Figure 1. Brain Adaptation to Hypoosmolality: Schematic diagram of brain volume adaptation to hyponatremia. Under normal conditions brain osmolality and extracellular fluid (ECF) osmolality are in equilibrium (top panel; for simplicity the predominant intracellular solutes are depicted as K+ and organic osmolytes, and the extracellular solute as Na+). Following the induction of ECF hypoosmolality, water moves into the brain in response to osmotic gradients producing brain edema (middle panel, #1, dotted lines). However, in response to the induced swelling the brain rapidly loses both extracellular and intracellular solutes (middle panel, #2). As water losses accompany the losses of brain solute, the expanded brain volume then decreases back toward normal (middle panel, #3). If hypoosmolality is sustained, brain volume eventually normalizes completely and the brain becomes fully adapted to the ECF hyponatremia (bottom panel). Reproduced with permission from (1).
Experimental studies in animals over the last century have elucidated many of the physiological mechanisms underlying brain adaptation to hypoosmolality (7-9).
Following decreases in plasma osmolality, water moves into the brain along osmotic gradients, causing cerebral edema. In response, the brain loses solute from the extracellular (10) and the intracellular (7,8) fluid spaces, thereby decreasing brain water content back toward normal levels (Fig. 1). The marked variability in the presenting neurological symptoms of hyponatremic patients can be understood in the context provided by this process of brain volume regulation. Most of the neurological symptoms associated with hyponatremia are thought to reflect brain edema as a consequence of osmotic water movement into the brain (5). However, once the brain has volume-adapted through solute losses, thereby reducing brain edema, neurological symptoms will not be as prominent, and in some cases may even be totally absent (Fig. 1).
It has also long been appreciated that the rate of fall of serum [Na+] is generally more strongly correlated with morbidity and mortality than the actual magnitude of the decrease. This is due to the fact that brain volume regulation occurs over a finite period; the more rapid the fall in serum [Na+], the more water will be accumulated before the brain is able to lose solute, and with it the increased water. This temporal association explains the much higher incidence of neurological symptoms in patients with acute hyponatremia compared to those with chronic hyponatremia. It is therefore important to understand the mechanisms underlying brain volume regulation during both acute and chronic hypoosmolality.
The clinical distinction between acute and chronic hypoosmolality is somewhat arbitrary, but generally hypoosmolality is considered to be acute when it develops over 24 to 48 hours. Such patients are indeed at high risk for neurological complications, with mortality rates as high as 50% in some studies. Induction of rapid hyponatremia has similarly been shown to cause severe neurological dysfunction in rabbits, and virtually all animals so treated die with marked brain edema. In these animals, brain water content increased by an amount equivalent to the fall in their serum [Na+], and brain electrolyte contents did not decrease significantly, indicating an absence of brain volume regulation
Thus, when hypoosmolality develops at a rate that exceeds the brain's ability to regulate its volume by electrolyte losses, severe brain edema results, potentially leading to neurological dysfunction and sometimes death. It is therefore important to define the time course over which brain volume regulation can occur. This has been studied in rats by measuring brain water and electrolyte contents at various times after induction of an acute dilutional hyponatremia (10). Na+ and Cl- losses began very rapidly, generally within 30 minutes, whereas brain K+ losses were somewhat more delayed. Nonetheless, all electrolyte losses were found to be maximal by 3 hours, and they completely accounted for the degree of brain volume regulation that was achieved over this period. Although brain edema still occurred, with measured increases in brain water from 6 to 9%, the ability of the brain to lose electrolytes rapidly within several hours limited the severity of brain swelling. These results are consistent with many experimental studies in animals that have reported variable neurological symptoms and survival rates following induction of acute hyponatremia, since over short periods of time (i.e., several hours) relatively small differences in the rates of loss of electrolytes can have profound effects on the resulting brain edema and neurological dysfunction.
In contrast to acute hyponatremia, many experimental studies of chronic hyponatremia have been characterized by a relative absence of neurological symptoms and mortality. These findings suggest that more complete degrees of brain volume regulation occur after longer periods of sustained hyponatremia. Studies in rats in which hyponatremia was maintained for 21 days confirmed virtually complete normalization of brain water content (11). However, in these and other studies the measured electrolyte losses accounted for only 60 to 70% of the observed brain volume regulation, which suggested a potential contribution from losses of other brain solutes as well. Subsequent studies confirmed that brain content of most organic osmolytes also decreases markedly during induced hyponatremia in mice (12) and rats (13,14). The organic osmolytes involved in volume regulation are amino acids, methylamines, and polyols. The major organic osmolytes in the brain are glutamine, glutamate, taurine, and myoinositol. Organic osmolytes of lesser significance include several other amino acids, two methylamines glycerophosphorylcholine (GPC) and betaine], phosphocreatine/creatine, and the neurotransmitter y-aminobutyric acid (GABA). W-acetylaspartate (NAA) is included among the solutes that are lost during volume regulation, but this amino acid represents a relatively minor component of the total brain solute losses (2). Figure 2 shows the relative brain losses of organic osmolytes compared to electrolytes after 14 days of sustained hyponatremia in rats (14). Total brain electrolyte losses are larger, as expected, nonetheless the measured brain organic osmolyte losses accounted for roughly one third of the measured brain solute losses during sustained hypoosmolality. Such coordinate losses of both electrolytes and organic osmolytes from brain tissue enable very effective regulation of brain volume during chronic hyponatremia (Fig. 1). Consequently, it is now clear that cellular volume regulation in vivo occurs predominantly through depletion, rather than intracellular osmotic "inactivation," of a variety of intracellular solutes (2). Studies using NMR spectroscopy in hyponatremic patients have confirmed that similar mechanisms occur in humans with hyponatremia (15).
In addition to physiological implications for brain volume regulation, the large decrease in brain organic osmolyte contents over relatively short periods (i.e. <48 hours) has potentially important functional implications. Such relatively rapid decreases suggest the possibility that some of these losses are occurring via effluxes of intracellular osmolytes from brain cells during the process of volume regulation. This could result in transiently increased local brain extracellular fluid concentrations of organic osmolytes, which in the case of amino acids could produce significant effects on neuronal membrane potential. In particular, given the known actions of glutamate as an excitatory neurotransmitter, locally increased brain glutamate concentrations occurring at the time of the active phase of volume regulation during hyponatremia could potentially account for some of the neurological abnormalities known to occur during this period, especially the increased incidence of seizure activity (16,17). This hypothesis could also explain, at least in part, the observation that when hypoosmolality is maintained for longer periods of time, both animals and patients become less symptomatic, since increased brain neurotransmitter concentrations would likely occur only transiently during the initial development of hyponatremia and then return to more normal levels after the completion of brain volume regulation.
Taurine if Inositol Glutamine Other
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