Objective: Endothelial cells are known to be targets for aldosterone. It was shown that the hormone modifies the biomechanical properties of the cells and thereby provokes a reduction of nitric oxide (NO) release. Furthermore, high levels of plasma sodium (150 mM) also increase the stiffness of endothelial cells (Oberleithner et al. 2007). This suggests that sodium per se affects endothelial functions by a yet unknown mechanism. We tested the hypothesis that these effects are mediated by the epithelial sodium channel (ENaC) in vascular endothelium. Methods: Human endothelial cells were incubated in low (130mM) and high (150mM) sodium concentrations. With a combination of immunofluorescence techniques, atomic force microscopy (AFM) and molecular biological methods the expression of ENaC, endogenous aldosterone production and the mechanical properties of the cells were studied. Results: Incubation of the cells in high sodium and in the absence of exogenous aldosterone induces the following sequence of events: (i) endogenous synthesis of aldosterone is stimulated, (ii) membrane insertion of active ENaC is increased by more than 70% within 30 minutes and (iii) the mechanical stiffness of endothelial cells is enhanced by approximately 70% compared to cells incubated in low sodium. Spironolactone and the aldosterone synthase blocker FAD286 effectively prevented this response. Conclusions: It is postulated that in endothelial cells sodium per se triggers endogenous aldosterone production by activation of the aldosterone synthase. This in turn enables the rapid delivery of ENaC molecules to the apical membrane via a fast non-genomic mineralocorticoid receptor-mediated pathway. A new concept of endothelial function in the control of blood pressure and tissue perfusion may evolve based on sodium-dependent and local aldosterone release. Oberleithner, H., Riethmuller, C., Schillers, H., MacGregor, G.A., de Wardener, H.E., & Hausberg, M. 2007. Proc Natl Acad Sci 104, 16281-16286.