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CFTR involvement in nasal potential differences in mice and pigs studied using a thiazolidinone CFTR inhibitor

¹Departments of Medicine and Physiology, Cardiovascular Research Institute, and Departments of ²Pediatrics and ³Pathology, University of California, San Francisco, California 94143

Submitted 6 October 2003 ; accepted in final form 26 June 2004

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.

cystic fibrosis; cystic fibrosis transmembrane conductance regulator; nasal potential difference; chloride channels

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