Tryptophan catabolism to serotonin and kynurenine in women undergoing in-vitro fertilization.

This cross-sectional clinical study was designed to explore the impact of tryptophan-kynurenine and tryptophan-serotonin (5 HT) pathways on reproductive performance during in vitro fertilization (IVF). Paired serum and follicular fluid (FF) samples were obtained from 64 consecutive IVF patients. The analysis was done by using LC-MS/MS. Ovarian hyperstimulation resulted in decreased serum tryptophan (p<0.004), 5-HT (p<0.049) and kynurenine (p<0.001). FF levels of tryptophan (R=0.245, p<0.051), kynurenine (R=0.556, p<0.001) and 5-HT (R=0.523, p<0.001) were positively related to their respective serum levels. Clinical pregnancy was associated with higher serum 5-HT (p<0.045) and FF 5-HT (p<0.020) and lower kynurenine to 5-HT ratio (p<0.024). Chemical pregnancy was also positively related to FF 5-HT (R=0.362, p<0.024). Moreover, there was a direct relationship of the number of mature oocytes to the FF 5-HT (R=0.363, p<0.020) but it was inversely related to FF tryptophan to 5-HT and FF kynurenine to 5-HT ratios (R=-0.389, p<0.016 and R=-0.337, p<0.036, respectively). Multivariate logistic regression revealed that the number of mature oocytes was significantly influenced by FF 5-HT (?=0.473, p<0.001). In IVF patients ovarian hyperstimulation results in a reduction of the availability of tryptophan to catabolic pathways to kynurenine and 5-HT. Outcome measures improved significantly when 5-HT predominated over kynurenine.

Pro- and anti-inflammatory factors, vascular stiffness and outcomes in chronic hemodialysis patients.

OBJECTIVE: In this observational study we addressed accelerated arteriosclerosis (AS) in patients with chronic renal failure (CRF) on hemodialysis (HD) by measuring vascular stiffness (VS) parameters and attempted to relate them to pro-inflammatory and protective factors. PATIENTS: 96 consecutive patients receiving regular HD were included. 20 adult patients without major renal, cardiovascular or metabolic morbidities served as controls. METHODS: AS parameters (carotid-femoral pulse wave velocity - PWV, aortic augmentation index - Aix) were measured by using applanation tonometry (SphygmoCor, AtCor Medical, Sidney). In addition to routine laboratory tests 25(OH) vitamin D3 (vitamin D3) and high-sensitivity C-reactive protein (hsCRP) were quantified by immunometric assay; whereas fetuin-A, α-Klotho, tumor necrosis factor-α (TNF-α) and transforming growth factor-ß1 (TGF-ß1) were determined by ELISA. RESULTS: Pro-inflammatory biomarkers (hsCRP, TNF-α and TGF-ß1) were markedly elevated (P < 0.01), while anti-inflammatory factors (fetuin-A: P < 0.05, α-Klotho: P < 0.01, vitamin D3: P < 0.01) significantly depressed in HD patients when compared to controls. PWV was significantly affected only by total cholesterol, fetuin-A and dialysis time. Multiple linear regression analyses revealed that several clinical and laboratory parameters were associated with pro- and anti-inflammatory biomarkers rather than VS. The impact of baseline clinical and biochemical variables on outcome measures were also analyzed after three-year follow-up, and it was demonstrated that low levels of vitamin D, α-Klotho protein and fetuin-A were related to adverse cardiovascular outcomes, whereas all-cause mortality was associated with elevated hsCRP and depressed vitamin D. CONCLUSIONS: Our results provide additional information on the pathomechanism of accelerated AS in patients with CRF, and documented direct influence of pro- and anti-inflammatory biomarkers on major outcome measures.

The contribution of skin glycosaminoglycans to the regulation of sodium homeostasis in rats.

