Altered Sodium Homeostasis Research Articles

What can 7T sodium MRI tell us about cellular energy depletion and neurotransmission in Alzheimer's disease?

The pathophysiological processes underlying the development and progression of Alzheimer's disease (AD) on the neuronal level are still unclear. Previous research has hinted at metabolic energy deficits and altered sodium homeostasis with impaired neuronal function as a potential metabolic marker relevant for neurotransmission in AD. Using sodium (23 Na) magnetic resonance (MR) imaging on an ultra-high-field 7 Tesla MR scanner, we found increased cerebral tissue sodium concentration (TSC) in 17 biomarker-defined AD patients compared to 22 age-matched control subjects in vivo. TSC was highly discriminative between controls and early AD stages and was predictive for cognitive state, and associated with regional tau load assessed with flortaucipir-positron emission tomography as a possible mediator of TSC-associated neurodegeneration. TSC could therefore serve as a non-invasive, stage-dependent, metabolic imaging marker. Setting a focus on cellular metabolism and potentially disturbed interneuronal communication due to energy-dependent altered cell homeostasis could hamper progressive cognitive decline by targeting these processes in future interventions.

Onco-hypertension: Overview of hypertension with anti-cancer agents

Onco-hypertension is an emerging field investigating the relationship between hypertension and cancer. This paper details one part of this relationship—the effect of anti-cancer agents on blood pressure. We review the evidence linking targeted therapies, immunotherapy, traditional chemotherapies, and hormonal agents with hypertension. Proposed pathophysiological mechanisms vary by drug but include endothelial dysfunction, altered sodium homeostasis, and nephrotoxicity. Despite growing interest in the field, there is a paucity of data on the clinical significance of treatment related hypertension and the optimal management strategy. This should be a focus of future studies.

Regulation of CSF and Brain Tissue Sodium Levels by the Blood-CSF and Blood-Brain Barriers During Migraine

Cerebrospinal fluid (CSF) and brain tissue sodium levels increase during migraine. However, little is known regarding the underlying mechanisms of sodium homeostasis disturbance in the brain during the onset and propagation of migraine. Exploring the cause of sodium dysregulation in the brain is important, since correction of the altered sodium homeostasis could potentially treat migraine. Under the hypothesis that disturbances in sodium transport mechanisms at the blood-CSF barrier (BCSFB) and/or the blood-brain barrier (BBB) are the underlying cause of the elevated CSF and brain tissue sodium levels during migraines, we developed a mechanistic, differential equation model of a rat's brain to compare the significance of the BCSFB and the BBB in controlling CSF and brain tissue sodium levels. The model includes the ventricular system, subarachnoid space, brain tissue and blood. Sodium transport from blood to CSF across the BCSFB, and from blood to brain tissue across the BBB were modeled by influx permeability coefficients PBCSFB and PBBB, respectively, while sodium movement from CSF into blood across the BCSFB, and from brain tissue to blood across the BBB were modeled by efflux permeability coefficients and , respectively. We then performed a global sensitivity analysis to investigate the sensitivity of the ventricular CSF, subarachnoid CSF and brain tissue sodium concentrations to pathophysiological variations in PBCSFB, PBBB, and . Our results show that the ventricular CSF sodium concentration is highly influenced by perturbations of PBCSFB, and to a much lesser extent by perturbations of . Brain tissue and subarachnoid CSF sodium concentrations are more sensitive to pathophysiological variations of PBBB and than variations of PBCSFB and within 30 min of the onset of the perturbations. However, PBCSFB is the most sensitive model parameter, followed by PBBB and , in controlling brain tissue and subarachnoid CSF sodium levels within 3 h of the perturbation onset.

Severe Headache or Migraine History is Inversely Correlated With Dietary Sodium Intake: NHANES 1999-2004.

