The maintenance of body volume and a stable concentration of electrolytes are essential for the homeostasis of the human body. To understand the regulating mechanisms related to body fluid and electrolyte homeostasis, it is assumed that the total body fluid is mainly distributed between two compartments: the intracellular and the extracellular compartment. The extracellular compartment in turn is divided into the intravascular fluid volume and the interstitial fluid. These two body fluid compartments are characterized by a certain composition of cations and anions: the main constituents of the extracellular space being Na+, Cl−, Ca2+, and HCO3−, of the intracellular space being K+, PO43−, organic acid ions, Mg2+, and protein. The concentration of the electrolytes in the extracellular spaces is assumed to be constant. So if certain stimuli lead to deviating concentrations, fluid shifts - mainly induced by hydrostatic and colloid osmotic forces across the capillary membranes - ensure that the original set-point will be regained almost immediately. However, it might be questionable whether the electrolyte concentration, that is, sodium, is identical everywhere in the interstitial space and comparable with the plasma concentration. Aukland et al. (1) hypothesized that there might be a central mechanism for regulating blood volume but locally acting mechanisms for regulating interstitial volume. This hypothesis would concur with the observations by Mobasheri (17) who found levels of up to 450 mEq·L1 Na+ in the interstitium of bovine cartilage.
In contrast to the mechanism keeping the electrolyte concentrations in the extracellular space constant, the relationship of the electrolytes between intra- and extracellular fluid is different. Hence, if concentrations change in either the intra- or the extracellular space, mainly the osmotic effect only of the smaller solutes, especially Na+ and Cl−, induce fluid redistributions to maintain the relation between intra- and extracellular compartments.
CONVENTIONAL WISDOM OF SODIUM REGULATION
There might be different stimuli affecting sodium regulation, the most prominent of which is sodium intake. The conventional wisdom according to the two-compartment model is that increasing sodium intake leads to a transient increase in serum sodium concentration and a concomitant fluid retention (19). As a result, extracellular volume is increased. Both mechanisms increase in extracellular volume as well as serum sodium concentration, elevating the sodium excretion to keep the extracellular volume constant (Fig. 1).
OSMOTICALLY ACTIVE OR INACTIVE SODIUM REGULATION?
However, during a joint German-Russian space mission in 1992 (MIR 92 mission), we first found that - in contrast to the common understanding of increased sodium excretion at the beginning of a spaceflight (8,14) - natriuresis was reduced in microgravity (3). As a follow-up to that mission, we continued with a metabolic ward experiment in another joint German-Russian space mission (MIR 97 mission) and observed positive sodium balances each day for the entire mission (2,4). We kept the sodium intake of an astronaut constant for 15 d at a level of 180 mEq·d1, which is comparable to the average normal intake in Germany but is still considered to be a high sodium intake level. The respective control experiment on Earth was carried out for 13 d. In microgravity, sodium balance was positive by about 50 mEq·d1, reaching a level of 750 mEq of sodium retained in the body, while in the control experiment, sodium almost was balanced. Surprisingly, sodium retention in microgravity was not accompanied by fluid retention (4), which should have been approximately 5 L in case isotonic sodium retention would have taken place.
These rather unexpected results led to the question of whether sodium retention without fluid retention is induced by the microgravity environment or if similar results also could be obtained under normal gravity conditions. In a first metabolic ward study (11), we had chosen an open study design and increased NaCl intake starting from an average normal level of 220 mEq·d1 NaCl for 8 d to 440 mEq·d1 NaCl for the following 8 d, and finished the experiment with 660 mEq·d1 NaCl intake for another 8 d. Fluid intake was kept constant at a level of 40 mL·kg body weight1·d1. Comparable with the observations in spaceflight, we found that doubling and tripling NaCl intake (440 mEq·d1 NaCl and 660 mEq·d1 NaCl) for 8 d led to an overall sodium retention of approximately 700 mEq and 1000 mEq, respectively. If sodium retention is compensated by fluid retention, extracellular volume should have been increased by approximately 12 L after the 24 d of the study. However, the extracellular volume remains unchanged (11). Based upon these results, we came to the conclusion that both an average normal NaCl intake in microgravity and a high NaCl intake on Earth lead to increased sodium excretion. Nevertheless, that increase in sodium excretion (via kidney, skin, and feces) did not match the intake level, indicating that sodium was retained without fluid retention (Fig. 2). Similar results, namely positive sodium balances without fluid retention, also were described by Titze et al. in an isolation experiment, in which a confined situation as in spaceflight had been simulated (24). The question remains where the sodium can be retained without changing osmolality and following fluid retention. Farber et al. (5,6) examined the binding of actions by a certain glycosaminoglycan (GAG), namely chondroitin sulfate. They hypothesized that one possibility of an excess sodium binding without osmotic activity could be the binding to polyelectrolytes with a high negative charge, such as chondroitin sulfate. They studied sodium, potassium and calcium chlorides and their potential binding to chondroitin sulfate. Their results indicate "that the amount of cation bound is constant over the concentration range studied, and is approximately 0.9 equivalent per period of chondroitin sulfate for sodium or potassium, and 1.3 equivalent per period for calcium." They conclude that "Bound cation in the present discussion means osmotically inactive" (6). In a journal club discussion (10,13), we therefore hypothesized that possibly GAG may bind sodium in a way to prevent it from being osmotically active. Titze et al. (22,23,25) continued their studies in animal experiments. They used Sprague Dawley rats and fed them with either low (0.1%) or high (8%) NaCl chow. Similar to the experiments in humans they observed positive sodium balances without fluid retention (23,25). In their studies, however, they skinned the rats and analyzed sodium and water content in the skin (23). In fact, most of the retained sodium was found in the skin, suggesting that GAG may play an important role in osmotically inactive sodium retention, as shown earlier by Farber et al. (6). Furthermore, when Titze et al. (25) analyzed changes in skin GAG content and key enzymes of GAG chain polymerization in Sprague Dawley rats fed either low (0.1%) or high (8%) NaCl for 8 wk, they found that increasing skin sodium coincided with increasing GAG content in cartilage and skin. Dietary NaCl loading coincided also with increased chondroitin synthase mRNA content in the skin (25).
