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PubMed2005

NHE-1-dependent intracellular sodium overload in hypertrophic hereditary cardiomyopathy: prevention by NHE-1 inhibitor.

The purpose of this study was to verify whether myocardial intracellular Na(+) overload may take place in the hereditary cardiomyopathic hamster (CMH), as a result of an increased activity of the Na(+)-H(+) exchanger isoform-1 (NHE-1). Our results showed that simultaneous intracellular Na(+) and Ca(2+) overloads as well as an increase of NHE-1 protein level took place during the development of necrosis and hypertrophy in the CMH. Treatment of 30-day-old CMHs during the development of necrosis and in the absence of hypertrophy with the specific NHE-1 inhibitor EMD87580 (EMD) for 50 days significantly prevented the increase of NHE-1 protein level and intracellular Na(+) and Ca(2+) overloads as well as necrosis. Treatment of CMHs during the development of hypertrophy with EMD for 198 days prevented the development of both necrosis and hypertrophy. In conclusion, our results suggest that NHE-1 overexpression as well as Na(+) and Ca(2+) overloads do take place during the development of necrosis and hypertrophy in hereditary CMHs. Moreover, our results suggest that the blockade of NHE-1 by EMD87580 prevents these diseases by preventing the increase of Na(+) influx through the NHE-1.

Animals↗
PubMed1976

The effect of water, sodium overloading and diuretics upon urinary kallikrein.

The effects of acute administration of either water or 2% NaCl solution via a stomach tube and injections of diurecits, furosemide (5, 10 mg) and acetazoleamide (5, 20 mg per rat), in adult rats upon urinary kallikrein (Kal), Na and K, were studied. Hyperhydration with water (5% b.w.) produced in 121% increase and 2% NaCl overloading (5% b.w.) 275% increase in urinary Kal within 120 min after gavage, when compared with the excretion of non hyperhydrated rats. Furosemide 5 mg in hyperhydrated animals produced in the same period an excretion of 645 +/- 52 ng BR of Kal, which is 147% higher to that excreted by the hyperhydrated controls. The same dose of furosemide in 2% NaCl loaded rats, produced an excretion of Kal equivalent to 1333 +/- 72 ng BR which is 180% greater than in controls similarly loaded. Acetazoleamide 20 mg and furosemide 5 mg produced similar excretions of Kal even though natriuresis is greater tna kalliuresis is lesser in furosemide injected rats. Evaluation of total kidney Kal has shown that a single (10 mg) or a series of furosemide injections (8 days 5 mg + 1 day 10 mg), brings about a significant (p is less than 0.001) decrease in renal Kal, but the increase of Kal excreted in the urine (120 min) is 3.5 times more (under a single injection) and 42 times more (under 9 injections) than the amount which disappears from the kidneys. Apparently furosemide not only stimulates Kal excretion, but also Kal synthesis in the kidney. The results support the concept that the Kal system would be involved in excretory functions dealing both with sodium and water excretion.

Acetazolamide↗
PubMed2000

Sodium overload through voltage-dependent Na(+) channels induces necrosis and apoptosis of rat superior cervical ganglion cells in vitro.

Using the failure to exclude trypan blue as a criterion for cell death, we found that veratridine, the voltage-dependent Na(+) channel activator, exerted its toxicity to cultured sympathetic neurons in a dose-dependent manner (half-maximal toxicity occurred at 2 microM). The co-presence of tetrodotoxin completely reversed the toxicity only at concentrations of veratridine < 20 microM. Veratridine neurotoxicity was due to the influx of Na(+); a medium low in Na(+) (36 mM) completely abolished its neurotoxicity, whereas a Ca(2+)-free medium did not attenuate its neurotoxicity. Furthermore, the buffering action of 1, 2-Bis-(2-aminophenoxy)ethane-N,N,N',N',-tetraacetate (BAPTA) on veratridine-induced increase in intracellular Ca(2+) levels neither blocked veratridine neurotoxicity in normal medium, nor attenuated the low Na(+) effect. Elevated K(+) effectively blocked veratridine neurotoxicity in a Ca(2+)-dependent manner. Cytoplasmic pH measurements using a fluorescent pH indicator demonstrated that cellular acidification (from pH 7.0 to pH 6.5) occurred upon treatment with veratridine. Both veratridine-induced acidification and cell death were ameliorated by 5-(N-ethyl-N-isopropyl)amiloride, the specific inhibitor of the Na(+)/H(+) exchanger (IC(50) = 0.5 microM). Finally, necrosis occurred predominantly in veratridine neurotoxicity, but both staining with bis-benzimide and TUNEL analysis showed nuclear features of apoptosis in sympathetic neurons undergoing cell death.

