The idea that an osmotically inactive Na⁺ storage pool exists that can be varied to accommodate states of Na⁺ retention and/or Na⁺ loss is controversial. We speculated that considerable amounts of osmotically inactive Na⁺ are lost with growth and that additional dietary salt excess or salt deficit alters the polyanionic character of extracellular glycosaminoglycans in osmotically inactive Na⁺ reservoirs. Six-week-old Sprague-Dawley rats were fed low-salt (0.1%; LS) or high-salt (8%; HS) diets for 1 or 4 wk. At their death, we separated the tissues and determined their Na⁺, K⁺, and water content. Three weeks of growth reduced the total body Na⁺ content relative to dry weight (rTBNa⁺) by 23%. This “growth-programmed” Na⁺ loss originated from the bone and the completely skinned and bone-removed carcasses. The Na⁺ loss was osmotically inactive (45–50%) or osmotically active (50–55%). In rats aged 10 wk, compared with HS, 4 wk of LS reduced rTBNa⁺ by 9%. This dietary-induced Na⁺ loss was osmotically inactive (≈50%) and originated largely from the skin, while ≈50% was osmotically active. LS for 1 wk did not reduce skin Na⁺ content. The mobilization of osmotically inactive skin Na⁺ with long-term salt deprivation was associated with decreased negatively charged skin glycosaminoglycan content and thereby a decreased water-free Na⁺ binding capacity in the extracellular matrix. Our data not only serve to explain discrepant results in salt balance studies but also show that glycosaminoglycans may provide an actively regulated interstitial cation exchange mechanism that participates in volume and blood pressure homeostasis.