The epithelial sodium channel (ENaC) mediates transepithelial sodium absorption and is important for the control of vertebrate sodium and water balance. Canonical ENaC is composed of the α-, β- and γ-subunits, but the physiology of ENaCs composed of the δ-, β- and γ-subunits is poorly understood. We have previously shown that δβγ-ENaC has a higher open probability than αβγ-ENaC and generates larger currents when expressed in Xenopus oocytes. We hypothesise that δβγ-ENaC provides a route for maximised sodium absorption and studied the activity of ENaC isoforms in response to changes in the extracellular sodium concentration ([Na]e). Guinea pig αβγ- and δβγ-ENaC were heterologously expressed in Xenopus oocytes and channel activity was measured by the two-electrode voltage-clamp technique at a holding potential of -60 mV. ENaC-mediated current fractions were determined using the inhibitor amiloride (100 μM). Currents were measured under increasing [Na]e from 1 – 300 mM. N-methyl-D-glucamine chloride was used to maintain osmolarity. The allosteric inhibition of ENaC by extracellular sodium (sodium self-inhibition, SSI) was determined as the percentage of current decline within 3 min after rapidly changing [Na]e from 1 to 90 mM. Delivery of ENaC to the plasma membrane was blocked by brefeldin A (BFA, 5 μM) and the rate of retrieval (in %) of functional ENaC from the plasma membrane under 1 mM and 90 mM [Na]e was determined by monitoring ENaC currents 5 h after application of BFA. Data are reported as means ± standard error. Amiloride-sensitive currents generated by δβγ-ENaC were 6.03 ± 0.79 µA (n = 20) and were significantly larger than those generated by αβγ-ENaC (2.1 ± 0.21 µA, n = 19; p < 0.0001, Mann-Whitney U-test). Currents triggered by increasing [Na]e followed Michaelis-Menten kinetics and had a Vmax of 3.44 ± 0.79 μA (αβγ-ENaC, n = 12) and 7.035 ± 0.68 μA (δβγ-ENaC, n = 12; p = 0.0005; Mann-Whitney U-test). KM values were 26.78 ± 4.09 mM sodium for αβγ-ENaC (n = 12, p = <0.0001, Mann-Whitney U-test), and 76.86 ± 4.63 mM sodium for δβγ-ENaC expressing oocytes (n = 12). SSI of δβγ-ENaC expressing oocytes was 16.09 ± 2.49 % (n = 17) and significantly smaller than that of αβγ-ENaC (46.52 ± 2.71 %, n = 18; p < 0.0001, Student’s unpaired t-test). In the presence of BFA and 1 mM [Na]e, currents generated by αβγ-ENaC decreased by 23.74 ± 8.35 % (n = 14) and those generated by δβγ-ENaC by 28.84 ± 5.65 % (n = 14; p = 0.62, Student’s unpaired t-test). In the presence of BFA and 90 mM [Na]e, the current decrease was 16.76 ± 13.11 % (n = 10) for αβγ-ENaC and 4.72 ± 17.16 % (n = 10) for δβγ-ENaC (p = 0.58, Student’s unpaired t-test). In conclusion, there is no difference in membrane residency between ENaC isoforms but δβγ-ENaC has a decreased SSI and generates larger currents over a wider range of [Na]e. This suggests that δβγ-ENaC might provide a route for efficient transepithelial sodium absorption in the presence of high [Na]e.