Vardenafil corrects chloride transport across F508del-CFTR intestinal mucosa
(2012) 35th European Cystic Fibrosis Conference — Location: Dublin, Ireland (6.June.2012)
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- Abstract
- Objectives: Nasal potential difference measurements have previously shown that vardenafil, a phosphodiesterase type 5 inhibitor, improves CFTR-mediated chloride secretion across the nasal mucosa of mice homozygous for the F508del mutation (CF). This work aimed at studying the potential of vardenafil to rescue CFTR function across the rectal mucosa, representative of the GI tract. Methods: Distinct rectal potential difference (RPD) profiles were obtained in CF and normal homozygous wild-type mice (WT). Sodium absorption, measured by the response of 10-4M amiloride (in the presence of 5x10-3 M barium to block potassium channels), was much higher in CF (40.2±4.0 mV) than in WT mice (22.6±1.9 mV; p< 0.001). Chloride secretion recorded in the presence of chloride-free solution and 10-5 M forskolin was twice as low in CF (-4.2±0.5 mV) as in WT mice (-9.4±0.9 mV, p=0.002). Heterozygous mice showed preserved sodium transport (20±1.8 mV) but reduced chloride secretion (-5.4±1.5mV). Chloride secretion was restored in CF mice treated with a single ip dose of 0.14mg/kg vardenafil; values reached after treatment (-9.3±1.2 mV) were similar to those obtained in untreated WT mice. Conclusion: Our findings pointed out the rectal mucosa as an additional target tissue to study in vivo ion transport abnormalities. The RPD test discriminates between CF and non-CF and can be used to investigate the efficacy of therapeutic strategies to rescue CFTR function. As for the airways, vardenafil restores chloride secretion across the GI epithelium. Immunolocalization of CFTR protein in colon tissue preparations are under investigation in KO, CF and WT mice treated or not-treated with vardenafil.
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Dhooghe, B., Noël, S., Bouzin, C., Lebecque, P., Wallemacq, P., & Leal, T. (2012). Vardenafil corrects chloride transport across F508del-CFTR intestinal mucosa. Journal of Cystic Fibrosis, 11(1), S65. https://hdl.handle.net/2078.5/208163 (Original work published 2012)