In fetal pneumocytes, increasing P-O2 can raise apical Na+ conductance (G(Na+)) and increase the abundance of epithelial Na+ channel subunit (alpha-, beta-, and gamma-ENaC) mRNA, suggesting that the rise in G(Na+), which may be important to the perinatal maturation of the lung, reflects O-2-evoked ENaC gene expression. However, we now show that physiologically relevant increases in P-O2 do not affect alpha-, beta-, and gamma-ENaC mRNA abundance in pneumocytes maintained (similar to48 h) in hormone-free medium or in medium supplemented with dexamethasone and tri-iodothyronine, although the response does persist in cells maintained in medium containing a complex mixture of hormones/growth factors. However, parallel electrometric studies revealed clear increases in G(Na+) under all tested conditions and so it is now clear that O-2-evoked increases in G(Na+) can occur without corresponding increases in ENaC mRNA abundance. It is therefore unlikely that this rise in G(Na+) is secondary to O-2-evoked ENaC gene expression. (C) 2003 Elsevier Science (USA). All rights reserved.