PT  - JOURNAL ARTICLE
AU  - B. Lubamba
AU  - J. Lebacq
AU  - G. Reychler
AU  - E. Marbaix
AU  - P. Wallemacq
AU  - P. Lebecque
AU  - T. Leal
TI  - Inhaled PDE5 inhibitors restore chloride transport in cystic fibrosis mice
AID  - 10.1183/09031936.00013510
DP  - 2010 Jan 01
TA  - European Respiratory Journal
PG  - erj00135-2010
4099  - http://erj.ersjournals.com/content/early/2010/06/18/09031936.00013510.short
4100  - http://erj.ersjournals.com/content/early/2010/06/18/09031936.00013510.full
AB  - Sildenafil and vardenafil, two selective inhibitors of phosphodiesterase type 5 (PDE5) are able, when applied by intraperitoneal injection, to activate chloride transport in cystic fibrosis (CF) mice homozygous for the F508del mutation. Oral treatment with the drugs may be associated with adverse hemodynamic effects. We hypothesized that inhaled PDE5 inhibitors are able to restore ion transport in F508del-CF airway epithelium.We developed a restraint-free mouse chamber for inhalation studies. PDE5 inhibitors were nebulized for 15 minutes at concentrations adjusted from recommended therapeutic oral doses for male erectile dysfunction. We measured in vivo nasal transepithelial potential difference 1 hour after a single inhalation of sildenafil, vardenafil or tadalafil in F508del-CF and in normal homozygous mice.After nebulization with the drugs in F508del mice, chloride transport, evaluated by perfusing the nasal mucosa with chloride-free buffer containing amiloride followed by forskolin, was normalized; the forskolin response was increased with the largest values being observed with tadalafil and intermediate values with vardenafil. No detectable effect was observed on sodium conductance.Our results confirm the role of PDE5 inhibitors for restoring chloride transport function of F508del-CFTR protein and highlight the potential of inhaled sildenafil, vardenafil and tadalafil as a therapy for CF.