Ouabain-Sensitive α1 Na,K-ATPase Enhances Natriuretic Response to Saline Load

Na,K-ATPase is ubiquitously expressed and is essential for maintaining electrochemical and osmotic gradients. The α subunit of Na,K-ATPase is the receptor for cardiotonic steroids, which act through the ouabain-binding site and are important in cardiovascular regulation. Interestingly, the presence of endogenous Na,K-ATPase ligands has been implicated in the natriuretic response to perturbations such as hypertension and salt loading; therefore, it is important to characterize the role of the ouabain-binding sites in this context. Because the α1 isoform of mice and rats is relatively ouabain resistant, gene-targeting strategies were used to produce mice with reversed responses of the α1 and/or α2 isoforms to ouabain to assess for altered natriuretic responses to acute salt loading. Regardless of the sensitivity of the α2 isoform to ouabain, conferring ouabain sensitivity to α1 augmented the natriuretic response to an acute salt load. In addition, when endogenous Na,K-ATPase inhibitors were sequestered with an anti-digoxin antibody fragment, the sodium excretion rates in the ouabain-sensitive α1 isoform mice were equivalent to the ouabain-resistant α1 isoform mice. These data suggest that the ouabain-binding site of the α1 Na,K-ATPase can participate in the natriuretic response to a salt load by responding to endogenous Na,K-ATPase ligands.