ObjectiveWe investigated whether dietary sodium intake from respondents of a national cross‐sectional nutritional study differed by history of migraine or severe headaches.BackgroundSeveral lines of evidence support a disruption of sodium homeostasis in migraine.DesignOur analysis population was 8819 adults in the 1999–2004 National Health and Nutrition Examination Survey (NHANES) with reliable data on diet and headache history. We classified respondents who reported a history of migraine or severe headaches as having probable history of migraine. To reduce the diagnostic conflict from medication overuse headache, we excluded respondents who reported taking analgesic medications. Dietary sodium intake was measured using validated estimates of self‐reported total grams of daily sodium consumption and was analyzed as the residual value from the linear regression of total grams of sodium on total calories. Multivariable logistic regression that accounted for the stratified, multistage probability cluster sampling design of NHANES was used to analyze the relationship between migraine and dietary sodium.ResultsOdds of probable migraine history decreased with increasing dietary sodium intake (odds ratio = 0.93, 95% confidence interval = 0.87, 1.00, P = .0455). This relationship was maintained after adjusting for age, sex, and body mass index (BMI) with slightly reduced significance (P = .0505). In women, this inverse relationship was limited to those with lower BMI (P = .007), while in men the relationship did not differ by BMI. We likely excluded some migraineurs by omitting frequent analgesic users; however, a sensitivity analysis suggested little effect from this exclusion.ConclusionsThis study is the first evidence of an inverse relationship between migraine and dietary sodium intake. These results are consistent with altered sodium homeostasis in migraine and our hypothesis that dietary sodium may affect brain extracellular fluid sodium concentrations and neuronal excitability.

Apoptotic microtubules delimit an active caspase free area in the cellular cortex during the execution phase of apoptosis

Apoptotic microtubule network (AMN) is organized during apoptosis, forming a cortical structure beneath plasma membrane, which has an important role in preserving cell morphology and plasma membrane permeability. The aim of this study was to examine the role of AMN in maintaining plasma membrane integrity during the execution phase of apoptosis. We demonstrated in camptothecin-induced apoptosis in H460 cells that AMN delimits an active caspase free area beneath plasma membrane that permits the preservation of cellular cortex and transmembrane proteins. AMN depolymerization in apoptotic cells by a short exposure to colchicine allowed active caspases to reach the cellular cortex and cleave many key proteins involved in plasma membrane structural support, cell adhesion and ionic homeostasis. Cleavage of cellular cortex and plasma membrane proteins, such as α-spectrin, paxilin, focal adhesion kinase (FAK), E-cadherin and integrin subunit β4 was associated with cell collapse and cell detachment. Otherwise, cleavage-mediated inactivation of calcium ATPase pump (PMCA-4) and Na+/Ca2+ exchanger (NCX) involved in cell calcium extrusion resulted in calcium overload. Furthermore, cleavage of Na+/K+ pump subunit β was associated with altered sodium homeostasis. Cleavage of cell cortex and plasma membrane proteins in apoptotic cells after AMN depolymerization increased plasma permeability, ionic imbalance and bioenergetic collapse, leading apoptotic cells to secondary necrosis. The essential role of caspase-mediated cleavage in this process was demonstrated because the concomitant addition of colchicine that induces AMN depolymerization and the pan-caspase inhibitor z-VAD avoided the cleavage of cortical and plasma membrane proteins and prevented apoptotic cells to undergo secondary necrosis. Furthermore, the presence of AMN was also critical for proper phosphatidylserine externalization and apoptotic cell clearance by macrophages. These results indicate that AMN is essential to preserve an active caspase free area in the cellular cortex of apoptotic cells that allows plasma membrane integrity during the execution phase of apoptosis.

Role of [Na+]i and the emerging involvement of the late sodium current in the pathophysiology of cardiovascular disease

In recent years, it has become increasingly clear that, as well as abnormal intracellular calcium handling, changes in intracellular sodium homeostasis play an important role in the pathophysiology of heart failure. One key source of altered sodium homeostasis may be the slow inactivating sodium current. Altered intracellular sodium promotes alterations in intracellular calcium mainly through the sarcolemmal Na+/Ca2+ exchanger that can transport Ca2+ vs. Na+ in both directions. Changes in both calcium and sodium handling are the main factors associated with cardiac dysfunction and the propensity for cardiac arrhythmias. This article gives insight into the mechanisms involved in the pathophysiology of sodium homeostasis in heart failure.

More on the sodium saga.

