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ABSTRACT. Sugar alcohols have been found to play an important osmoregulatory role both in unicellular organisms and, more recently, in multicellular organisms, including mammals. This study shows that myo-inositol accumulates in the brains of chronically hypernatremic mice, as had been earlier found in rats, and demonstrates for the first time a profound decrease of myo-inositol in the brains of chronically hyponatremic mice. Together with decreases in better known cerebral osmoles (amino acids and related nitrogenous compounds), the decrease in myo-inositol apparently allows the brain to balance its intracellular osmolality with that of the plasma, permitting a normal brain water content (no edema) despite profound hyponatremia. (Pediatr Res 26:482-485, 1989)Cellular adaptation to osmotic stress is a vital biologic process that protects organisms from the possibly lethal effects of dehydration and shrinkage, or edema and swelling of cells. In 1955McDowell et al. (1) described the generation of unidentified ("idiogenic") osmotically active particles other than electrolytes in mammalian tissues in response to treatment with hyperosmolar solutions. Since then a large number of studies have appeared concerning the cellular adaptation of different species to osmotic stress. Duchateau et al. (2) were the first to show that loss or gain of free tissue amino acids played a prominent role in the adaptation of invertebrates to extremes of environmental salinities. The role of amino acids and related compounds in adaptation to salinity change has since been extended to bacteria (3), plants (4, 5), amphibians (6), and mammals (7-1 1). Not all amino acids contribute equally to cellular osmoregulation. For example, on a molar basis the greatest concentration change during salinity stress was in alanine in bivalve molluscs (12), glycine in lobsters (13), glutamate in toad (14), and taurine in mouse brain (9, 10). Also, not all osmoregulators are of nitrogenous origin. In osmophilic yeasts the predominant osmoregulatory molecule is arabitol (15), in green algae, it is glycerol (16). Recently a significant role of sugar alcohols in osmoregulation in higher species has been recognized. Pinitol and myo-inositol have been found to accumulate in drought-adapted varieties of maritime pine during water stress (1 7). Bagnasco et al. (19) that myo-inositol levels are increased in the brains of chronically hypernatremic rats. This was the first report citing an increase in inositol levels in brain and raises the important question of whether that change is reflected in the inositolcontaining lipids and in their function.We have earlier reported on the effects of chronic hyper-and hyponatremia and the effect that rapid restoration of plasma Na' levels to normal has on brain water, electrolyte, carbohydrate, energy and amino acid metabolism in young mice (10, 11). It was thus of interest to confirm the findings of Lohr et al. (19) in the chronic hypernatremic state and to examine the effect of chronic hyponatremia, and rapid correction, o...

The experimental model of central pontine myelinolysis--chronic (4-day) hyponatremia induced by daily injections of hypotonic dextrose solutions and vasopressin followed by rapid correction with saline--was used in young fasted and thirsted mice. In normal controls chronic fasting and thirsting lowered plasma and brain glucose levels and cerebral glycolytic and tricarboxylic acid cyclic metabolic fluxes. The fasting state had little effect on brain amino acids. Clinically, the animals became semistuporous; about one-third died. Chronic hyponatremia in fasted mice almost tripled the plasma glucose concentrations and increased the brain carbohydrate reserve. Levels of other brain glycolytic and Krebs citric acid cycle intermediates were similar to those of controls. Severe hyponatremia and hypoosmolality induced profound decreases in levels of brain electrolytes, amino acids (especially taurine), and creatine. These changes permitted a new osmotic balance between blood and brain and a normal brain water content. The behavior and mortality of the hyponatremic animals were not different from those of the fasted control mice. Correction of hyponatremia to normonatremic levels over a 9-hr period returned brain Na+ and K+ levels to normal but the contents of the measured amino acids and creatine were still reduced one-third or more. As a result, treatment produced a significant degree of dehydration and shrinkage of the brain. The findings stress the importance of amino acids (taurine in particular) and creatine levels, as well as electrolytes, in brain osmoregulation and suggest a role for an osmotic disequilibrium--blood osmolality higher than brain--in the production of brain lesions following rapid correction of chronic hyponatremia in animals and possibly in humans. Replenishment of depleted brain K+ and amino acid levels, as well as slow elevation of the chronically depressed level of plasma Na+, is recommended.