Animals↗
PubMed1997

Role of intracellular sodium overload in the genesis of cardiac arrhythmias.

A number of clinical cardiac disorders may be associated with a rise of the intracellular Na concentration (Na(i)) in heart muscle. A clear example is digitalis toxicity, in which excessive inhibition of the Na/K pump causes the Na(i) concentration to become raised above the normal level. Especially in digitalis toxicity, but also in many other situations, the rise of Na(i) may be an important (or contributory) cause of increased cardiac arrhythmias. In this review, we consider the mechanisms by which a raised Na(i) may cause cardiac arrhythmias. First, we describe the factors that regulate Na(i), and we demonstrate that the equilibrium level of Na(i) is determined by a balance between Na entry into the cell, and Na extrusion from the cell. A number of mechanisms are responsible for Na entry into the cell, whereas the Na/K pump appears to be the main mechanism for Na extrusion. We then consider the processes by which an increased level of Nai might contribute to cardiac arrhythmias. A rise of Na(i) is well known to result in an increase of intracellular Ca, via the important and influential Na/Ca exchange mechanism in the cell membrane of cardiac muscle cells. A rise of intracellular Ca modulates the activity of a number of sarcolemmal ion channels and affects release of intracellular Ca from the sarcoplasmic reticulum, all of which might be involved in causing arrhythmia. It is possible that the increase in contractile force that results from the rise of intracellular Ca may initiate or exacerbate arrhythmia, since this will increase wall stress and energy demands in the ventricle, and an increase in wall stress may be arrhythmogenic. In addition, the rise of Na(i) is anticipated to modulate directly a number of ion channels and to affect the regulation of intracellular pH, which also may be involved in causing arrhythmia. We also present experiments in this review, carried out on the working rat heart preparation, which suggest that a rise of Na(i) causes an increase of wall stress-induced arrhythmia in this model. In addition, we have investigated the effect on wall stress-induced arrhythmia of maneuvers that might be anticipated to change intracellular Ca, and this has allowed identification of some of the factors involved in causing arrhythmia in the working rat heart.

Action Potentials↗
PubMed2006

Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazine.

Pathological conditions linked to imbalances in oxygen supply and demand (for example, ischaemia, hypoxia and heart failure) are associated with disruptions in intracellular sodium ([Na(+)](i)) and calcium ([Ca(2+)](i)) concentration homeostasis of myocardial cells. A decreased efflux or increased influx of sodium may cause cellular sodium overload. Sodium overload is followed by an increased influx of calcium through sodium-calcium exchange. Failure to maintain the homeostasis of [Na(+)](i) and [Ca(2+)](i) leads to electrical instability (arrhythmias), mechanical dysfunction (reduced contractility and increased diastolic tension) and mitochondrial dysfunction. These events increase ATP hydrolysis and decrease ATP formation and, if left uncorrected, they cause cell injury and death. The relative contributions of various pathways (sodium channels, exchangers and transporters) to the rise in [Na(+)](i) remain a matter of debate. Nevertheless, both the sodium-hydrogen exchanger and abnormal sodium channel conductance (that is, increased late sodium current (I(Na))) are likely to contribute to the rise in [Na(+)](i). The focus of this review is on the role of the late (sustained/persistent) I(Na) in the ionic disturbances associated with ischaemia/hypoxia and heart failure, the consequences of these ionic disturbances, and the cardioprotective effects of the antianginal and anti-ischaemic drug ranolazine. Ranolazine selectively inhibits late I(Na), reduces [Na(+)](i)-dependent calcium overload and attenuates the abnormalities of ventricular repolarisation and contractility that are associated with ischaemia/reperfusion and heart failure. Thus, inhibition of late I(Na) can reduce [Na(+)](i)-dependent calcium overload and its detrimental effects on myocardial function.

