The molecular mechanisms by which corticosteroids affect fluid and electrolyte balance have yet to be fully elucidated. The apical amiloride-sensitive electrogenic epithelial sodium channel (ENaC) has been shown to have a central role in corticosteroid-mediated sodium transport in the distal colon. The acute response of the alpha-, beta- and gammaENaC subunit genes to a single parenteral dose of aldosterone or dexamethasone was examined in the rat distal colon in vivo. The response of the Nedd4 gene, whose product is involved in channel turnover, was also examined. Whilst the alphaENaC and Nedd4 genes showed no significant response to either steroid, both the beta- and gammaENaC mRNA levels were increased acutely by both aldosterone and dexamethasone. The gammaENaC mRNA appears to have a very short half-life. Use of the highly selective glucocorticoid receptor agonist RU28362 confirmed that the response was mediated by both the mineralocorticoid and glucocorticoid receptors.