Multi-target corrective effect of vardenafil on F508del-CFTR function and localization
(2013) 36th ECFS Conference — Location: Lisbon, Portugal (12.June.2013)
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- Abstract
- Vardenafil, a clinically approved cGMP-dependent phosphodiesterase type 5 inhibitor (PDE5i), is able to increase defective F508del-CFTR chloride transport across the mouse nasal mucosa. This work aimed at studying the effect of¬ vardenafil to rescue CFTR function and localization at the gastrointestinal (GI) tract, affected in 85% of CF patients. CFTR function was assessed by quantifying potential difference across the rectal mucosa. Sodium hyperabsorption (40.2 ± 4.0 mV vs 20 ± 1.8 mV; p< 0.001; mean ± SEM) and reduced chloride transport (-4.2 ± 0.5 mV vs -9.4 ± 0.9 mV; p=0.002) were typically found in F508del-CFTR (CF) compared to wild-type (WT) mice. Vardenafil, applied as a single intraperitoneal dose (0.14 mg/kg) completely restored chloride transport (-9.3 ± 1.2 mV) in CF. Immunohistostaining studies showed reduced CFTR expression at cell membrane in CF mouse colon preparations: in untreated conditions, the ratio of CFTR-specific fluorescence (RF) of the cell membrane and that of the rest of the cell was lower in CF (1.4 ± 0.1) than in WT (1.9 ± 0.1; p < 0.001). The RF was increased in vardenafil-treated (2.2 ± 0.1) compared to untreated CF colon tissues (p <0.0001). Our findings pointed out the intestinal mucosa as an additional valuable target tissue to study CFTR function and localization and to evaluate efficacy of therapeutic strategies in CF. Vardenafil also restores ion transport abnormalities across the GI epithelium acting as a corrector of the cell mislocalization of F508del-CFTR.
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Dhooghe, B., Noël, S., Bouzin, C., Lebecque, P., Wallemacq, P., & Leal, T. (2013). Multi-target corrective effect of vardenafil on F508del-CFTR function and localization. Journal of Cystic Fibrosis, 12(S1), S14. https://hdl.handle.net/2078.5/205587 (Original work published 2013)