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PubMed1984

Sodium-potassium ATPase in deoxycorticosterone-salt hypertension: opposing effects of sodium load and mineralocorticoids.

Previous studies of the sodium-potassium pump in the deoxycorticosterone (DOC)-salt (DS) model of hypertension yielded contrasting results, some investigators reporting increased and others finding decreased pump activity. To test the possibility that the net pump activity in the DS rats results from separate effects of sodium overload and mineralocorticoid activity, we compared the Na+-K+-ATPase pump in DS rats with that in other experimental models in which these potential determinants do not coincide. Renocortical and myocardial ATPase activities were measured in control rats; adrenalectomized-saline-repleted rats; adrenalectomized aldosterone- or dexamethasone-repleted rats; uninephrectomized, saline-drinking rats; and uninephrectomized, saline-drinking, DOC- and salt-treated rats. DOC- and salt-treated rats had higher (P less than 0.001) blood pressures and lower (P less than 0.05) serum potassium levels than control rats. Renocortical and myocardial ATPase activities were considerably (P less than 0.01) decreased in adrenalectomized, saline-repleted rats, but could be at least partially restituted by either aldosterone or dexamethasone therapy. Uninephrectomized, saline-drinking rats had reduced (P less than 0.01) renocortical and myocardial ATPase activities compared with control rats. In uninephrectomized, saline-drinking rats treated with DOC, renocortical and myocardial ATPase activities were not different from control values. The results of this study suggest that the Na+-K+-ATPase pump in DOC- and salt-treated rats is modulated by the opposing effects of sodium overload-associated suppression and DOC-mediated stimulation.

Adrenalectomy↗
PubMed2026

Construction of molecular signatures based on the co-expression network of NECSO-related gene TRPM4 and its prognostic value in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) demonstrates significant prognostic variability that is not entirely accounted for by traditional staging systems. Necrosis by sodium overload (NECSO) is an emerging programmed cell death pathway, but its clinical relevance in HCC remains undefined. Therefore, this study aimed to identify TRPM4-associated core genes, develop and validate a prognostic signature, and investigate its relationship with the tumor immune microenvironment, tumor mutational burden, and single-cell expression patterns in HCC. METHODS: We integrated transcriptomic, clinical, and mutational datasets from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) (n=421) and Gene Expression Omnibus (GEO) cohorts (n=115) to identify genes co-expressed with TRPM4-a key NECSO mediator-and those differentially expressed in HCC. A prognostic signature was developed using least absolute shrinkage and selection operator (LASSO)-Cox regression and validated through survival analysis, time-dependent receiver operating characteristic (ROC) curves, and multivariate Cox regression analysis. The immune landscape was characterized using CIBERSORT, somatic mutation data were used to calculate tumor mutational burden (TMB) and assess its correlation with the risk score, and single-cell RNA sequencing (scRNA-seq) resolved cell-type-specific expression patterns. RESULTS: From 294 TRPM4-associated core genes, we identified an 11-gene signature (BRSK1, MMP1, GRIN2D, GP6, MYOM2, N4BP3, CCDC112, TSEN54, MAP3K9, SPP1, B3GNT4) that independently predicted overall survival (OS) (hazard ratio =5.419, P<0.001) with areas under the curve (AUCs) of 0.779, 0.693, and 0.701 at 1, 3, and 5 years. These values were superior or comparable to conventional clinicopathologic variables after direct comparison. High-risk patients exhibited an immunosuppressive microenvironment, characterized by enrichment of M0 macrophage, a higher M2/M1 ratio (P<0.001) and distinct immune checkpoint profiles. When integrated with TMB, the prognostic stratification was further refined: high-TMB/high-risk patients had poorest outcomes (median OS, 15.3 months), while low-TMB/low-risk patients had the most favorable survival (median OS, 68.7 months). Single-cell analysis revealed that MMP1 was induced in cancer-associated fibroblasts (CAFs) and SPP1 was downregulated in macrophages, single-cell risk scores confirmed TAFs and macrophages as the main contributors to the prognostic model. CONCLUSIONS: The TRPM4-centered 11-gene signature provides robust and independent prognostic stratification in HCC by integrating immune, mutational, and single-cell features. This signature serves as a potential tool for prognostic evaluation and may help inform immunotherapeutic strategies for HCC.