Acetanilides↗
PubMed2006

Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium-calcium overload.

Late sodium current in cardiac cells is very small compared with the fast component, but as it flows throughout the action potential it may make a substantial contribution to sodium loading during each cardiac cycle. Late sodium current may contribute to triggering arrhythmia in two ways: by causing repolarisation failure (early after depolarisations); and by triggering late after depolarisations attributable to calcium oscillations in sodium-calcium overload conditions. Reduction of late sodium current would therefore be expected to have therapeutic benefits, particularly in disease states such as ischaemia in which sodium-calcium overload is a major feature.

Arrhythmias, Cardiac↗
PubMed2006

Renal function in juvenile rats subjected to prenatal malnutrition and chronic salt overload.

Dietary sodium may contribute to hypertension and to cardiovascular and renal disease if a primary deficiency of the kidney to excrete sodium exists. In order to investigate whether chronic 1% NaCl in the drinking water changes blood pressure and renal haemodynamics in juvenile Wistar rats subjected to prenatal malnutrition, an evaluation of plasma volume, oxidative stress in the kidney, proteinuria and renal haemodynamics was carried out. Malnutrition was induced by a multideficient diet. Mean arterial pressure, renal blood flow and glomerular filtration rate (GFR) were measured using a blood pressure transducer, a flow probe and inulin clearance, respectively. Plasma volume and oxidative stress were measured by means of the Evans Blue method and by monitoring thiobarbituric acid reactive substances (TBARS) in the kidneys, respectively. Urinary protein was measured by precipitation with 3% sulphosalicylic acid. It was observed that prenatally malnourished rats presented higher values of plasma volume (26%, P < 0.05), kidney TBARS (43%, P < 0.01) and blood pressure (10%, P < 0.01) when compared with the control group. However, they showed no change in renal haemodynamics or proteinuria. Neither prenatally malnourished nor control rats treated with sodium overload presented plasma volume or blood pressure values different from their respective control groups, but both groups presented elevated proteinuria (P < 0.01). The prenatally malnourished group treated with sodium overload presented higher values of kidney TBARS, GFR and filtration fraction (58, 87 and 72% higher, respectively, P < 0.01) than its respective control group. In summary, sodium overload did not exacerbate the hypertension in juvenile prenatally malnourished rats, but induced renal haemodynamic adjustments compatible with the development of renal disease.

Animals↗
PubMed2006

Renal protective role of atrial natriuretic peptide in acute sodium overload-induced inflammatory response.

BACKGROUND: The present study was performed to explore the effect of exogenous infusions of atrial natriuretic peptide (ANP) on the early inflammatory response during acute sodium overload in normal rats. METHODS: Sprague Dawley rats were exposed to acute sodium overload (Na 1.5 M). Nonhypotensive doses of ANP (1 and 5 microg x kg(-1) x h(-1)) were infused simultaneously with sodium or after sodium infusion in order to evaluate prevention or reversion of the inflammatory response, respectively. We determined inflammation markers in renal tissue by immunohistochemistry. RESULTS: Creatinine clearance was not reduced in any case. Sodium tubular reabsorption increased after sodium overload (334.3 +/- 18.7 vs. control 209.6 +/- 27.0 mEq x min(-1), p < 0.05) without changes in mean arterial pressure. This increase was prevented (228.9 +/- 26.4; p < 0.05) and reversed (231.5 +/- 13.9; p < 0.05) by ANP-5 microg x kg(-1) x h(-1). Sodium overload increased the expression of: RANTES (38.4.3 +/- 0.8 vs. 2.9 +/- 0.6%, p < 0.001), transforming-growth-factor-beta(1) (35.3 +/- 1.0 vs. 5.0 +/- 0.7%, p < 0.001), alpha-smooth muscle actin (15.6 +/- 0.7 vs. 3.1 +/- 0.3%, p < 0.001), NF-kappaB (9.4 +/- 1.3 to 2.2 +/- 0.5 cells/mm(2), p < 0.001), HIF-1alpha (38.2 +/- 1.7 to 8.4 +/- 0.8 cells/mm(2), p < 0.001) and angiotensin II (35.9 +/- 1.3 to 8.2 +/- 0.5%, p < 0.001). ANP-5 microg x kg(-1) x h(-1) prevented and reversed inflammation: RANTES (9.2 +/- 0.5 and 6.9 +/- 0.7, p < 0.001); transforming growth factor-beta(1) (13.2 +/- 0.7 and 10.2 +/- 0.5, p < 0.001) and alpha-smooth muscle actin (4.1 +/- 0.4 and 5.2 +/- 0.4, p < 0.001). Both prevention and reversion by ANP were associated with downregulation of NF-kappaB (3.2 +/- 0.4 and 2.8 +/- 0.5, p < 0.001) and angiotensin II (8.2 +/- 0.5 and 9.1 +/- 0.7, p < 0.001) and diminished hypoxia evaluated through HIF-1alpha expression (8.4 +/- 0.8 and 8.8 +/- 0.7, p < 0.001). CONCLUSION: Our study provides evidence supporting a protective role of ANP in both prevention and reversion of renal inflammation in rats with acute sodium overload.

