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Figure 2. Relative decreases in individual brain electrolytes and organic osmolytes during adaptation to chronic (14 days) hyponatremia in rats. The category "other" represents GPC, urea, and several other amino acids. Reproduced with permission from (2).

2.3. Cellular Mechanisms Underlying Brain Adaptation to Hypoosmolality

Although brain volume regulation in response to perturbations of extracellular osmolality represents the most dramatic demonstration of volume regulation in response to changes in extracellular osmolality, the ability to regulate intracellular volume is an evolutionarily conserved mechanism inherent to variable degrees in most cells. Abundant in vitro experimentation has yielded important insights into the cellular mechanisms that underlie this important adaptive process (18).

With acute decreases in external osmolality, cells initially behave as osmometers and swell in proportion to the reduction in extracellular osmolality as a result of movement of water into the cells along osmotic gradients. Very soon thereafter, a process known as volume regulatory decrease (VRD) in cell volume begins, in which intracellular solutes are extruded together with osmotically obligated water (19). The time necessary to activate RVD and restore normal, or near-normal, cell volume is variable across different cell types. RVD occurs very rapidly in vitro, with a 70-80% recovery of normal cell volume reached within a few minutes in most brain and epithelial cells (19,20).

RVD has been studied in detail in astrocytes and neurons from primary cultures (20,21), in neuroblastoma (22) and glioma (23) cells lines. The osmolytes responsible for RVD are essentially the same in most cell types and can be grouped into two broad categories: electrolytes (predominantly K+ and Cl-) and organic osmolytes (amino acids, polyalcohols, sugars, and methylamines). In most cells examined to date, electrolyte fluxes appear to occur by diffusive pathways, i.e., K+ and Cl- efflux through separate volume-sensitive channels, and organic osmolytes through "leak pathways" with no significant contribution from energy-dependent carriers (18). In brain cells, swelling activates at least two different types of K+ channels, both a large and a small conductance channel (24). The volume-sensitive Cl- channel (VSCC) has high selectivity of anions over cations, but exhibits broad anion selectivity, displaying permeability to the majority of monovalent anions (25,26). Although the molecular species of VSCC are as yet unidentified, recent evidence has supported the ClC3 channel gene as encoding the channel protein responsible for the volume-sensitive Cl- current (27), but different types of VSCC and other anion-permeating molecules coincide in the same cell allowing for participation of more than one VSCC in RVD (28).

Although many different organic osmolytes are also released by cells during RVD, their efflux pathways have been characterized for only a few, particularly taurine and myoinositol. In general, these are bidirectional leak pathways with net solute movement depending on concentration gradient direction (18,29). Organic osmolyte pathways commonly exhibit a pharmacologic profile similar to that of the VSCC, suggestive of a common pathway with Cl-, or of a close connection between the two pathways (29,30). Other amino acids also responsive to swelling are glycine, GABA, glutamate, and aspartate, which contribute to correction of osmotic disturbance. Recent evidence of hyposmolality-induced glutamate release that is insensitive to Cl- channel blockers is different from the pattern found with most other organic osmolytes (17). This suggests either different pathways, or different stimuli and mechanisms for release, of this amino acid.

Exactly how cells sense volume changes is a critical step in the reactions activated to achieve volume correction. Among possible mechanisms considered to play this role are membrane receptors such as integrins or receptors with intrinsic tyrosine kinase activity, cytoskeleton rearrangements, dilution of cytosolic macromolecules, decrease in intracellular ionic strength, stretch-induced activation of adhesion molecules, activation of phospholipases, or changes in the concentration of signaling molecules such as calcium or magnesium (31). Calcium and protein kinases are among the most likely candidates to act as osmotransductory elements. One of the most constant features of hyposmolar swelling is an increase in systolic Ca++. Despite this, the main corrective osmolyte efflux pathways and consequently RVD are Ca++-independent in a large variety of cell types. This is the case for brain cells, in which VSCC, VSKC, and organic efflux pathways are largely Ca++-independent (24). This is an area of active ongoing research, and the reader is referred to excellent recent reviews of this topic for more details (18,31,32).