The relationship between sodium (salt) intake and blood pressure has been convincingly established by epidemiological, observational, interventional, physiological, and some genetic evidence for some time. Yet the interaction remains the subject of passionate and heated debate. Even among those who are convinced of the salt–blood pressure interaction, some advocate a population-wide attempt to reduce dietary salt intake, arguing on the basis of epidemiological and interventional evidence, and others who suggest that such interventions should be targeted toward those most likely to benefit: the “salt-sensitive” subpopulation. Studies have characterized such subgroups on the basis of higher blood pressure, increased age or African-American ethnicity.1 The issue is rendered even more compelling by the findings that salt sensitivity can be identified among “normotensive” subjects (ie, those with blood pressure <140/90) as well as those with hypertension1 and the designation of those with blood pressure levels between 120 and 139 mm Hg systolic and 80 and 89 diastolic as prehypertensive2 and at increased risk for development of fixed hypertension and for cardiovascular events compared with those with lower blood pressure.3 Observational data have provided a starting point for the quantitative considerations of dietary salt intake. The most recent (1999–2000) NHANES survey provides an estimated dietary sodium intake based on food records, excluding discretionary sodium, of 135 to 204 mmol per day for men and 100 to 135 mmol per day for women in the United States.4 Questionnaires are acknowledged to underestimate actual intake, and urinary sodium excretion has been shown to provide a more accurate index of total sodium intake because it represents ≈93% of intake at steady-state conditions.5 A recent British survey reported that urinary sodium excretion averaged 187 mmol per day for men and 139 mmol per day for women.5 This was very similar to …

Low-renin hypertension, altered sodium homeostasis, and an alpha-adducin polymorphism.

Defining the genetic basis of common forms of human essential hypertension is most informative when correlated with physiological mechanisms that underlie blood pressure regulation. A polymorphism of the alpha-adducin gene as been associated with elevated blood pressure in the rat, but previous studies of the 460Trp polymorphism of the human alpha-adducin gene have not clearly identified an association with hypertension. In this study, the frequency of the 460Trp allele was 19% and 9 of 279 subjects (3.2%) were homozygous for the 460Trp allele. The systolic blood pressure response to changes in dietary sodium was significantly greater in subjects homozygous for the 460Trp allele (25 +/- 4 mm Hg) compared with subjects heterozygous for 460Trp (12 +/- 2 mm Hg) or homozygous for the 460Gly allele (14 +/- 1 mm Hg). Intracellular erythrocyte sodium content, sodium-lithium countertransport, and renal fractional excretion of sodium were significantly decreased in subjects homozygous for the 460Trp polymorphism (P<0.05). There was a significant association between homozygosity for the 460Trp allele and low-renin hypertension. Subjects heterozygous for the 460Trp allele did not have increased salt-sensitivity or an increased frequency of low-renin hypertension. Therefore, this study demonstrates a common genetic basis for altered cellular sodium homeostasis, impaired renal sodium handling, and salt-sensitivity of systolic blood pressure in individuals homozygous for the 460Trp polymorphism of the alpha-adducin gene. Homozygosity for this alpha-adducin allele may be an important determinant for approximately 10% of individuals with low-renin hypertension.

Sodium-lithium countertransport in children with nephrotic syndrome.

The mechanisms of sodium retention in edema-forming minimal change nephrotic syndrome (MCNS) have not been completely evaluated. The aim of this study was to characterize the transmembrane sodium transport in nephrotic syndrome by measuring the erythrocyte sodium-lithium countertransport (SLC) in vitro. Eighteen children with MCNS were studied in the edema-forming state, and subsequently at the beginning of remission. Nephrotic children with edema retained sodium (10+/-12 micromol/day) and had a higher SLC [426+/-118 vs. 281+/-60 micromol/l red blood cells (RBC) per hour, P=0.003). The intracellular sodium concentration of nephrotics was 6.1+/-2.1 mmol/l RBC, which did not differ from that of controls (6.42+/-2.24, n=13). In remission sodium balance became negative (-30+/-21 mmol/day), and the SLC decreased but still differed significantly from control values (P=0.009). The intracellular sodium content decreased to 4.4+/-0.9 mmol/l RBC (P=0.002). There was a negative correlation between erythrocyte SLC and plasma albumin concentration (r=0.48, P=0.003), and urinary sodium excretion rate (r=0.66, P=0.001). In conclusion, erythrocyte SLC is high in the edema-forming state of childhood nephrotic syndrome and decreases with the onset of remission. A role for the SLC in the altered sodium homeostasis of nephrotic syndrome is suggested.

Sustained volume expansion and [Na,K]ATPase inhibition in chronic renal failure.