Hepatocellular carcinoma (HCC)↗
PubMed2000

Renal excretion and saline intake during post-stress immobilization period in rats.

An experiment in which the rats access either to 0.5% or 1.5% saline was designed in order to further characterise the relationship between sodium intake and renal excretion after acute immobilization stress. A saline solution for 3 days was provided to the rats previous to the experimental day. On that day, after finishing acute immobilization stress, all variables under observation were measured every 6 h for 24 h. These periods were denominated as follows: T1 (12.00 to 18.00 h), T2 (18.00 to 24.00 h), T3 (24.00 to 06.00 h) and T4 (06.00 to 12.00 h). Acute immobilization stress reduced sodium renal excretion in both T1 and T2. Sodium intake in acute immobilization stress rats was lower than in control rats during all observed periods, while the urine volume was only reduced in the stressed animals in T1. These results were similar in both saline solution concentrations. A good correlation was observed between sodium intake and sodium excretion in control rats having access to either 0.5% or 1.5% saline as well as in stressed rats having access to 0.5% saline, this correlation was not observed in stressed rats with 1.5% saline. This suggests that stress impaired the renal capability of rats to handle high sodium but not a slight sodium overload. The inability of the kidney to excrete sodium may be critical to reduce sodium intake after acute immobilization stress.

Animals↗
PubMed1996

Effect of salt intake and inhibitor dose on arterial hypertension and renal injury induced by chronic nitric oxide blockade.

Long-term nitric oxide blockade by N omega -nitro-L-arginine methyl ester (L-NAME) leads to severe and progressive hypertension. The role of salt intake in this model is unclear. To verify whether salt dependence in this model is related to the extent of nitric oxide inhibition, we gave adult male Munich-Wistar rats a low salt, standard salt, or high salt diet and oral L-NAME treatment at either 3 or 25 mg/kg per day. At 10 to 15 days of treatment, the slope of the pressure-natriuresis line was decreased in rats receiving low-dose L-NAME compared with untreated controls. In rats treated with the higher dose, the line was shifted to the right but remained parallel to that obtained in untreated controls. Renal vascular resistance was moderately increased in rats receiving low-dose L-NAME, whereas high-dose L-NAME induced a marked vasoconstriction that was aggravated by salt overload. Low-dose L-NAME treatment induced hypertension only when associated with sodium overload. In rats receiving high-dose L-NAME, hypertension was aggravated by sodium excess but was not ameliorated by sodium restriction. Long-term (6 weeks) L-NAME treatment was associated with progressive hypertension, which was aggravated by salt overload, and with the development of albuminuria, focal glomerular collapse, glomerulosclerosis, and renal interstitial expansion. These abnormalities were worsened by salt overload and largely prevented by salt restriction. In the model of chronic nitric oxide blockade, salt dependence is a function of the inhibitor dose, and renal injury varies directly with the level of salt intake.

Albuminuria↗
PubMed2002

[Salt, renal function and high blood pressure--reflections on a current issue].

The role of salt intake for blood pressure control has been discussed for a long time. A brief review is given of some pertinent physiological facts to explain this relationship and evolutionary aspects of renal function are emphasized. Salt intake is very high in the modern society, often as high as 15 g sodium chloride per 24 hours while 3-6 g may be more than enough to maintain an adequate salt balance. If the kidneys cannot cope with this severe sodium overload, blood pressure will rise. Therefore, the kidneys' ability to excrete sodium is a key factor and the salt excretion capacity is the kidneys' major barostatic function. As barostats, the kidneys control the blood pressure by ultimately determining the sodium excretion. Reducing sodium intake is, however, difficult as more than 50% of the intake is contained in the food we buy such as bread, sausages, canned food, chips and fast-food. Food products should therefore be "salt declared", but information on this aspect is generally lacking. If the population's salt intake could be reduced by 50%, the prevalence of hypertension will be much reduced, perhaps also by as much as 50%. The cost to society for treating hypertension would be reduced accordingly. Salt intake is also an important aspect of the overweight problem among today's youth. Salt and overweight impose great health risks later in life. Preventive measures in this area must be given high priority in future health care work.