The glycosaminoglycan (GAG) molecules are a group of high molecular weight, negatively charged polysaccharides present abundantly in the mammalian organism. By their virtue of ion and water binding capacity, they may affect the redistribution of body fluids and ultimately the blood pressure. Data from the literature suggests that the mitogens Vascular Endothelial Growth Factor (VEGF)-A and VEGF-C are able to regulate the amount and charge density of GAGs and their detachment from the cell surface. Based on these findings we investigated the relationship between the level of dietary sodium intake, the expression levels of VEGF-A and VEGF-C, and the amount of the skin GAGs hyaluronic acid and chondroitin sulfate in an in vivo rat model. Significant correlation between dietary sodium intake, skin sodium levels and GAG content was found. We confirmed the GAG synthesizing role of VEGF-C but failed to prove that GAGs are degraded by VEGF-A. No significant difference in blood pressure was registered between the different dietary groups. A quotient calculated form the ion and water content of the skin tissue samples suggests that - in contrast to previous findings - the osmotically inactive ions and bound water fractions are proportional.

Selective association of endogenous ouabain with subclinical organ damage in treated hypertensive patients.

According to previous studies endogenous ouabain (EO) closely correlates with high blood pressure, congestive heart failure and kidney disease in humans. Our aims were to analyse associations between plasma, urinary EO level and various markers of cardiovascular damage in treated hypertensive patients. Forty-one adult patients with hypertension and/or diabetes mellitus (DM) and/or chronic kidney disease (CKD) were studied. We assessed plasma and urinary EO, pro-brain natriuretic peptide and catecholamines, profile of ambulatory blood pressure monitor and cardiovascular status by echocardiography and echo-tracking. The highest level of plasma EO (19.7±9.5 pmol l⁻¹) was measured in hypertensive patients with DM and CKD. The nighttime mean arterial blood pressure independently correlated with the level of plasma EO (P=0.004), while independent predictor of the ß-stiffness of carotid artery was the urinary EO (P=0.011). Elevated level of EO was associated with nighttime blood pressure and subclinical organ damage in treated hypertensive patients, suggesting possible role of EO in the pathogenesis of impaired diurnal blood pressure rhythm and arterial stiffness.

Negative association of L-arginine methylation products with oocyte numbers.

BACKGROUND: The aim of this study was to determine the concentrations of L-arginine and methylarginines in follicular fluid obtained from women participating in our IVF program and to find clinical correlates of these biochemical parameters. METHODS: Follicular fluid was obtained from 108 women by ultrasonography guided transvaginal puncture following controlled ovarian hyperstimulation. Follicular fluid L-arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and monomethylarginine (MMA) concentrations were determined with liquid chromatography-tandem mass spectrometry. The integrated index of arginine methylation (arg-MI) was calculated according to the formula: arg-MI = (ADMA + SDMA)/MMA. RESULTS: There were significant inverse relationships between IVF embryo number and follicular fluid L-arginine (r = -0.507, P < 0.001), ADMA (r = -0.356, P < 0.024), SDMA (r = -0.347, P < 0.028), MMA (r = -0.449, P < 0.004) and to L-arginine/ADMA ratio (r = -0.328, P < 0.031). By contrast, arg-MI was directly related to IVF embryo number (r = 0.426, P < 0.006). Moreover, the number of IVF oocytes was also inversely related to ADMA (r = -0.202, P < 0.037) and MMA (r = -0.384, P < 0.012) and positively to arg-MI (r = 0.450, P < 0.03). CONCLUSIONS: The elevated levels of follicular fluid l-arginine and methylarginines appear to have an adverse influence on the reproductive processes as reflected by a reduction in the number of oocytes and embryos conceived. In contrast, the integrated methylation index proved to be positively correlated to the above parameters of fertilization.

L-carnitine supplementation and adipokines in patients with end-stage renal disease on regular hemodialysis.

Chronic hemodialysis (HD) patients frequently encounter carnitine depletion, elevated adipose tissue-derived hormones/cytokines, that may contribute to accelerated arteriosclerosis. 10 non-diabetic HD patients were studied over 28 weeks. In the 12 weeks treatment period 1 g L-carnitine was given iv after each HD session. Measurements of plasma free- and acylcarnitines, insulin, leptin, adiponectin, resistin and ghrelin were performed at baseline, at weeks 2, 4, 8, 12 (treatment period) and at weeks 24-28 (post-treatment period). L-carnitine supplementation resulted in progressive increase of free- and acylcarnitine levels. Plasma levels of insulin, resistin, leptin and ghrelin remained at the already elevated baseline values. L-carnitine therapy induced a significant increase in plasma adiponectin from 20.2 ± 12.7 µg/ml (baseline) to 32.7 ± 20.2 µg/ml in week 2 (p<0.05) and 35.4 ± 19.6 µg/ml in week 12 (p < 0.03), which remained unchanged in the post-carnitine period. Plasma insulin levels correlated positively with leptin (r = 0.525, p<0.0001) and resistin (r = 0.284, p<0.005); adiponectin levels correlated inversely with leptin (r = -0.255, p<0.02) and resistin (r = -0.213, p<0.04) irrespective of carnitine status. Plasma levels of adipokines and related hormones are greatly elevated in patients on regular HD. L-carnitine administration further augmented the plasma levels of protective adiponectin, therefore it may have a role in preventing cardiovascular complications of uremia.