2.4. Recovery from Hypoosmolality (Deadaptation)

Compensatory adaptations that enable organisms to survive chronic perturbations of body homeostasis must be reversed after recovering from the underlying abnormality. In some cases reversal of the adaptive process, or "de-adaptation," may be more problematical than the initial adaptation itself. This appears to be true for correction of chronic hyponatremia (33). Multiple studies have shown that rapid correction of chronic hyponatremia causes dehydration of brain tissue (34-36), and in some cases demyelination of white matter in various parts of the brain (37-39). Because this dehydration occurs to a greater degree in hyponatremic rats than in normonatremic rats following similarly large increases in osmolality, it has been suggested that this phenomenon reflects a loss of osmotic buffering capacity by brain tissue as a consequence of the initial brain solute losses that allowed survival despite hypoosmolar conditions (33).

Figure 3. Time course of changes in brain electrolytes (top panel) and organic osmolytes (bottom panel) during adaptation to chronic hyponatremia and following correction of hyponatremia in rats. Dotted lines depict normal brain levels; *p<0.05 compared to day 0. Reproduced with permission from (3).

Figure 3. Time course of changes in brain electrolytes (top panel) and organic osmolytes (bottom panel) during adaptation to chronic hyponatremia and following correction of hyponatremia in rats. Dotted lines depict normal brain levels; *p<0.05 compared to day 0. Reproduced with permission from (3).

Several studies have now demonstrated markedly different rates of reaccumulation of brain solutes after normalization of hypoosmolality in hyponatremic mice and rats (13,40). In response to hyponatremia, brain tissue rapidly loses all classes of osmotically active solutes, including both electrolytes and organic osmolytes, thereby allowing the brain to efficiently regulate its volume. On the other hand, after recovery from hyponatremia organic osmolytes, with the exception of glutamate, return to normal brain contents very slowly over a period of many days, while electrolytes reach normal or supranormal contents in the brain within 24 hours after correction of hyponatremia (Fig. 3). This slow reaccumulation of organic solutes is very analogous to the similarly slow increases in osmolytes that occur during chronic hypernatremia (see below), and suggests that in general the brain is much better able to lose organic solutes than to reaccumulate them. Furthermore, the rapid electrolyte reaccumulation after correction of hypoosmolality consists mainly of the extracellular electrolytes Na+ and Cl-, and these significantly overshoot brain contents necessary to achieve normal volume regulation (Fig. 3). This again is quite analogous to the rapid increases in brain Na+ and Cl- that occur in response to acute hyperosmolality (41,42), and it suggests that in this situation these electrolytes are similarly gaining access to the brain rapidly via the CSF and are acting to stabilize intracellular volume (43). Consequently, the mechanisms that enable the brain to adapt to hypoosmolar conditions and those that accomplish de-adaptation after subsequent normalization of plasma osmolality are not simply mirror images of each other.

Knowledge of this greater inefficiency of brain solute reaccumulation and volume regulation following correction of chronic hyponatremia is very relevant to understanding the pathological sequelae known to be associated with rapid correction of chronic hypoosmolality, namely the occurrence of osmotic demyelination. Every adaptation made by the body in response to a perturbation of homeostasis bears within it the potential to create new problems. Although the mechanism(s) by which rapid correction of hyponatremia leads to brain demyelination remain unproven, this pathological disorder likely results from the brain dehydration that has been demonstrated to occur following correction of plasma [Na+] toward normal ranges in animal models of chronic hyponatremia. Because the degree of osmotic brain shrinkage is greater in animals that are chronically hyponatremic than in normonatremic animals undergoing similar increases in plasma osmolality, by analogy the brains of human patients adapted to hyponatremia are likely to be particularly susceptible to dehydration following subsequent increases in osmolality. This, in turn, can lead to pathological demyelination. Further support for dehydration-induced demyelination has come from recent reports that acute hyperosmolality can also cause demyelination in experimental animals (44), though larger increases in plasma osmolality are required than in hyponatremic rats. Although the exact mechanisms responsible for production of brain demyelination following correction of hyponatremia remain uncertain, one possibility is that acute brain dehydration produced by rapid correction could potentially disrupt the tight junctions of the blood-brain barrier. Recent magnetic resonance studies in animals have shown that chronic hypoosmolality predisposes rats to opening of the blood-brain barrier following rapid correction of hyponatremia, and that the disruption of the blood-brain barrier is highly correlated with subsequent demyelination (45). A potential mechanism by which blood-brain barrier disruption might lead to subsequent myelinolysis is via an influx of complement, which is toxic to the oligodendrocytes that manufacture and maintain myelin sheaths of neurons, into the brain (46).

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