Blood Pressure↗
PubMed2003

[Na+ overload-induced mitochondrial dysfunction in myocardial ischemia/reperfusion injury].

An accumulation of Na+ is induced in the ischemic myocardium, which is so-called "Na+ overload". The exact role of Na+ overload in the genesis of myocardial ischemia/reperfusion injury remains unclear except for the role as a driving force of Ca2+ overload in the reperfused myocardium. Excessive activation of Na+/H+ exchanger (NHE) and Na+ channels may contribute to Na+ influx into the ischemic myocardium, resulting in sodium overload under ischemic conditions. A decrease in energy-producing ability of mitochondria in the ischemic myocardium is also observed in an ischemic duration-dependent manner. Attenuation of Na+ overload by an NHE inhibitor or a Na+ channel blocker preserved mitochondrial energy production in the ischemic myocardium and enhanced post-ischemic contractile recovery. To mimic Na+ overload in the ischemic myocardium, isolated mitochondria were incubated with sodium lactate, a possible end product of anaerobic glycolysis. Sodium lactate induced an irreversible reduction in the mitochondrial energy production. The mitochondrial damage induced by sodium lactate was not attenuated by the NHE inhibitor or the Na+ channel blocker, suggesting that these agents may indirectly preserve mitochondrial function in the ischemic myocardium. Taken together, Na+ overload in the ischemic myocardium may induce mitochondrial dysfunction, leading to contractile failure of the reperfused myocardium.

Humans↗
PubMed1991

Enhanced responsiveness to CNS-induced natriuresis in anesthetized nonascitic cirrhotic rats.

Central nervous system (CNS)-induced natriuresis was investigated in nonascitic rats with CCl4-induced cirrhosis (CTC rats) under pentobarbital anesthesia. At baseline, urine sodium output (UNa+V, in mumol.min-1.100 g body wt-1) (-30%, P less than 0.01) and mean arterial pressure (MAP, in mmHg) (-12%, P less than 0.001) were significantly reduced in CTC rats (n = 32) compared with matched controls (n = 34). In response to intracerebroventricular infusion of sodium-rich (349 mM) artificial cerebrospinal fluid (Na(+)-CSF infusion), UNa+V was significantly higher in CTC rats (2.8 +/- 0.3; n = 15) than in controls (1.7 +/- 0.2; n = 17; P less than 0.01); no differences were found in pressor changes (24 +/- 3 vs. 19 +/- 2). A similar but normal sodium CSF (150 mM) infusion did not influence UNa+V or MAP in any group (n = 12, both). In contrast, CTC rats (n = 5) showed, compared with controls (n = 5), significantly reduced natriuretic (UNa+V, 6.9 +/- 0.5 vs. 12.4 +/- 0.9; P less than 0.001) and pressor (+16 +/- 3 vs. +31 +/- 2; P less than 0.01) responses to an intravenous hypertonic sodium overload. Natriuresis induced by Na(+)-CSF infusion was related to increases in creatinine clearance (similar in both groups) and in fractional sodium excretion, which was significantly higher in CTC rats (5.90 +/- 0.15%) than in controls (3.65 +/- 0.14%; P less than 0.01). In summary, CNS-dependent efferent natriuretic mechanisms were preserved in CTC rats and were able to reverse renal tubular sodium retention in these animals. It is proposed that Na(+)-CSF infusion may be a useful tool for the study of renal sodium retention in experimental liver cirrhosis.

Animals↗
PubMed1990

Regulation of dopamine synthesis in the rat kidney.

1. Both animal and clinical studies clearly suggest a close link between dopamine production and renal delivery of sodium. 2. It appears that tubular transport of sodium and DOPA could represent the rate limiting step for the renal synthesis of dopamine; the membrane transport mechanism is sensitive to the nucleotide cyclic GMP. 3. In sodium overloaded animals AAAD activity appears to be greater than that in controls, but the tubular transport of L-DOPA might be decreased. 4. Since the final product of an increased sodium delivery to the kidney is an increased urinary excretion of dopamine, it might be hypothesized that the outward transport of newly formed dopamine in tubular epithelial cells is also affected by high tubular sodium.