Physical water compartments: a revised concept of perinatal body water physiology.

This review presents experimental data on the perinatal significance of the recently developed concept of physical water compartments. This concept implies that in addition to the compartmentalization of body water into the intra- and extracellular spaces, motionally distinct water fractions - designated as physical water compartments - are also of importance in the neonatal body fluid redistribution. H(1)-NMR spectroscopy provides a quantitative estimate of tissue water fractions with different mobility as multicomponent analysis of the T(2) relaxation decay curves allows us to determine the fast and slow relaxing components of the curves corresponding to the bound and free fractions of tissue water. Using this method, free and bound water fractions were measured in fetal and neonatal rabbit tissues (skin, skeletal muscle, liver, brain, lung) at different stages of maturity and under conditions of various fluid intake. It has been demonstrated that water mobility in individual fetal/neonatal tissues varies greatly and there is a general tendency of increasing free water at the expense of bound water fraction with progressing maturation. This tendency appears to be accelerated in the immediate postnatal period when the tissue water content is markedly reduced. The importance of hyaluronan in this process has also been addressed as the hyaluronan content is markedly elevated in the fetal/neonatal tissues and due to its polyanionic, hydrophilic nature it has been claimed to play a prominent but not clearly defined role in the control of tissue hydration.

Hyaluronan-related limited concentration by the immature kidney.

The limited renal concentration performance by the immature kidney traditionally is thought to be attributed to blunted renal response to arginine vasopressin (AVP) and medullary hypotonicity. The diminished AVP-dependent osmotic water permeability of the collecting duct is the result of decreased AVP binding and adenylate cyclase activation, and low expression of aquaporin-2 (AQP2) mRNA and low levels of AQP2 protein. Moreover, the immature kidney fails to establish deep cortico-papillary osmotic gradient because of structural immaturity, limited solute transport and increased medullary blood flow. Based on indirect clinical and experimental evidences this article puts forward a hypothesis that during perinatal period the abundant hyaluronan (HA) content in the renomedullary interstitium has a primary role in antagonizing water reabsorption and limiting concentration performance. Hydration-related alterations in renal HA appears to be mediated by antidiuretic hormone. The concept of HA-mediated renal water transport may imply that interfering selectively with renal HA metabolism may provide a new therapeutic approach to promote diuresis or antidiuresis, respectively, according to the elevation or reduction in renomedullary HA.

Studies of mdx mice.

Cerebral water accumulation-clinically denoted as brain edema-is a potentially life threatening complication of almost every intracranial neuropathological state. The molecular membrane water channel aquaporin-4 (AQP4) has been shown to be present at the blood-brain barrier (BBB) where it plays pivotal role in the transport of water between the tissue water compartments of the brain. Accumulating evidence indicates that the blockade of AQP4 function at the BBB would be a new therapeutic approach to the treatment and prevention of brain swelling. The cytoskeletal protein dystrophin has been shown to be involved in the maintenance of the polarized expression of AQP4 at the BBB. In order to further elucidate the mechanisms responsible for the highly polarized AQP4 expression, we studied brain tissue water accumulation during induction of brain edema in dystrophin-null transgenic mice (mdx-bgeo) and control mice. Immunofluorescence and immunoelectron microscopic analyses of dystrophin-null brains revealed a dramatic reduction of AQP4 in astroglial end-feet surrounding capillaries (BBB) and at the glia limitans (cerebrospinal fluid-brain interface). The AQP4 protein is mislocalized, because immunoblotting showed that the total AQP4 protein abundance was unaltered. Brain edema was induced by i.p. injection of distilled water and 8-deamino-arginine vasopressin. Changes in cerebral water compartments were assessed by diffusion-weighted MRI (DWI) with determination of the apparent diffusion coefficient (ADC). In dystrophin-null mice and control mice, ADC gradually decreased by 5-6% from baseline levels during the first 35 min, indicating the initial phase of intracellular water accumulation is similar in the two groups. At this point, the control mice sustained an abrupt, rapid decline in ADC to 58%+/-2.2% of the baseline at 52.5 min, and all of the animals were dead by 56 min. After a consistent delay, the dystrophin-null mice sustained a similar decline in ADC to 55%+/-3.4% at 66.5 min, when all of the mice were dead. These results demonstrate that dystrophin is necessary for polarized distribution of AQP4 protein in brain where facilitated movements of water occur across the BBB and cerebrospinal fluid-brain interface. Moreover, these results predict that interference with the subcellular localization of AQP4 may have therapeutic potential for delaying the onset of impending brain edema.

