Liddle's syndrome is a hereditary form of arterial hypertension caused by mutations of the epithelial sodium channel (ENaC). The mutations affect PY-motifs in the C-termini of the channel's b- or [gamma]-subunit thereby reducing the channel's interaction with Nedd4-2. Stimulation of Nedd4-2 mediated channel retrieval is thought to be important for Na⁺-feedback inhibition of the channel. We compared the effect of different apical Na⁺ concentrations on ENaC mediated transepithelial Na⁺ transport in distal colon using a recently established mouse model for Liddle's syndrome (Pradervand et al., JASN 1999 & 2003). After exposing partially stripped colon to an apical bath solution containing either 4mM of Na⁺ (low Na⁺ group) or 123mM of Na⁺ (high Na⁺ group) for 8h, the amiloride-sensitive short-circuit current ([Delta]I_sc-ami ) was determined 15min after switching to an apical bath solution containing 63.5mM Na⁺. In both genotypes [Delta]I_scami [mA/cm ²] was significantly lower in the high Na⁺ group than in the low Na⁺ group, averaging 38±9 versus 72±13 (wild type, n=12) and 47±4 versus 104±15 (Liddle, n=12), respectively. Thus, sodium feedback regulation is partially preserved in the absence of the PY-motif in b-ENaC which is deleted in the mouse model in analogy to patients with Liddle's syndrome. This indicates that the PY-motifs in a- and/or [gamma]-ENaC and possibly other mechanisms contribute to Na⁺-feedback regulation.