Animals↗
PubMedDate not supplied

Sodium balance in hemodialysis therapy.

Water and sodium overload is the predominant factor in the pathogenesis of hypertension in dialysis patients. In many dialysis patients, dry weight is not reached because of an imbalance between the interdialytic accumulation of water and sodium and the brief and discontinuous nature of routine dialysis therapy. During dialysis, sodium is removed by convection and to a lesser degree by diffusion. However, with supraphysiologic dialysate sodium concentrations, diffusive influx from dialysate may occur, especially in patients with low predialytic plasma sodium concentrations. Measuring sodium removal during dialysis is difficult and hampered by the variability in conventional sodium measurements. Ionic mass removal by continuous measurement of conductivity in the dialysate ports appears to be a promising tool for the approximation of sodium removal during dialysis. While the beneficial effects of concomitant water and sodium removal on blood pressure control in dialysis patients are undisputed, it is less well known whether a change in hydrosodium balance solely by reducing dialysate sodium is beneficial. Considering the inherent dangers of such an approach (intradialytic hemodynamic instability), the beneficial effects of strict dietary sodium restriction appear to be of much larger clinical benefit. It has become possible to individualize dialysate sodium concentration by means of online measurements of plasma conductivity and adjustment of dialysate conductivity by feedback technologies. The clinical benefits of this approach deserve further study. Still, reducing dietary sodium intake remains the most important tool in improving blood control in dialysis patients.

Blood Pressure↗
PubMed1988

Increase in plasma concentrations of atrial natriuretic peptide during infusion of hypertonic saline in conscious newborn calves.

Plasma concentrations of atrial natriuretic peptide (ANP), plasma renin activity (PRA), plasma concentrations of aldosterone, urine flow rate and sodium and potassium excretion were studied in two groups of four conscious 3-day-old male calves, infused with hypertonic saline or vehicle. Hypertonic saline infusion (20 mmol NaCl/kg body weight) was accompanied by a progressive rise in plasma concentrations of ANP (from 16.5 +/- 0.2 pmol/l at time 0 to 29.3 +/- 3.0 pmol/l at 30 min; P less than 0.05) and by a gradual decrease in PRA (from 1.61 +/- 0.23 nmol angiotensin I/l per h at time 0 to 0.54 +/- 15 nmol angiotensin I/l per h at 90 min; P less than 0.05); there was no change in the plasma concentration of aldosterone. Within the first 2 h of the 24-h urine collection period there was a marked rise in urine flow rate and sodium excretion in treated calves when compared with control animals (66.0 +/- 8.3 vs 15.9 +/- 1.2 ml/kg body weight per 2 h (P less than 0.05) and 6.7 +/- 1.3 vs 0.4 +/- 0.02 mmol/kg body weight per 2 h (P less than 0.01) respectively). During the following 22 h, urinary water and sodium excretion remained at significantly high levels. Thus, in the conscious newborn calf, changes in plasma ANP levels and urinary water and sodium excretion during hypertonic saline infusion are compatible with the hypothesis that endogenous ANP participates, at least in part, in the immediate diuretic and natriuretic renal response induced by the sodium overload.

Animals↗
PubMed1991

Renal function derangements induced by portacaval anastomosis in normal rats.

The purpose of this study was to determine the renal function derangements that portacaval shunting caused in previously normal rats. Eight rats suffered a surgical portacaval shunt (PCS) and another 8 a sham operation (SHAM). Renal function was investigated by determining urinary volume, sodium, potassium, creatinine and aldosterone excretion, in basal conditions and after sodium overload. Plasma renin concentration and urinary excretion of PGE2, 6-keto-PGF1 alpha and TXB2 were also determined in basal conditions. PCS rats showed increased urinary volume, creatinine excretion and endogenous creatinine clearance, either in basal conditions or after sodium load. After the latter, PCS animals also showed sodium retention and hyperaldosteronuria. PCS caused in basal conditions a striking diminution in urinary excretion of all prostaglandins and no changes in plasma renin. In conclusion, PCS in the normal rat caused a renal dysfunction consisting of polyuria, possibly related to ADH disfunction and an inability to manage a sodium load.

Aldosterone↗
PubMed1998

Characterization of the precipitants of hospitalization for heart failure decompensation.

