Red Blood Cell Sodium Research Articles

The Li+-Na+ exchange and Na+-K+-Cl- cotransport systems in essential hypertension.

This review examines the physiological functions of the Li+-Na+ exchanger and Na+-K+-Cl- cotransport system in human red blood cells. Both transporters are family aggregated and determined mainly by genetic factors; they are present in kidney and vascular cells, where they are regulated by vasoactive substances. To assess the physiological function of these two transporters, we investigated their kinetic and equilibrium properties, and their modulation by vasoactive substances. Recent studies in red blood cells indicate that the Li+-Na+ exchanger may be a mode of operation of the Na+-H+ exchanger, which plays an important role in the regulation of cell pH, cell volume, and transtubular sodium transport. In vascular cells, Na+-H+ exchanger is modulated by vasoconstrictors such as growth factors and angiotensin, while Na+-K+-Cl- cotransport is modulated by vasodilators such as atrial natriuretic factor and bradykinin. Kinetic studies in red blood cells of hypertensive patients and their offspring indicate the presence of subsets with elevated Vmax of Li+-Na+ exchange or high Km for cell sodium for outward Na+-K+-Cl- cotransport. The latter alteration is found most frequently in young blacks born of hypertensive parents, and it appears to be dependent on their level of sodium intake. The relationship between the alterations of the red blood cell sodium exchanger and Na+-K+-Cl- cotransport and risk factors for hypertension indicates that they can provide a tool to examine the interaction of genetic, hormonal, and environmental factors in human hypertension.

Kinetic aspects of red blood cell sodium transport systems in essential hypertension.

A kinetic study of the interaction of internal sodium with four different erythrocyte sodium transport pathways (ouabain-sensitive Na+-K+ pump, bumetanide-sensitive Na+-K+ cotransport system, Na+-Li+ countertransport, and Na+leak) has facilitated the distinction of the following subgroups of patients with essential hypertension: 1) Leak (+), exhibiting increased passive sodium permeability; 2) Co (-), showing low apparent affinity of the Na+-K+ cotransport system for internal sodium; 3) Counter (+), characterized by increased maximal rates of Na+-Li+ countertransport; and 4) Pump (-), characterized by an abnormally low apparent affinity of the Na+-K+ pump for internal sodium. We present here a new and simple sodium-loading method that allows a simultaneous kinetic study of the above abnormalities. The use of this kinetic assay may improve estimation of the frequencies, clinical features, and other properties of each subgroup of hypertensive patients in different populations.

Effects of temperature, buffer osmolarity, and shift reagent concentration on the intracellular sodium and potassium relaxation times of red blood cells

Effects of temperature, buffer osmolarity, and shift reagent concentration on the intracellular sodium and potassium relaxation times of red blood cells

Further evidence for coupling of sodium and proton movements in dog red blood cells

Using 4,4′-diisothiocyanostilbene-2,2′-disulfonate (DIDS) and tributyltin the sodium transport pathway activated by shrinkage in dog red blood cells is shown to behave as expected for an electroneutral Na +/H + exchanger. When the driving forces for sodium and protons are equal, flow through the pathway stops. Amiloride inhibits the shrinkage-induced Na +/H + exchange.

Management of hypertension in high school students by using new salt titrator tape.

In a blood pressure screening program involving 6589 high school students, 180 male (4.7%) and 17 female (0.6%) students were identified as borderline hypertensive. The 174 hypertensive male adolescents studied further showed pathophysiological features such as a significantly higher frequency of obesity, higher 24-hour urinary sodium excretion, higher hematocrit value, higher sodium and lower potassium concentration in red blood cells, and higher ouabain-sensitive sodium efflux compared with the control group (231 male students; p less than 0.05). When used alone, the ordinary 10-week period of counseling about a low salt diet failed to significantly reduce the blood pressure of hypertensive students. However, when education and counseling efforts were combined with self-monitoring of salt (chloride) excretion in overnight urine samples using a new salt titrator tape developed in our laboratory, 24-hour urinary sodium excretion, weight, and blood pressure decreased significantly over 10 weeks (mean reduction: 52 mEq/day for 24-hour urinary sodium excretion, 1.7 kg for weight, 12/7 mm Hg for blood pressure). These results indicate that blood pressure of borderline hypertensive adolescents could be effectively reduced with this nonpharmacological method of dietary education. Such systematic management might be of importance for the prevention of essential hypertension.

