We have recently reported that type A intercalated cells of the collecting duct secrete Na⁺ by a mechanism coupling the basolateral type 1 Na⁺-K⁺-2Cl⁻ cotransporter with apical type 2 H⁺-K⁺-ATPase (HKA2) functioning under its Na⁺/K⁺ exchange mode. The first aim of the present study was to evaluate whether this secretory pathway is a target of atrial natriuretic peptide (ANP). Despite hyperaldosteronemia, metabolic acidosis is not associated with Na⁺ retention. The second aim of the present study was to evaluate whether ANP-induced stimulation of Na⁺ secretion by type A intercalated cells might account for mineralocorticoid escape during metabolic acidosis. In Xenopus oocytes expressing HKA2, cGMP, the second messenger of ANP, increased the membrane expression, activity, and Na⁺-transporting rate of HKA2. Feeding mice with a NH₄Cl-enriched diet increased urinary excretion of aldosterone and induced a transient Na⁺ retention that reversed within 3 days. At that time, expression of ANP mRNA in the collecting duct and urinary excretion of cGMP were increased. Reversion of Na⁺ retention was prevented by treatment with an inhibitor of ANP receptors and was absent in HKA2-null mice. In conclusion, paracrine stimulation of HKA2 by ANP is responsible for the escape of the Na⁺-retaining effect of aldosterone during metabolic acidosis.