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Am J Physiol Lung Cell Mol Physiol (July 9, 2004). doi:10.1152/ajplung.00354.2003
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Submitted on October 6, 2003
Accepted on June 26, 2004

CFTR INVOLVEMENT IN NASAL POTENTIAL DIFFERENCES IN MICE AND PIGS STUDIED USING A THIAZOLIDINONE CFTR INHIBITOR

Danieli B. Salinas1, Nicoletta Pedemonte1, Chatchai Muanprasat1, Walter F. Finkbeiner1, Dennis W. Nielson1, and A. S. Verkman1*

1 Department of Medicine and Physiology, Cardiovascular Research Institute, University of California, San Francisco, USA

* To whom correspondence should be addressed. E-mail: verkman{at}itsa.ucsf.edu.

Nasal potential difference (PD) measurements have been used to demonstrate defective cystic fibrosis transmembrane conductance regulator (CFTR) function in cystic fibrosis (CF), and more recently to evaluate CFTR-targeted drug therapies in CF mice. Nasal PD measurements involve topical perfusion with an amiloride-containing saline solution, followed by a low Cl- solution and then cAMP agonist(s) to induce Cl- channel-dependent transepithelial hyperpolarization. We used the selective thiazolidinone CFTR inhibitor CFTRinh-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 (SE, 19 mice), hyperpolarizing by 15 ± 1 mV after a low Cl- solution, and a further 3.9 ± 0.5 mV after forskolin. CFTRinh-172 produced 1.1 ± 0.9 and 4.3 ± 0.7 mV depolarizations when added after low Cl- and forskolin, respectively. Systemically administered CFTRinh-172 (2 mg/kg, 2-3 h before measurements) reduced the forskolininduced 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 (SE, 16 pigs) after amiloride, hyperpolarizing by 13 ± 2 mV after low Cl- and a further 9 ± 1 mV after forskolin. In contrast to mice, CFTRinh-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.




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