Urinary aquaporin-2 excretion in preterm and full-term neonates.

The study was undertaken to define the role of aquaporin-2 (AQP2) in renal concentrating performance by measuring urinary AQP2 excretion and urine osmolality in healthy preterm and full-term neonates during early postnatal life. Random urine samples were obtained from 9 full-term newborn infants (mean birth weight 3,218 g, mean gestational age 39.2 weeks) at postnatal ages of 1, 3 and 5 days. Five premature infants with a mean birth weight of 1,570 g and mean gestational age of 30.6 weeks were studied at the end of the 1st week and then weekly up to the 6th week. Urine osmolality (Knauer osmometer), creatinine (modified Jaffé's method) and AQP2 concentrations (radioimmunoassay) were measured. In full-term neonates, urinary AQP2 excretion showed no consistent changes over the age period studied, while urine osmolality decreased significantly with advancing age. In premature infants, urinary AQP2 excretion remained practically unchanged during the first 4 weeks followed by an abrupt increase thereafter. Urine osmolality did not follow the developmental pattern of AQP2 excretion; its mean values varied only from 78 +/- 39 to 174 +/- 146 mosm/l during the experimental period. It is concluded that during the early postnatal period, urinary AQP2 excretion does not serve as a direct marker of the renal action of AVP and the renal capacity to concentrate urine.

Effects of centrally administered arginine vasopressin and atrial natriuretic peptide on the development of brain edema in hyponatremic rats.

OBJECTIVE: Centrally released arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) have been shown to participate in brain volume regulation. The aim of the present study was to evaluate the effects of centrally administered AVP and ANP on the time course of development of brain edema in vivo in hyponatremic rats, using diffusion-weighted magnetic resonance imaging. METHODS: We performed intracerebroventricular (ICV) administration of 120 microg AVP, 20 microg ANP, or physiological saline into the right lateral ventricle in 18 rats. Twenty-five minutes after the treatment, we induced systemic hyponatremia by the intraperitoneal administration of 140 mmol/L dextrose solution. Serial diffusion-weighted imaging scans were obtained up to 96 minutes after the start of the hyponatremia. Changes in the brain extra-to intracellular volume fraction ratio were estimated as changes in the apparent diffusion coefficient (ADC). RESULTS: No change in the ADC was observed after the ICV injection of saline or AVP. The onset of hyponatremia induced a rapid and marked ADC reduction in both groups, indicating an increased intracellular space. However, the ADC decrease became significantly more pronounced in the ICV AVP group (83.3+/-4.7% of baseline level, mean +/- standard deviation) than in the saline group (93.7+/-3.3% of baseline, P < 0.001) after 78 minutes of hyponatremia. The ICV injection of ANP induced a prompt ADC increase to 111.5+/-10.0% (P < 0.05) of the baseline level, indicating a rapid reduction in the intracellular compartment. In the initial phase of hyponatremia, the ADC values in the ANP group were consistently higher than those in the saline group, decreasing finally to 86.9+/-9.6% after 96 minutes of hyponatremia. CONCLUSION: Our findings demonstrate the opposite effects of AVP and ANP on the intracellular volume fraction of the brain during the development of cellular brain edema, with an immediate effect on ANP and a delayed effect on AVP. The results emphasize the direct effects of these hormones on the cellular volume regulatory mechanisms in the brain during the development of cerebral edema.

Natriuresis of fasting: the possible role of leptin-neuropeptide Y system.

