The following is the abstract of the article discussed in the subsequent letter:
Seeliger, Erdmann, Mechthild Ladwig, and H. Wolfgang Reinhardt. Are large amounts of sodium stored in an osmotically inactive form during sodium retention? Balance studies in freely moving dogs. Am J Physiol Regul Integr Comp Physiol 290: R857–R858, 2006; First published December 22, 2005; doi:10.1152/ajpregu.00676.2005.—Alterations in total body sodium (TBSodium) that covered the range from moderate deficit to large surplus were induced by 10 experimental protocols in 66 dogs to study whether large amounts of Na+ are stored in an osmotically inactive form during Na+ retention. Changes in TBSodium, total body potassium (TBPotassium), and total body water (TBWater) were determined by 4-day balance studies. A rather close correlation was found between individual changes in TBSodium and those in TBWater (r2 = 0.83). Changes in TBSodium were often accompanied by changes in TBPotassium. Taking changes of both TBSodium and TBPotassium into account, the correlation with TBWater changes became very close (r2 = 0.93). The sum of changes in TBSodium and TBPotassium was accompanied by osmotically adequate TBWater changes, and plasma osmolality remained unchanged. Calculations reveal that even moderate TBSodium changes often included substantial Na+/K+ exchanges between extracellular and cellular space. The results support the theory that osmocontrol effectively adjusts TBWater to the body's present content of the major cations, Na+ and K+, and do not support the notion that, during Na+ retention, large portions of Na+are stored in an osmotically inactive form. Furthermore, the finding that TBSodium changes are often accompanied by TBPotassium changes and also include Na+/K+ redistributions between fluid compartments suggests that cells may serve as readily available Na+ store. This Na+ storage, however, is osmotically active, since osmotical equilibration is achieved by opposite redistribution of K+.
With respect to the conclusions of Seeliger et al. (3) regarding the fate of ingested sodium, I wish to make two points. First, Heer et al.'s (2) potassium excretion data are consistent with osmotic inactivation of sodium and not with Seeliger et al.'s sodium-potassium exchange hypothesis. Secondly, it is inappropriate to compare results of the two studies because of significant differences in experimental details.
If the fate of ingested sodium is to remain osmotically active, then a positive sodium balance can have one or a combination of two straightforward consequences: an increase in body water osmolality or an increase in total body water (TBWater) resulting from increased water ingestion. In experiments on beagle dogs, in which total body sodium (TBSodium) was increased or decreased, Seeliger et al. (3) observed primarily the latter, and never the former. TBWater was a linear function of TBSodium (R2 = 0.83) and an even stronger function of the sum of TBSodium and total body potassium (TBPotassium; R2= 0.93). However, they also report instances where a TBSodium increase was accompanied by a TBPotassium decrease, as ascertained by urinary excretion data. The authors concluded that there is a third way for osmotically active sodium to increase, namely, to exchange with intracellular K+. If this sodium/potassium exchange mechanism is operative, then when TBSodium increases, sodium remains osmotically active while TBWater or osmolality remain constant and TBPotassium decreases. Evidence for this mechanism is a negative potassium balance, that is, potassium excretion is greater than potassium intake. Thus, to conclude that the sodium of a positive sodium balance has been rendered osmotically inactive requires not only that there be no increase in TBWater or osmolality but also a zero potassium balance. (More precisely, the positive sodium balance must exceed the total that can be accounted for by changes in potassium, TBWater, and osmolality.)
In recent sodium balance studies, Heer et al. (2) observed positive sodium balances, of up to 1700 meq, without a change in either TBWater or body water osmolality and concluded that sodium had been osmotically inactivated. Seeliger et al. (3) challenge this conclusion, saying that Heer et al. did not account for potassium balance. Although correct, this is misleading. Heer et al. do report potassium excretion. If sodium is exchanging with potassium, then potassium excretion should increase. Significantly, when sodium intake was doubled from 220 to 440 meq/day and then tripled to 660 meq/day potassium excretion remained constant at 90–96 meq/day [calculated from their Table 1 data (2)]. In a second study, potassium excretion (124–134 meq/day) did not vary among males on 24-day sodium intakes of 50, 200, 400, or 550 meq/day [calculated from their Table 2 (2)]. Thus, these results are not consistent with the Seeliger sodium/potassium exchange hypothesis. Instead, they support Heer et al.'s hypothesis of sodium osmotic inactivation and storage.
Additionally, according to the Seeliger hypothesis (3), 1700 meq of sodium must enter the intracellular space for TBWater not to increase. The intracellular volume can be estimated at ∼31 liters for the Heer et al. (2) 76.8-kg males (assuming TBWater of 0.6 × weight, and intracellular fluid volume of 2/3 of TBWater)(1). Intracellular sodium concentration would therefore be required to increase by 1704/30.7 = 55.5 meq/l, an improbably large number.
