title: Sildenafil acts as potentiator and corrector of CFTR but might be not suitable for the treatment of CF lung disease.
abstract: The phosphodiesterase-5 inhibitor sildenafil is an established and approved drug to treat symptoms of a variety of human diseases. In the context of cystic fibrosis (CF), a genetic disease caused by a defective CFTR gene (e.g. ΔF508-CFTR), it was assumed that sildenafil could be a promising substance to correct impaired protein expression. This study focuses on the molecular mechanisms of sildenafil on CFTR recovery. We used ΔF508-CFTR/wt-CFTR expressing Xenopus laevis oocytes and human bronchial epithelial cell lines (CFBE41o(-)/16HBE14o(-)) to investigate the pathways of sildenafil action. Cells were treated with sildenafil and cAMP-mediated current (I(m)), conductance (G(m)), and capacitance (C(m)) were determined. Sildenafil increased I(m), G(m), and C(m) of wt-CFTR and functionally restored ΔF508-CFTR in oocytes. These effects were also seen in CFBE41o(-) and 16HBE14o(-) cells. Transepithelial measurements revealed that sildenafil mediated increase (wt-CFTR) and restoration (ΔF508-CFTR) of channel activity. cGMP pathway blocker inhibited the activity increase but not CFTR/ΔF508-CFTR exocytosis. From these data we conclude that sildenafil mediates potentiation of CFTR activity by a cGMP-dependent and initiates cGMP-independent functional insertion of CFTR/ΔF508-CFTR molecules into the apical membranes. Thus, sildenafil is a corrector and potentiator of CFTR/ΔF508-CFTR. Yet, the necessary high doses of the drug for CFTR recovery demonstrate that sildenafil might not be suited as a therapeutic drug for CF lung disease.
authors.affiliation: Institute of Animal Physiology, Westphalian Wilhelms-University, Muenster, Germany.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Leier
authors.forename: Nadine
authors.initials: N
authors.lastname: Bangel-Ruland
authors.forename: Katja
authors.initials: K
authors.lastname: Sobczak
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Knieper
authors.forename: Wolf-Michael
authors.initials: WM
authors.lastname: Weber
mesh_terms: D000818:Animals; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011687:Purines / Q000494:pharmacology / Q000627:therapeutic use; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use; D014982:Xenopus laevis
chemical_list: D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000068677:Sildenafil Citrate