We developed a new hypothesis claiming that natriuresis of fasting is not only caused by diminished insulin resistance and hyperinsulinaemia with the subsequent reduction of renal sodium retention but it can also be attributed to the function of the leptin-NPY system. Each element of this concept has been substantiated by convincing experimental evidences as follows:1. Leptin, the adipocyte-derived peptide hormone conveys information to the central nervous system about the size of body energy stores and it reciprocally regulates the hypothalamic expression of NPY, the major mediator of its metabolic and neuroendocrine actions.2. NPY has been demonstrated to be intimately involved in the regulation of renal functions; under various experimental conditions it increased urine flow rate and urinary sodium excretion presumably through stimulating the synthesis and/or release of other natriuretic factors.3. Fasting-induced suppression of tissue expression of leptin mRNA and circulating plasma leptin levels is associated with simultaneous activation of NPY system.4. This sequence of events implies that NPY contributes to natriuresis that occurs in response to fasting.

[Aquaporins in cerebral volume regulation and edema formation]. / Aquaporinok az agyi térfogat-szabályozásban és az agyödéma kialakulásában.

Regulation of tissue water content and brain volume is of critical importance for the normal functioning of the central nervous system (CNS), which, surrounded by the rigid cranium, is highly sensitive to any increase in the intracranial pressure. Alterations in cerebral water homeostasis and distribution may lead to neuronal and glial swelling known as cytotoxic brain edema, due to accumulation of intracellular water. Although numerous investigations have been performed to elucidate the underlying molecular basis and pathophysiology of brain edema, little is known about the regulation of water transport across the blood-brain barrier and between extra- and intracellular compartments of the brain parenchyma. The discovery and characterization of the aquaporin (AQP) family of membrane water channels provided molecular insight into fundamental processes of water transport across plasma membranes. Two AQPs are expressed abundantly in the mammalian brain: AQP1 in the apical plasma membranes of the cells of choroid plexus in the ventricles, where it has been suggested to participate in the secretion of cerebrospinal fluid and AQP4 in plasma membranes of ependymal cells and astrocytes. The role of AQP4 in the formation of brain oedema was suggested by some recent studies. These findings offer new potentials in brain oedema treatment.

Hyponatremia and sensorineural hearing loss in preterm infants.

In a case-control study the role of hyponatremia in the hearing loss of preterm infants was investigated. One hundred and sixty-four premature infants treated at the neonatal intensive care unit were screened with transient evoked otoacoustic emission (TEAOE). In 32 infants TEAOE results indicated the need for further investigations. Auditory brainstem response was performed and 22 of 32 cases had bilateral hearing impairment (HI). The birth weight and gestational age in the HI group were 1,425 +/- 528 g and 30.4 +/- 3.7 weeks. The matched control group consisted of 25 infants with a mean birth weight and gestational age of 1,410 +/- 280 g and 31.1 +/- 2.1 weeks. Significant differences were found between the HI and control groups: Apgar score (p < 0.05), pH value (p < 0.01) and pO(2) level (p < 0.05) were lower; the total dose of aminoglycosides (p < 0.01), furosemide usage (p < 0.01), the maximum pCO(2) level (p < 0.01), incubator stay (p < 0.05) and hyponatremia (p < 0.01) were higher, and the duration of hyponatremia (p < 0.05) was longer in the HI group. Multivariate logistic regression revealed that aminoglycoside treatment and hyponatremia were the two most significant factors in the development of hearing impairment. These results suggest that hyponatraemia is an additional risk factor for hearing loss in preterm infants.

Brain water and proton magnetic resonance relaxation in preterm and term rabbit pups: their relation to tissue hyaluronan.

