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 β ₂-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±12cm vs. 171±10cm; wt.=68±12kg vs. 73±14kg; BMI=22±3kg/m ² vs. 25±4kg/m ², mean±SD, for AA and AT/TT, respectively). Measurements were made at baseline and at 30, 60 and 90min following the administration of a nebulized β ₂-agonist (albuterol sulfate, 2.5mg diluted in 3ml normal saline). The AA group had a higher baseline level of exhaled Na ⁺ and a greater response to β ₂-agonist stimulation (baseline=3.1±1.8mmol/l vs. 2.3±1.5mmol/l; 30min-post=2.1±0.7mmol/l vs. 2.2±0.8mmol/l; 60min-post=2.0±0.5mmol/l vs. 2.3±1.0mmol/l; 90min-post=1.8±0.8mmol/l vs. 2.6±1.5mmol/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 β ₂-adrenergic receptor stimulated Na ⁺ clearance in the lungs, as there was a significant reduction in exhaled Na ⁺ over time in the AA group.