Angiotensin II↗
PubMed2026

Sodium Overload-Related Molecular Subtypes and a Four-Gene Prognostic Signature Predict Survival, Immune Landscape, and Therapeutic Response in Acute Myeloid Leukemia.

Sodium overload has recently emerged as a critical metabolic stressor involved in cancer progression; however, its molecular characteristics and clinical relevance in acute myeloid leukemia (AML) remain unexplored. RNA-seq data sets, clinical annotations, and mutational profiles of AML patients were annotations from The Cancer Genome Atlas and integrated with Genotype-Tissue Expression normal samples. Sodium overload-related genes (SORGs) were obtained from GeneCards. Differentially expressed SORGs (DESORGs) screened by applying the limma statistical model, followed by univariate Cox proportional hazards regression, consensus clustering, functional enrichment, immune infiltration analysis, and pathway evaluation. A prognostic signature was developed through least absolute shrinkage and selection operator regression followed by multivariate Cox modeling. The model's performance was further verified in two external GEO data sets (GSE71014 and GSE37642). Nomogram construction, subgroup analysis, tumor mutational burden (TMB) assessment, drug sensitivity prediction, transcription factor (TF) analysis, and competing endogenous RNA (ceRNA) network analyses were also performed. A total of 57 DESORGs were identified, and 2 sodium overload-related molecular subtypes exhibited distinct survival, immune infiltration, and inflammatory pathway activation. A robust four-gene signature (DOCK1, GABRE, HTR7, ACSM1) stratified patients into high- and low-risk categories with significantly different survival across training and validation cohorts. High-risk patients displayed increased immune infiltration, higher TMB, reduced sensitivity to multiple chemotherapeutic drugs, and inferior predicted response to PD-L1 blockade. TF and ceRNA networks revealed multilayered transcriptional and post-transcriptional regulation of the signature genes. This study identifies sodium overload-related molecular heterogeneity in AML and establishes a validated four-gene prognostic signature that integrates genomic, immunologic, and therapeutic features, offering potential utility for personalized risk assessment and treatment optimization.

Humans↗
PubMed1976

[Degree of granularity of the atrial cardiocytes. Morphometric study in rats subjected to different types of water and sodium load (author's transl)].

Morphometric analysis was applied to the evaluation of the atrial cardiocytes specific granules, in rats subjected to different types of water and sodium load. In control animals, the right atrium is more granulated than the left one and the interauricular septum. Ipsilateral atrium and auricle have the same index of granularity. Five types of water and sodium load were tested - I. Full water restriction - II. Sodium restriction with normal water intake - III. Controls - IV. Sodium overloading - V. Sodium and Doca overloading. From groups I to V, the index of granularity decreases progressively. The same phenomenon does not appear in the left atrium, except for the group II (sodium restriction) whose index is higher (p less than 0.001) than in the other groups. These data are not incompatible with the existence of a relationship between the presence of atrial specific granules and the atrial volosensitivity. An analogy between these cells and the myopithelioid cells of the juxtaglomerular apparatus is then suggested.

