1. Sildenafil Acts as Potentiator and Corrector of CFTR but Might be not Suitable for the Treatment of CF Lung Disease
- Author
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Katja Sobczak, Nadine Bangel-Ruland, Wolf-Michael Weber, Yvonne Knieper, and Geraldine Leier
- Subjects
Drug ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Cystic Fibrosis ,Phosphodiesterase Inhibitors ,Physiology ,Sildenafil ,media_common.quotation_subject ,Xenopus ,Cystic Fibrosis Transmembrane Conductance Regulator ,Fluorescent Antibody Technique ,Bronchi ,Context (language use) ,Pharmacology ,Cystic fibrosis ,Piperazines ,Sildenafil Citrate ,Exocytosis ,Cell Line ,Xenopus laevis ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Humans ,Sulfones ,media_common ,biology ,business.industry ,Epithelial Cells ,Long-term potentiation ,respiratory system ,Potentiator ,medicine.disease ,biology.organism_classification ,digestive system diseases ,respiratory tract diseases ,Endocrinology ,chemistry ,Purines ,cardiovascular system ,Female ,business - 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.
- Published
- 2012
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