Why are amiloride or triamterene used to treat Liddle syndrome?
First described by Grant W. Liddle in 1963, individuals with this autosomal-dominant form of hypertension feature hypokalemia and metabolic alkalosis, suggesting hyperaldosteronism; however, their aldosterone levels are completely suppressed. Interestingly, affected individuals do not respond to spironolactone treatment; however, they show significant improvement of blood pressure with any blockers of ENaC. Candidate gene analysis identified gain-of-function mutations in two of the three subunits that form the epithelial sodium channel ENaC as responsible cause for this syndrome. Missense mutations and deletions in the cytoplasmic tails of the β- or γ-subunits of ENaC lead to impaired deactivation of the channel from the luminal surface in the distal nephron, thereby causing upregulated sodium reabsorption.
In vitro studies showed that the internalization of the mutated ENaC channels from the cell surface (either by ubiquitination or clathrin-mediated endocytosis) is impaired, and the ENaC channels remain active on the apical cell surface mediating unopposed sodium reabsorption. This mechanism explains the superb efficacy of ENaC blockers, such as amiloride, in the treatment of this disease.