Sodium transport in red blood cells from dialyzed uremic patients

Studies on red blood cell (RBC) sodium (Na) transport in chronic renal failure have described abnormalities in the ouabain-sensitive Na, K pump. We now report Na transport in RBC using cation flux methodology, measuring both the ouabain-sensitive Na, K pump and the ouabain-insensitive Na, K cotransport (CoT) and Na, lithium (Li) countertransport (CTT) in 28 subjects on hemodialysis, eight subjects on chronic ambulatory peritoneal dialysis (CAPD) and 29 control subjects. Intracellular cation content and passive permeability of Na were also examined. Mean Na efflux through the ouabain-sensitive Na, K pump was not reduced in dialysis patients when compared to normal subjects, whether measured in fresh cells (1.41 +/- 0.05 vs. 1.30 +/- 0.03 mmole/liter RBC/hr; P less than 0.05) or in Na-loaded cells (7.10 +/- 0.24 vs. 6.90 +/- 0.22; NS). There was, however, a marked and uniform suppression of the CoT pathway in Na-loaded cells from dialysis patients versus controls (0.14 +/- 0.02 vs. 0.41 +/- 0.05 mmole/liter RBC/hr; P less than 0.001). Mean CTT activity, as measured by Li efflux, was not different between dialysis and normal subjects. Uremic and normal RBC had similar intracellular Na or K content as well as passive permeability for either ion. This indicates that intracellular cationic homeostasis is maintained, perhaps secondary to balanced changes in cationic flux activity through these transport pathways.

Uremia and Red Blood Cell Sodium Transport

Uremia and Red Blood Cell Sodium Transport

FAMILIAL AGGREGATION OF RED BLOOD CELL CATION TRANSPORT SYSTEMS IN JAPANESE FAMILIES

The rate of lithium, sodium, and potassium transport in red blood cells is thought to be associated with essential hypertension. In order to investigate the contribution of genetic and environmental factors to cation transport, their correlation was analyzed in 60 parent-offspring pairs and 17 husband-wife pairs in Toyama City, Japan. Lithium-sodium countertransport and sodium-potassium cotransport rates were significantly correlated in parent-offspring pairs (r = 0.52, p less than 0.01 and r = 0.46, p less than 0.01, respectively) but not in husband-wife pairs. Sodium pump rates were significantly correlated in both pairs (r = 0.48, p less than 0.01 in parent-offspring pairs, r = 0.46, p less than 0.05 in husband-wife pairs). Therefore, lithium-sodium countertransport and sodium-potassium cotransport were found to have a substantial genetic component and the sodium pump to have a substantial environmental component. Sodium pump rates were significantly correlated with sodium/creatinine (r = 0.21, p less than 0.05) and sodium/potassium (r = 0.32, p less than 0.01) in casual urine.

Red blood cell electrolytes for monitoring digoxin therapy in adults.

Red blood cell (RBC) electrolyte concentrations were determined, with a method that can be applied easily in any clinical chemistry laboratory, in 18 patients not on digoxin therapy and 37 patients on maintenance digoxin therapy for various diagnoses. Of the digoxin-treated patients, 11 had electrocardiographic changes and other clinical evidence of digoxin toxicity. Mean RBC sodium was higher and mean RBC potassium was lower in patients on prolonged digoxin therapy than in controls, and these changes were more pronounced in patients with toxic symptoms. In the group of 11 patients with toxicity, a positive correlation was found between the ratio of RBC sodium to potassium and plasma digoxin levels (r = 0.8234, p less than 0.05). Plasma digoxin concentrations did not clearly distinguish between toxic and nontoxic patients. The RBC sodium/potassium ratio, however, identified 35 of 37 patients correctly, with two patients from the toxic and two patients from the nontoxic group giving the same results. Changes in intracellular erythrocyte electrolytes in adults appear to correlate closely with clinical signs of digoxin toxicity.

Quantitative local x-ray spectral microanalysis of single erythrocytes

Quantitative x-ray microanalysis was used to study the content of sodium, potassium, phosphorus and chlorine in single peripheral red blood cells of man. The method for sample preparation described permits its successful use under clinical and field conditions.

Red blood cell sodium in the DOCA hypertensive pig.