Animals↗
PubMed1987

Effect of sodium intake on blood pressure, serum levels and renal excretion of sodium and potassium in normotensives with and without familial predisposition to hypertension.

1. Seventeen normal volunteers aged 19 to 22 were randomly subjected, in a trial of crossover design, to three distinct regimens of sodium chloride intake: high (16 to 20 g), normal (8 to 12 g) and low (0.5 to 1 g). Each regimen lasted nine days, with determination of blood pressure and heart rate (in the supine position and after sudden rising), body weight, and urinary output of creatinine, sodium and potassium on the third, sixth and ninth days. In addition, plasma levels of creatinine, sodium and potassium were determined on the ninth day so that sodium and potassium clearance and fractional excretion could be calculated. 2. Eleven of the volunteers had a family history of hypertension. Compared to the six without such a history, these subjects showed: 1) higher supine systolic blood pressure on the third day of sodium overload (124.7 +/- 3.0 vs 112.3 +/- 2.9 mmHg, P less than 0.02); 2) higher supine diastolic blood pressure on the third day of sodium overload (76.5 +/- 2.8 vs 64.5 +/- 4.3 mmHg; P less than 0.05); 3) higher supine diastolic blood pressure on the sixth day of sodium overload (73.7 +/- 2.3 vs 63.8 +/- 3.2 mmHg, P less than 0.05); 4) lower supine heart rate on the ninth day of sodium overload (61.0 +/- 3.1 vs 72.7 +/- 4.6, P less than 0.05), and 5) lower plasma potassium on the ninth day of sodium overload (4.10 +/- 0.05 vs 4.28 +/- 0.06 mEq/l, P less than 0.05). 3. These results suggest that normal individuals whose familial history places them at risk for the development of hypertension differ from those not at risk during their adaptation to sodium load by suffering a transient elevation of blood pressure within a few days of the increase in load. The low levels of plasma potassium observed in these volunteers after a period of sodium load may be due to the operation of different renal mechanisms of sodium excretion in this group, leading to increased kaliuresis, and may explain the high vascular reactivity of such individuals.

Adult↗
PubMed1999

Sodium management in dialysis by conductivity.

The determination of dialysate sodium concentration is one of the challenges of dialysis prescription, because no accurate information on the predialytic sodium overload is available. Too low dialysate sodium is responsible for intradialytic intolerance symptoms, whereas too high sodium may lead to long-term water sodium overload with cardiovascular hazards (hypertension, left heart failure). We propose here a biofeedback system based on noninvasive repeated measures of ionic dialysance and plasma water conductivity used here as a surrogate of plasma water sodium. This system achieves a stable postdialytic sodium pool and subsequently a dialysate sodium concentration adapted to the inter dialytic sodium load. This new tool in dialysate sodium prescription aims at reducing the morbidity related to patient sodium balance impairment.

Biofeedback, Psychology↗
PubMed2003

Effects of N-(2-mercaptopropionyl)-glycine on mitochondrial function in ischemic-reperfused heart.

OBJECTIVE: A possible mechanism for N-(2-mercaptopropionyl)-glycine (MPG) underlying the improvement of contractile function and mitochondrial activity of ischemic-reperfused rat hearts was examined. METHODS: Isolated, perfused hearts were subjected to 35 min ischemia-60 min reperfusion. At the end of ischemia or reperfusion, myocardial Na(+) content and mitochondrial oxygen consumption rate (OCR) were examined. The perfused heart was treated with 0.1-1 mM MPG for 30 min prior to ischemia or for the first 30 min of reperfusion. RESULTS: Ischemia increased myocardial Na(+) content (sodium overload) and decreased mitochondrial OCR. The left ventricular developed pressure (LVDP) of the untreated heart recovered to 19.8+/-3.8% of the preischemic value and the infarct area amounted to 23.3+/-1.7% of the left ventricle. The thiobarbiturate-reacting substance (TRS) was also increased in the reperfused, but not ischemic, myocardium. Pretreatment of the perfused heart with 0.3-1 mM MPG attenuated the ischemia-induced sodium overload and decrease in the OCR. Pretreatment with the agent also enhanced the postischemic recovery of LVDP, attenuated reperfusion-induced increase in TRS, and reduced the infarct area. Although the postischemic treatment with MPG suppressed the increase in TRS in the reperfused myocardium, a LVDP recovery of reperfused hearts was not observed. Cardiac mitochondria were isolated and examined for the direct effect of MPG on their function. Incubation with either 12.5 mM sodium lactate or 1 microM phenylarsine oxide neither altered the mitochondrial membrane potential nor induced mitochondrial swelling, whereas incubation with a combination of these agents elicited the membrane potential depolarization and swelling. Incubation of mitochondria with 1 mM MPG attenuated these events. CONCLUSION: These results suggest that both attenuation of sodium overload and preservation of the mitochondrial function may largely contribute to cardioprotection of MPG in the ischemic-reperfused heart.

