Genetic variation of the alpha subunit of the epithelial Na+ channel influences exhaled Na+ in healthy humans

Epithelial Na+ channels (ENaC) are located in alveolar cells and are important in β2-adrenergic receptor-mediated lung fluid clearance through the removal of Na+ from the alveolar airspace. Previous work has demonstrated that genetic variation of the alpha subunit of ENaC at amino acid 663 is important in channel function: cells with the genotype resulting in alanine at amino acid 663 (A663) demonstrate attenuated function when compared to genotypes with at least one allele encoding threonine (T663, AT/TT). We sought to determine the influence of genetic variation at position 663 of ENaC on exhaled Na+ in healthy humans. Exhaled Na+ was measured in 18 AA and 13 AT/TT subjects (age = 27 ± 8 years vs. 30 ± 10 years; ht. = 174 ± 12 cm vs. 171 ± 10 cm; wt. = 68 ± 12 kg vs. 73 ± 14 kg; BMI = 22 ± 3 kg/m2 vs. 25 ± 4 kg/m2, mean ± SD, for AA and AT/TT, respectively). Measurements were made at baseline and at 30, 60 and 90 min following the administration of a nebulized β2-agonist (albuterol sulfate, 2.5 mg diluted in 3 ml normal saline). The AA group had a higher baseline level of exhaled Na+ and a greater response to β2-agonist stimulation (baseline = 3.1 ± 1.8 mmol/l vs. 2.3 ± 1.5 mmol/l; 30 min-post = 2.1 ± 0.7 mmol/l vs. 2.2 ± 0.8 mmol/l; 60 min-post = 2.0 ± 0.5 mmol/l vs. 2.3 ± 1.0 mmol/l; 90 min-post = 1.8 ± 0.8 mmol/l vs. 2.6 ± 1.5 mmol/l, mean ± SD, for AA and AT/TT, respectively, p < 0.05). The results are consistent with the notion that genetic variation of ENaC influences β2-adrenergic receptor stimulated Na+ clearance in the lungs, as there was a significant reduction in exhaled Na+ over time in the AA group.

► We explored the influence of genetics of SCNN1A on exhaled Na+ and lung diffusion. ► We found that the AA genotype had greater decrease in exhaled Na+ with albuterol. ► Both groups had a similar increase in lung conductance with albuterol.