CFTR involvement in nasal potential differences in mice and pigs studied using a thiazolidinone CFTR inhibitor.
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.
Salinas
Danieli B
DB
Department of Medicine and Physiology, Cardiovascular Research Institute, University of California, San Francisco, California 94143, USA.
Pedemonte
Nicoletta
N
Muanprasat
Chatchai
C
Finkbeiner
Walter F
WF
Nielson
Dennis W
DW
Verkman
A S
AS
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D004232:Diuretics / Q000494:pharmacology; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018181:Mice, Inbred CFTR; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism*; D034421:Sus scrofa; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines
C482900:3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone; D001565:Benzoates; D004232:Diuretics; D007004:Hypoglycemic Agents; D013844:Thiazoles; D053778:Thiazolidines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; D000584:Amiloride; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D005905:Glyburide