The amiloride-inhibitable Na+ conductance is reduced by the cystic fibrosis transmembrane conductance regulator in normal but not in cystic fibrosis airways

Cystic fibrosis (CF) airway cells, besides their well-known defect in cAMP-dependent Cl- conductance, are characterized by an enhanced Na+ conductance, In this study we have examined the Na+ conductance in human respiratory tract by measuring transepithelial voltage and resistance (V-te, R-te) and by assessing membrane voltages (V-m) of freshly isolated airway epithelial cells from CF and non-CF patients. Basal amiloride inhibitable (10 mu mol/liter) equivalent short circuit current (I-sc = V-te/R-te) was significantly increased in CF compared with non-CF tissues. After stimulation by forskolin (10 mu mol/liter) a significant depolarization of V-m corresponding to the cAMP-dependent activation of a Cl- conductance was observed in non-CF but not in CF airway cells. In non-CF tissue but not in CF tissue the effects of amiloride and N-methyl-D-glucamine on V-m were attenuated in the presence of forskolin, Also the amiloride-inhibitable I-sc was significantly reduced by forskolin (1 mu mol/liter) and isobutylmethylxanthine (IBMX; 100 mu mol/liter) only in non-CF tissue. We conclude that cystic fibrosis transmembrane conductance regulator acts as a downregulator of epithelial Na+ channels in human airways. This downregulation of epithelial Na+ channels is absent in CF airways, leading to hyperabsorption and to the characteristic increase in mucus viscosity.