Experimental details differ significantly between the Seeliger et al. (3) and Heer et al. (2) experiments. Two points are the most significant. First, Seeliger et al. induced sodium retention in Beagle dogs by several techniques, including stimulating the renin-angiotensin-aldosterone system, and/or administering aldosterone and/or angiotensin. Heer's human subjects simply increased their dietary sodium intake. Second, daily water intakes were fixed at significantly different levels, 100 ml·kg−1·day−1 for Seeliger et al.'s dogs vs. 40 ml·kg−1·day−1 for Heer et al.'s humans. Thus, a 75-kg Heer et al. subject ingested 3 l/day. The same subject on a Seeliger et al. schedule would have ingested 7.5 l/day, and it should be noted, in one feeding period (see Seeliger et al.'s Ref. 3).
The conclusions of both Seeliger et al. (3) and Heer et al. (2) are consistent with their respective studies. Osmotic inactivation of sodium remains a viable hypothesis. The challenge is to characterize the conditions under which ingested sodium is or is not rendered osmotically inactive.
- Copyright © 2006 the American Physiological Society
However, I would also like to underline further the differences in study designs between our examinations in humans and Seeliger et al.'s (3) examinations in dogs. As outlined by Weschler, the dogs in Seeliger's experiments were given food and fluid once a day in the morning between 8:30 and 9:00 AM. In our human study, the test subjects were provided with three main meals (8:00 AM, 1:00 PM, and 7:00 PM) and three snacks (11:00 AM, 4:00 PM, and 9:00 PM) in which the daily sodium amount was distributed. The entire amount of sodium was given by dietary intake and fluid supplied together with the meals. This is a significant difference in study design because the entire sodium regulation system has been challenged six times a day by high salt intake in our study compared to only once per day in Seeliger's experiment.
As already mentioned by Weschler, fluid intake was kept constant at a level of 40 ml/kg body weight/day in our study, whereas the dogs received 100 ml/kg body weight/day. Considering our subjects' daily fluid and sodium intakes, the calculated concentration of ingested sodium was about 214 meq/l, i.e., a clearly hypertonic saline solution. However, fluid intake of 3 l/day, of which two liters are taken as beverages, is already higher than average in Germany. The average day-by-day fluid intake in Germany is rather low, especially in elderly people. One might argue that the chosen level of sodium intake in our study is extremely high. Yes, this is true; but on the basis of salt intake levels in the Western world and the average fluid intakes, it is not uncommon that, calculated as the concentration of sodium, the daily fluid intake be hypertonic. Under the chosen study conditions, which, albeit to some extent extreme, indeed do reflect characteristics of nutritional habits; positive sodium balances occurred without any changes in potassium excretion or extracellular volume, which inevitably led to osmotically inactive sodium storage.
Another difference between these studies is the level of potassium intake. Although in our study, we did not balance potassium intake, our test subjects received an intake, independent of body weight, between 50 and 100 mmol/day (meaning 0.65 to 1.3 mmol potassium/kg body weight/day) provided by meals. In the studies by Seeliger (3), potassium intake was 3.5 mmol/kg body weight/day, which was about 3 to 5 times higher than in our study and the recommended intake for humans in Germany (1). This high potassium intake could also have influenced Na+/K+ exchange.
In their experiments, Seeliger et al. (3) went directly from a low salt intake (0.5 mmol/kg body weight/day) to a high salt intake (5.5 mmol/kg body weight/day). A study group with average normal sodium ingestion was apparently not examined. Now, one might speculate that the onset level of sodium intake rather than the total body sodium (TBSodium) content is important in the regulation of sodium balance because the organism is adapted to a certain level of intake. More precisely, the effect when starting from a low-sodium diet and then switching to an average sodium intake might be different from that of starting from an average sodium intake and then switching to a high-sodium diet. So, it might well be that in the first case, the increase in TBSodium is compensated by fluid retention, i.e., the undisputed physiological mechanism. This would most likely fit very well with the correlation that Seeliger et al. (3) found in their dogs. However, in the second case, i.e., when starting from an average intake level and then switching to a high-sodium diet, the mechanism might be different, namely, sodium is stored in an osmotically inactive form. Serum sodium levels would increase in both cases, and sodium has to be excreted by the kidney, but the maximum excretion capability of the kidney might have already been reached when being on an average intake level. Then, other mechanisms have to compensate for the increased serum sodium level. Because there was no intermediate sodium level in the studies by Seeliger et al. (3), this would mean that increasing sodium intake from low to high intake demands activation of both mechanisms: compensation by fluid retention and storage of osmotically inactive sodium. Obviously, total body fluid content and TBSodium must correlate in Seeliger et al.'s (3) studies because total body fluid is retained up to a certain level.
Certainly, additional studies (animal and human) are mandatory to further improve our knowledge of sodium and water metabolism, including the capability to store sodium in an osmotically inactive way.