Liddle's syndrome is an autosomal dominant form of human hypertension, caused by gain-of-function mutations of the epithelial sodium channel (ENaC) which is expressed in aldosterone target tissues including the distal colon. We used a mouse model for Liddle's syndrome to investigate ENaC-mediated Na(+) transport in late distal colon by measuring the amiloride-sensitive transepithelial short circuit current (DeltaISC-Ami) ex vivo. In Liddle mice maintained on a standard salt diet, DeltaISC-Ami was only slightly increased but plasma aldosterone (PAldo) was severely suppressed. Liddle mice responded to a low or a high salt diet by increasing or decreasing, respectively, their PAldo and DeltaISC-Ami. However, less aldosterone was required in Liddle animals to achieve similar or even higher Na(+) transport rates than wild type animals. Indeed, the ability of aldosterone to stimulate DeltaISC-Ami was about threefold higher in Liddle animals than in the wild type controls. Application of aldosterone to colon tissue in vitro confirmed that ENaC stimulation by aldosterone was not only preserved but enhanced in Liddle mice. Aldosterone induced transcriptional up-regulation of the channel's beta- and gamma-subunit (betaENaC, gammaENaC) and of the serum- and glucocorticoid-inducible kinase 1 (SGK1) was similar in colon tissue from Liddle and wild type animals, while aldosterone had no transcriptional effect on the alpha-subunit (alphaENaC) Moreover, Na(+) feedback regulation was largely preserved in colon tissue of Liddle animals. In conclusion, we have demonstrated that in the colon of Liddle mice, ENaC-mediated Na(+) transport is enhanced with an increased responsiveness to aldosterone. This may be pathophysiologically relevant in patients with Liddle's syndrome, in particular on a high salt diet, when suppression of PAldo is likely to be insufficient to reduce Na(+) absorption to an appropriate level.