BACKGROUND: The model for management of patients with heart failure may be a key determinant of morbidity and quality of life. Development of a better management strategy for these patients requires determination of the reasons for decompensation that leads to hospitalization. OBJECTIVES: To ascertain and rank the principal reasons for hospitalization of patients who have heart failure. METHODS: Retrospective audit of all 1992 admissions (N = 1031; 691 patients) coded for heart failure at a Veterans Affairs medical center and a tertiary care university medical center. RESULTS: The diagnosis of heart failure was verified by preset criteria in 72% of the patients. Of the 496 patients with documented heart failure, worsening heart failure was a main reason for admission in 390 (79%). Despite different socioeconomic backgrounds, excessive sodium retention was the leading factor (55%) associated with decompensation in patients at both institutions. Other factors precipitated admission much less often. CONCLUSIONS: Many hospitalizations for heart failure might be avoided by case management directed at lessening sodium overload. Increased use of medications known to be effective in persons with heart failure (angiotensin-converting enzyme inhibitors, digoxin, and adequate diuretic therapy) might reduce the likelihood of decompensation. Implementation of behavioral interventions to assist patients with self-monitoring signs of sodium retention and to improve compliance with medications and dietary sodium restrictions are strategies for further reducing the risk of decompensation.

Aged↗
PubMed2002

Sodium accumulation during ischemia induces mitochondrial damage in perfused rat hearts.

OBJECTIVE: The present study aimed to elucidate the involvement of sodium overload and following damage to mitochondria during ischemia in the genesis of ischemia/reperfusion injury of perfused rat hearts. METHODS: Isolated, perfused hearts were exposed to different durations (15-35 min) of ischemia followed by 60-min reperfusion. At the end of ischemia or reperfusion, myocardial sodium and calcium contents and myocardial high-energy phosphates were determined. The cardiac mitochondrial ability to produce ATP was measured using saponin-skinned bundles. The effects of sodium on the mitochondrial membrane potential and the oxidative phosphorylation rate were examined using isolated mitochondria from normal hearts. RESULTS: Post-ischemic recovery of left ventricular developed pressure decreased in an ischemic duration-dependent manner. Ischemia induced an increase in myocardial sodium, but not calcium. This increase was dependent on the duration of ischemia. The oxygen consumption rate of skinned bundles from the ischemic heart decreased at the end of ischemia. Incubation of mitochondria with various concentrations of sodium chloride or sodium lactate in vitro resulted in a depolarization of mitochondrial membrane potential and a decrease in ATP-generating activity. This decrease was not restored after elimination of sodium compounds. CONCLUSIONS: The present findings suggest that ischemia induces an increase in sodium influx from the extracellular space and that accumulated sodium may induce irreversible damage to mitochondria during ischemia. This mitochondrial dysfunction may be one of the most important determinants for the genesis of ischemia/reperfusion injury in perfused rat hearts.

Analysis of Variance↗
PubMed1993

[Mechanism of the protective effects of berbamine on ischemia-reperfusion injury in isolated rat heart].

Isolated perfused rat heart model was used to observe the protective effects of berbamine on myocardial ischemia/reperfusion injury. The hearts were remarkably injured by 40 min global ischemia followed by 20 min reperfusion. Berbamine could significantly improve heart function, prevent ventricular fibrillation, reduce CK release, preserve Na, K-ATPase activity, and reduce Na+ gain and K+ loss during ischemia and Ca2+ overload during reperfusion. With the use of low temperature ESR technique, we found that, in hearts subjected to 40 min ischemia and 15 sec reperfusion, oxygen-centered free radical signals became much more intense. In the presence of berbamine, these signals decreased. The results showed that berbamine could alleviate myocardial ischemia/reperfusion injury. This effect might be due to (1) preserved myocardial Na, K-ATPase activity and inhibition of sodium overload at the end of ischemia, which might further lead to attenuation of reperfusion-induced calcium overload, and (2) reduction of oxygen free radical generation during reperfusion.

Alkaloids↗
PubMed1991

Role of Na(+)-Ca2+ exchange system in the pathogenesis of myocardial ischemia-reperfusion damage.

