Abstract
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 haemodynamic effects. We hypothesised 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 nebulised for 15 min at concentrations adjusted from recommended therapeutic oral doses for male erectile dysfunction. We measured in vivo nasal transepithelial potential difference 1 h after a single inhalation of sildenafil, vardenafil or tadalafil in F508del CF and normal homozygous mice.
After nebulisation with the drugs in F508del mice, chloride transport, evaluated by perfusing the nasal mucosa with chloride-free buffer containing amiloride followed by forskolin, was normalised; 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 in restoring chloride transport function of F508del CF transmembrane conductance regulator protein and highlight the potential of inhaled sildenafil, vardenafil and tadalafil as a therapy for CF.
Footnotes
For editorial comments see page 8.
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Support Statement
This study was supported by the Dept of Pneumology and the Fondation St Luc, St Luc University Hospital and Université Catholique de Louvain, Brussels, Belgium. Breeding pairs of cftrtm1eur (F508del (FVB/129)) mice were obtained from B. Scholte (Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands) with the support of European Economic Community European Coordination Action for Research in Cystic Fibrosis EU FP6 LSHM-CT-2005-018932).
Statement of Interest
None declared.
- Received January 26, 2010.
- Accepted May 30, 2010.
- ©ERS 2011