Animals↗
PubMed1995

A possible involvement of sodium channel blockade of class-I-type antiarrhythmic agents in postischemic contractile recovery of isolated, perfused hearts.

The present study was undertaken to test the hypothesis that the degree of sodium channel blockade by class-I-type antiarrhythmic agents accounts for enhancement of postischemic contractile recovery of ischemic/reperfused hearts. Electrophysiological studies showed that the class-I-type antiarrhythmic agents quinidine, disopyramide, procainamide, lidocaine, mexiletine, flecainide and pilsicainide suppressed the Vmax value of the rat left ventricular muscle cell, a marker of sodium channel blockade, in a concentration-dependent manner. Isolated rat hearts were subjected to 35 min of ischemia and 60 min of reperfusion. Postischemic contractile recovery, which was never detected in untreated hearts, was enhanced in hearts pretreated with these antiarrhythmic agents during the last 3 min before ischemia at concentrations ranging from 3 to 300 microM. Tissue Na, but not Ca, accumulation was also detected in the ischemic heart, and tissue Na and Ca accumulation was observed in the reperfused heart, which suggests that sodium overload occurs during ischemia, followed by sodium and calcium overload during reperfusion. The degree of postischemic contractile recovery seen in the presence of these antiarrhythmic agents was inversely related to tissue Na or Ca accumulation after reperfusion, which suggests that class-I-type antiarrhythmic agents inhibit sodium overload occurring in ischemic/reperfused myocardial cells. A close relationship between postischemic contractile recovery of the perfused heart and depression in the Vmax value of the ventricular muscle was also observed. These results suggest that the ability class-I-type antiarrhythmic agents to inhibit myocardial sodium channels plays a significant role in the enhancement of postischemic contractile recovery of the ischemic/reperfused heart.

Animals↗
PubMed1983

[Advantage of a high-sodium hemodialysis solution: theoretical bases].

In hemodialysis, an excessive oversimplification leads to confuse the transfer direction of a given solute (patient towards dialysate or dialysate towards patient) and the direction of transmembranar concentration gradient. Applied to sodium, this confusion leads to the usual iso- or hypotonic dialysate use, in order to eliminate the patient's sodium overload. We show here how the use of a high sodium dialysate allows the elimination of the sodium overload and makes the free water clearance (approached by the Na-free water clearance) positive, which is the necessary condition to restore an hydro-electrolytic equilibrium near from the normal. That allows a disappearance of hypovolemic symptoms during hemodialysis, a better general condition and a possible increase of water intake between sessions.

Humans↗
PubMed2005

[Drug-induced edema].

It is well known that there are many drugs which induce edema. Drug-induced edema can be divided into three types by the mechanism as follows, 1) sodium overload, 2) renal dysfunction and 3) hyperpermeability of blood vessel. In the category of sodium overload, edema is induced by much fluid replacement and antibiotics which contain large amount of sodium and sodium bicarbonate. As the category of renal dysfunction, NSAIDs, antihypertensive drugs, anticancer drugs and so on induce edema in patients with renal dysfunction. In the category of hyperpermeability of blood vessel, edema is induced by calcium antagonist, insuline and so on. In order to diagnose drug-induced edema early, it is important that we interrupt or reduce the quantity of suspicious drug.

Edema↗