The present study was performed to investigate simultaneously total brain water, T1 and T2 relaxation times, and hyaluronan (HA) in fetal and neonatal rabbits. Attempts were also made to establish the relationship of HA to total brain water and to T2-derived motionally distinct water fractions, since HA is known to bind water and to limit tissue water mobility. Experiments were carried out in fetal Pannon white rabbit pups at gestational ages of 25, 27, 29, and 31 days and at a postnatal age of 4 days. The brain tissue water content (desiccation method), T1 and T2 relaxation times (H1-NMR method), and HA concentration (radioassay HA 50) were measured, and free and bound water fractions were calculated by using multicomponent fits of the T2 relaxation curves. Compared with values in newborn pups, water and HA contents were found to be highly elevated in the preterm brain and decreased markedly during early postnatal life. The trends and time courses of T1 and T2 relaxation times proved to be similar, but the postnatal decrease in T2 was preceded by a significant decline in late gestation. Maturity-related changes occurred in the T2 relaxation derived bound water fraction which amounted to 4-19% of brain water. The bound water fraction appeared to be independent of total brain water and HA concentration, and HA is, therefore, unlikely to be the only factor controlling brain water mobility. The clear dissociation of bound water fraction from total water suggests restructuring of brain water during the perinatal period.

Lung water and proton magnetic resonance relaxation in preterm and term rabbit pups: their relation to tissue hyaluronan.

The present study was performed to investigate simultaneously total lung water, T(1) and T(2) relaxation times, and hyaluronan (HA) in preterm and term rabbits. Attempts were also made to establish the relationship of HA to total lung water and to T(2)-derived motionally distinct water fractions. Experiments were performed in fetal Pannon white rabbit pups at gestational ages of 25, 27, 29, and 31 d and at a postnatal age of 4 d. Lung tissue water content (desiccation method), T(1) and T(2) relaxation times (H(1)-NMR method), and HA concentration (radioassay) were measured, and free and bound water fractions were calculated by using multicomponent fits of the T(2) relaxation curves. Lung water content and T(1) and T(2) relaxation times were highest at a gestational age of 27 d and then declined steadily during the whole study period. Similar trends and time courses were seen for the fast and slow components of the T(2) relaxation curve. The T(2)-derived free water fraction remained unchanged at a gestational age of 25-29 d ( approximately 67%), but increased progressively to a value of 78.5 +/- 7.9% at 31 d (p < 0. 001) and to 83.4 +/- 9.4% at the postnatal age of 4 d (p < 0.01). Opposite changes occurred in the bound water fraction. Lung HA concentration decreased with advancing gestation from 870.8 +/- 205.2 microg/g dry weight at 25 d to 162.6 +/- 32.4 microg/g dry weight at 31 d (p < 0.001), but it was increased 2-fold postnatally. HA correlated positively with total lung water (r = 0.39; p < 0.001) but not with the bound water fraction. It is suggested that the physiologic lung dehydration is associated with macromolecule-related reorganization of lung water and that the role of HA in this process needs to be further investigated.

Increased aquaporin-4 immunoreactivity in rat brain in response to systemic hyponatremia.

The present study was undertaken to assess whether the protein and mRNA expression levels of the glial water channel aquaporin-4 (AQP4) undergo downregulation and whether there is a subcellular redistribution of AQP4 protein in rat brain in response to systemic hyponatremia and brain edema. Systemic hyponatremia was induced for 4 or 48 h by combined administration of hypotonic dextrose i.p. and 8-deamino-arginine vasopressin (dDAVP) s.c. Semiquantitative immunoblotting of membrane enriched fractions showed significantly increased immunoreactivity to 164 +/- 12% (n = 6) and 153 +/- 12% (n = 6) of control levels in brain after 4 or 48 h of systemic hyponatremia, respectively. Similarly, immunoblots of cerebellar samples revealed an increase in AQP4 immunoreactivity to 136 +/- 6% (n = 6) and 218 +/- 44% (n = 6) of control levels, after 4 or 48 h of hyponatremia. In contrast, AQP4 mRNA levels were unchanged after 4 h of severe hyponatremia (104 +/- 14% of control levels; n = 17), indicating that there are no changes in AQP4 expression in response to systemic hypoosmolarity. Immunocytochemistry and high-resolution immunogold electron microscopy revealed highly polarized labeling of AQP4 in astrocyte end-feet surrounding capillaries and forming the glia limitans. This pattern of labeling was not changed whereas an increased labeling intensity of AQP4 could be observed in response to hyponatremia. In conclusion, hyponatremia causes a pronounced and rapid increase in AQP4 immunoreactivity that is not accompanied by any increase in AQP4 mRNA expression. The increased AQP4 immunosignal may reflect secondary conformational modifications of AQP4 protein, leading to enhanced antibody binding. This post-translational modification of AQP4 may participate in the adaptation of cerebral tissue to systemic hyponatremia.