Hypotheses regarding the pathogenesis of volume-dependent hypertension have invoked an endogenous sodium pump inhibitor or digitalis-like factor (DLF) to link altered sodium homeostasis to the rise in blood pressure. Our goal was to develop a clinical protocol that achieved predictable, sustained volume expansion, with the premise that renal failure patients on peritoneal dialysis would increase intravascular volume, gain weight, and raise blood pressure (BP) in relation to measured increases in DLF. In a 5-day protocol, dialysis was kept constant but dietary NaCl and fluids were modified in 7 patients. DLF was measured as inhibition of [Na,K]ATPase. Likewise, the first 2 L of daily peritoneal dialysate (PD) was processed on HPLC and the eluate analyzed for DLF. The group achieved significant weight gain (WT) by day 3 (delta WT = 4.1 +/- 1.2 kg, P < .05). Likewise, mean arterial pressure (MAP) and plasma DLF activity increased significantly. All variables were highly correlated (DLF v WT: R = 0.88, P = .004; MAP v DLF: R = 0.82, P = .01; MAP v WT: R = 0.90, P = .003). Although a number of HPLC fractions contained agents that interacted with the assay, only one PD HPLC fraction (at 19.5 min) contained DLF activity that correlated with changes in MAP (R = 0.60, P = .002), and body weight (R = 0.67, P = .0003). We conclude that candidate DLF responds to sustained volume expansion and the relationship suggests that it could influence blood pressure. Moreover, the application of stringent criteria to the confusing array of factors in plasma that may affect assays for DLF appears to reduce the field dramatically, to a single candidate in this setting.

Independent effects of hyperinsulinemia and hyperglycemia on intracellular sodium in normal human red cells.

To study the contribution of glucose vis-à-vis insulin in the altered sodium homeostasis of diabetes mellitus, we utilized 23Na-NMR spectroscopy to noninvasively measure intracellular sodium (Nai) in red blood cells of non-diabetic, thin, normotensive subjects (n = 9), before and 60, 120, and 180 min after in vitro incubation with elevated glucose (15 mmol/L) and insulin (200 mumol/L) concentrations. Hyperglycemia caused a significant rise in Nai compared to basal values at 60 (9.1 +/- 0.8 to 9.7 +/- 0.8 mEq/L, P < .05), and 120 min (10.0 +/- 0.7 mEq/L, P < .05 v basal). Hyperinsulinemia induced a more pronounced and prolonged elevation of Nai. Significant elevations occurred at 60 (8.0 +/- 0.5 to 10.2 +/- 0.7 mEq/L, P < .05), 120 (10.5 +/- 1.1) mEq/L, P < .05 v basal), and 180 (9.1 +/- 0.5 mEq/L, P < .05 v basal) minutes. Thus, both hyperinsulinemia, and to a lesser extent, hyperglycemia cause intracellular sodium accumulation in normal human red cells. Since glucose transport in red cells is not insulin-dependent, insulin and glucose presumably exert their effects independently. Altogether, we suggest that these insulin- and glucose-mediated effects on cellular sodium, if present in other tissues as well, may underlie the increased total body sodium and the salt-dependent hypertension characteristic of chronic diabetic or hyperinsulinemic syndromes.

Role of atrial natriuretic peptide in sodium homeostasis in premature infants

To examine the possible involvement of atrial natriuretic peptide (ANP) in sodium homeostasis in premature infants, two groups of low birth weight infants with different dietary sodium regimens were studied. Sodium balance and plasma concentration of ANP were measured at weekly intervals for 5 weeks. At 1 week of age the study was started by dividing infants into two groups, group 1 with low and group 2 with increased sodium intake. Mean plasma concentrations of ANP were 47.7 +/- 7.6 and 51.4 +/- 9.5 fmol/ml, respectively. A steady decrease in plasma ANP concentration to 18.8 +/- 2.9 fmol/ml was observed in infants with sodium intake 1.5 mmol/kg/d (group 1), which was related to the decrease in serum sodium concentration in this group. In contrast, supplementation with NaCl 4.6 mmol/kg/d (group 2) was associated with a 30% increase in plasma ANP concentration, significantly different (P less than 0.025) from that in infants not given supplement, and was also higher than the values in full-term neonates. Our data suggest that altered sodium homeostasis induces regulatory changes in plasma ANP levels. ANP may provide a sensitive and important hormonal system for the control of sodium balance, even in premature neonates.