Volume:  287     ISSN:  1040-0605     ISO Abbreviation:  Am. J. Physiol. Lung Cell Mol. Physiol.     Publication Date:  2004 Nov 
Date Detail:
Created Date:  2004-10-11     Completed Date:  2004-11-19     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  100901229     Medline TA:  Am J Physiol Lung Cell Mol Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  L936-43     Citation Subset:  IM    
Affiliation:
Department of Medicine and Physiology, Cardiovascular Research Institute, University of California, San Francisco, California 94143, USA.
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MeSH Terms
Descriptor/Qualifier:
4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / pharmacology
Amiloride / pharmacology
Animals
Benzoic Acids / pharmacology*
Cystic Fibrosis Transmembrane Conductance Regulator / antagonists & inhibitors*,  genetics,  metabolism*
Diuretics / pharmacology
Female
Forskolin / pharmacology
Glyburide / pharmacology
Hypoglycemic Agents / pharmacology
Male
Membrane Potentials / drug effects
Mice
Mice, Inbred CFTR
Nasal Mucosa / drug effects,  metabolism*
Sus scrofa
Thiazoles / pharmacology*
Thiazolidines
Grant Support
ID/Acronym/Agency:
DK-35124/DK/NIDDK NIH HHS; EB-00415/EB/NIBIB NIH HHS; EY-13574/EY/NEI NIH HHS; HL-59198/HL/NHLBI NIH HHS; HL-73856/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone; 0/Benzoic Acids; 0/Diuretics; 0/Hypoglycemic Agents; 0/Thiazoles; 0/Thiazolidines; 10238-21-8/Glyburide; 126880-72-6/Cystic Fibrosis Transmembrane Conductance Regulator; 2609-46-3/Amiloride; 53005-05-3/4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; 66428-89-5/Forskolin

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