On the other hand, Seeliger et al. (21) and Nguyen et al. (18) question the possibility of osmotically inactive sodium retention. Seeliger et al. (21) states that "The data of Heer's study in humans that hitherto appeared to demonstrate that osmotically inactive Na+ storage is a rapid process, can no longer be regarded as positive prove for this storage, because K+ balances were not assessed."
Besides the question of whether positive sodium balances that are not accompanied by fluid retention are compensated by negative potassium balances, as proposed by Seeliger et al. (21) and Nguyen and Kurtz (18), another question arouse. As described in the section "Conventional Wisdom of Sodium Regulation," it has been shown in several studies (15,16) and is meanwhile physiological textbook knowledge (9) that increasing NaCl intake leads to increases in serum sodium concentration and fluid retention as well as to extracellular volume extension. However, most of the studies showing a gain in extracellular volume started from a low sodium intake level rather than an average normal or high intake level. In a further study in our metabolic ward, we therefore examined the effect of different onset levels of NaCl intake. When increasing NaCl intake from a low intake level (50 mEq·d1 NaCl) to an average normal level (200 mEq·d1 NaCl), our results concur with the conventional wisdom (12), leading to sodium retention together with fluid retention. However, when starting from an average normal level (200 mEq·d1 NaCl) and the NaCl intake is increased further to very high levels (550 mEq·d1), sodium is also retained, but this time without any fluid retention (12). In addition, we also analyzed potassium balances and found that although potassium balances were somewhat negative, they could only explain 22% of the positive sodium balances. We therefore conclude that high NaCl intake, in combination with a constant fluid intake of 40 mL·kg body weight1·d1, leads to osmotically inactive sodium retention.
POTENTIAL MECHANISM OF OSMOTICALLY INACTIVE SODIUM RETENTION
As mentioned previously, Titze et al. have convincingly shown that in rats, elevated sodium is associated with an increased GAG content in cartilage and skin (23,25). Furthermore, the same group demonstrated that decreasing NaCl intake over 4 wk following high NaCl intake was associated with a decreased negatively charged skin GAG content (20). Thus an osmotically inactive sodium retention seems to be somewhat coupled with an actively regulated interstitial cation exchange mechanism. We therefore analyzed in our volunteers the mRNA expression of some key enzymes of GAG chain polymerization in skin biopsies when changing NaCl intake from a low (50 mEq·d1) to a high (550 mEq·d1) NaCl intake. What we found was indeed a doubling of the mRNA expression of key enzymes of GAG chain polymerization enzyme and hyaluronidase (unpublished results). Now, in case GAG binds sodium - as described by Farber et al. already in the 1950s (6) - this would lead to hydrogen release and may lead to pH decreases in the surrounding tissue and possibly to a pH reduction on the systemic level. Analyses of pH, bicarbonate, and base excess levels of arterialized blood show that high NaCl intake was accompanied by significant decreases in these levels, describing a state of low-grade metabolic acidosis. Based upon these results, we hypothesize that under the given study conditions, high NaCl intake leads to osmotically inactive sodium retention by binding sodium to GAG, resulting in a low-grade metabolic acidosis (Fig. 3).
The question now remains whether a reduction in NaCl intake for a certain period of time would also lead to sodium release from GAG. First results from studies performed by Garnett et al. (7) in obese female patients suggest that during periods of total starvation, osmotically inactive sodium might have been made available for exchange. So we hypothesized that lowering NaCl intake after a period of high NaCl intake and osmotically inactive sodium retention might lead to the release of the bound sodium. Subsequent to the high NaCl intake phase, we therefore added - in the previously described study - another 6-d period with low NaCl intake of 50 mEq·d1. Sodium was lost during the first days of that study period, but this sodium loss could be attributed to an osmotically active sodium loss, since water was lost concurrently. Approximately 75% of the sodium retained during the average normal and high NaCl intake phases was continuously retained, while blood pH, bicarbonate, and base excess levels returned to the level of the first low NaCl intake phase (12). These data are supported by the animal data published by Schafflhuber et al. (20). They show that 1 wk of low salt intake in rats was not sufficient to release the retained sodium. However, 4 wk of low sodium intake did promote sodium loss and a concomitant decrease in negatively charged skin GAG content. Despite the current findings, it remains an open issue as to which stimulus eventually induces the sodium release.
Based upon recent findings, we conclude that the two-compartment model might no longer be adequate for understanding sodium regulation and that regulating mechanisms located in the interstitial space might be included in our model.
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