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Preclinical Evidence that Sildenafil and Vardenafil Activate Chloride Transport in Cystic Fibrosis

Departments of ¹ Clinical Chemistry, ² Cell Physiology, and ³ Pediatric Pulmonology, Université Catholique de Louvain, Brussels, Belgium; and ⁴ Department of Biochemistry, Erasmus University Medical Center, Rotterdam, The Netherlands

Correspondence and requests for reprints should be addressed to Teresinha Leal, M.D., Ph.D., Department of Clinical Chemistry, St. Luc University Hospital, 10 Av. Hippocrate, B-1200 Brussels, Belgium. E-mail: teresinha.leal{at}clin.ucl.ac.be

Rationale: Sildenafil has been implicated in the activation of cystic fibrosis transmembrane conductance regulator (CFTR) protein. The effect was observed in vitro and in the presence of doses roughly 300 times larger than those commonly used for treating erectile dysfunction.

Objectives: To evaluate in vivo the therapeutic efficacy of clinical doses of sildenafil and vardenafil, two clinically approved phosphodiesterase 5 inhibitors, for activating ion transport in cystic fibrosis.

Methods: We used transepithelial potential difference in vivo across the nasal mucosa as a measure of sodium and chloride transport. The effect of a single intraperitoneal injection of sildenafil (0.7 mg/kg) or vardenafil (0.14 mg/kg) was investigated in F508del, cftr knockout and normal homozygous mice.

Measurements and Main Results: In F508del mice, but not in cftr knockout mice, the chloride conductance, evaluated by perfusing the nasal mucosa with a chloride-free solution in the presence of amiloride and with forskolin, was corrected 1 hour after sildenafil administration. A more prolonged effect, persisting for at least 24 hours, was observed with vardenafil. The forskolin response was increased after sildenafil and vardenafil in both normal and F508del mutant animals. In F508del mice, the chloride conductance in the presence of 200 µM 4-4'-diisothiocyanostilbene-2,2'-disulphonic acid, an inhibitor of alternative chloride channels, was much higher after sildenafil injection than after placebo treatment. No effect on the sodium conductance was detected in any group of animals.

Conclusions: Our results provide preclinical evidence that both drugs stimulate chloride transport activity of F508del-CFTR protein.

Key Words: cystic fibrosis • phosphodiesterase inhibitors • sildenafil • chloride transport • nasal potential difference

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Sildenafil increases the expression of the F508del-CFTR protein in nasal epithelial cells harvested from patients. The effect was observed with a dose 300 times larger than that used in male erectile dysfunction. What This Study Adds to the Field This work provides preclinical evidence that in vivo treatment with pharmacological doses of sildenafil and vardenafil, two clinically approved drugs, corrects chloride transport defects of F508del-CFTR.

 

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Phosphodiesterase 5 Inhibitors and Cystic Fibrosis: Correcting Chloride Channel Dysfunction

Lane L. Clarke
AJRCCM 2008 177: 469-470. [Full Text]  

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				L. L. Clarke Phosphodiesterase 5 Inhibitors and Cystic Fibrosis: Correcting Chloride Channel Dysfunction Am. J. Respir. Crit. Care Med., March 1, 2008; 177(5): 469 - 470. [Full Text] [PDF]