Results from a systematic experiment on isolated perfused rat heart and isolated myocytes of adult rat showed that the mechanism of calcium influx during myocardial ischemia-reperfusion is due to the development of intracellular sodium overload during ischemic period; on reperfusion, the high intracellular Na+ content activated the reverse direction of Na(+)-Ca2+ exchange over myocardial sarcolemma (SL), thus a large quantity of extracellular Ca2+ fluxed over the SL to the intracellular space, forming a condition of intracellular Ca2+ overload, which leads to irreversible damage of the myocardium.

Animals↗
PubMed2006

[Regulative effects of temperature, intracellular sodium, ATP and pH on I(Na/Ca) of cardiac myocytes].

The Na(+)-Ca(2+) exchange is a major pathway for removal of cytosolic Ca(2+) in cardiac myocytes. To explore the effects of temperature, intracellular Na(+), ATP and pH on Na(+)-Ca(2+) exchange currents (I(Na/Ca)) of intact guinea-pig myocytes, the whole-cell patch-clamp technique was used to record I(Na/Ca) in isolated guinea-pig ventricular myocytes. We found that I(Na/Ca) at 34 degrees C was four times higher than that at 22 degrees C. However, intracellular acidification had no obvious influence on bidirectional I(Na/Ca). At 22~24 degrees C , intracellular ATP depletion and intracellular acidification did not markedly affect bidirectional I(Na/Ca) either. At 34~37 degrees C , intracellular ATP depletion and intracellular acidification synergistically inhibited the outward and inward currents of I(Na/Ca), and blocked the inward currents of I(Na/Ca)more potently than the outward currents of I(Na/Ca). The effect of ATP on I(Na/Ca) is temperature-dependent. Intracellular higher sodium increased the outward currents of I(Na/Ca) however it did not increase, even sometimes decreased the inward currents of I(Na/Ca). These results suggest that intracellular ATP depletion and intracellular acidification synergistically impair Ca(2+) extrusion via forward mode Na(+)-Ca(2+) exchange, and intracellular sodium overload increases Ca(2+) influx via reverse mode Na(+)-Ca(2+) exchange, leading to calcium overload respectively.

Adenosine Triphosphate↗
PubMed1992

Mechanisms of protective effects of berbamine on ischemia/reperfusion injury in isolated rat heart.

Isolated perfused rat heart model was used to observe the protective effects of berbamine on myocardial ischemia/reperfusion injury. The hearts were significantly injured by 40 min global ischemia followed by 20 min reperfusion. Berbamine could significantly improve heart function, prevent ventricular fibrillation, reduce CK release, preserve Na,K-ATPase activity, and reduce Na+ gain and K+ loss during ischemia and Ca2+ overload during reperfusion. With the use of low temperature ESR technique, in hearts subjected to 40 min ischemia and 15 sec reperfusion, oxygen-centered free radical signals became much more intense. In the presence of berbamine, these signals decreased. Results showed that berbamine could alleviate myocardial ischemia/reperfusion injury. This effect might be due to: 1) preserved myocardial Na,K-ATPase activity and inhibition of sodium overload at the end of ischemia, which might further lead to attenuation of reperfusion-induced calcium overload, and 2) reduction of oxygen free radical generation during reperfusion.

Alkaloids↗
PubMed1976

[Severe hyperkalemia in cardiac patients].

Hyperkalaemia with severe myocardial consequence may complicate the treatment of heart failure. In five patients who developed kalaemia ranging from 6.5. to 8.6. mEq/l, the ECG showed altered auriculogram and/or widened QRS, the latter change being associated with ST segment elevation and very large T wave in one case. Such hyperkalaemia cannot be termed iatrogenic, although it is promoted by diuretic-induced hyponatraemia and dehydration. The essential part is played by an aggravation of the haemodynamic status, responsible for acute renal insufficiency with oligoanuria, and by the attendant metabolic acidosis. The correction of this metabolic acidosis promotes diuresis, causing potassium depletion and the rapid regression of electrocardiographic abnormalities. Parenteral alkalinization with sodium bicarbonate, associated with furosemid to prevent sodium overload, instituted in emergency, is the only way to prevent asystole or ventricular fibrillation when kalaemia exceeds 8 mEq/l.

Acidosis↗