Sildenafil Acts as Potentiator and Corrector of CFTR but Might be not Suitable for the Treatment of CF Lung Disease

Cellular Physiology and Biochemistry

关键词: CFTR;    cGMP;    Corrector;    Cystic fibrosis;    Potentiator;    Xenopus laevis oocyte;   

DOI  :  10.1159/000265129

学科分类：分子生物学，细胞生物学和基因

来源: S Karger AG

【 摘 要 】

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 CFBE41oand 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.

【 授权许可】

CC BY-NC-ND