The influence of deoxycorticosterone acetate (DOCA) on the sodium content of the red blood cell was determined in the pig. DOCA (100 mg/kg), impregnated in Silastic, was implanted subcutaneously (s.c.) in six male pigs; seven additional pigs received Silastic implants without the DOCA. Those receiving DOCA had an increase in mean arterial pressure (MAP) that was significant in 48 hours and reached a plateau that was 24 mm Hg greater than that of the controls after 15 days. These animals also developed hypokalemia and polydipsia over approximately the same time course. Red blood cell sodium content increased in DOCA-treated pigs 24 hours after implant (5.57 +/- 0.17 vs 5.23 +/- 0.05, mEq/liter cells). The sodium content continued to rise, reaching a plateau 28% above that of control value by the 5th postimplant day (6.37 +/- 0.40 mEq/liter cells). In vitro tests of possible mechanisms that might have caused the in vivo increase in red blood cell sodium content gave the following results: 1) Incubations of red blood cells in a physiological salt solution (PSS) containing deoxycorticosterone failed to cause an increase in cell sodium content. 2) No ouabain-like factor was demonstrated in plasma from the DOCA hypertensive pigs. 3) An elevation in bicarbonate concentration in the PSS caused an increase in red blood cell sodium content. 4) A decrease in potassium concentration in the PSS also caused an increase in red blood cell sodium content.(ABSTRACT TRUNCATED AT 250 WORDS)

Red blood cell sodium transport and phosphate release in uremia.

Red blood cell (RBC) phosphate release was linear for more than 1 h and dependent on the intracellular hydrolysis of organic phosphate esters. In uremics on chronic hemodialysis total phosphate release was significantly increased suggesting an elevated RBC energy metabolism. Ouabain-sensitive phosphate release, however, was decreased. For RBCs of controls and uremic subjects approximately 80% of inorganic phosphate liberated within the cell was recycled. Thus, RBC phosphate release represents 20% of intracellular phosphate ester metabolism. In uremia active electrolyte transport was diminished, suggesting an impaired Na-K-ATPase activity. It resulted in an increased RBC sodium and a decreased potassium concentration. The positive correlation between ouabain-sensitive rate constant for sodium efflux and ouabain-sensitive RBC phosphate release indicates that ouabain inhibition of phosphate elimination might be related to Na-K-ATPase. In RBCs of uremic subjects almost 4% of the increased energy metabolism was needed for active electrolyte transport mechanisms, in control RBCs 12% was required.

Chronic lithium treatment and twenty-four hour rhythm of serum prolactin, growth hormone and melatonin in rats

This study was undertaken to extend the observations that lithium chloride has the ability to phase shift the 24-hour pattern of a large number of physiological parameters relative to the environmental lighting cycle. Adult male Wistar rats were housed individually in a temperature and sound controlled environment under a lighting schedule of 12 hours dark/12 hours light. Six point 24-hour maps were generated by taking measurements every four hours throughout 24 hours on separate groups of rats maintained for six weeks on ad lib water and one of three diets: 1) normal lab chow, 2) lab chow supplemented with 50 mM/kg of lithium chloride, 3) lab chow supplemented with 50 mM/kg of sodium chloride to control for the effects of a possible salt load. Variables measured included plasma and red blood cell lithium and sodium concentrations, serum prolactin, growth hormone and melatonin. Plasma lithium levels were 0.7–1.0 mEq/L. Plasma, but not red blood cell lithium levels deomonstrated a 24-hour rhythm with higher levels following the normal feeding period. Serum and red blood cell sodium levels did not differ among the diets and showed no 24-hour variation. The sodium diet had no significant effects on any of the variables measured. The 24-hour pattern of prolactin was not significantly affected by the diets, while growth hormone and melatonin levels differed in animals on the lithium diet. During the light hours when growth hormone levels are normally falling and melatonin levels are barely detectable, there were no differences on these measurements among the diets. However. during the dark hours when growth hormone and melatonin normally evidence a rise that peaks near the end of the dark phase, lithium fed animals evidence low unchanging levels of growth hormone, while melatonin levels reached peak values in the middle of the dark phase, four hours prior to the controls. The delay in peak values for growth hormone levels is in agreement with the pattern of phase shifting effects observed for many other physiological variables following lithium treatment, namely, a delay or shift to the right. However, the shifting of the melatonin peak to an earlier time In the 24-hour cycle is a unique finding. In rats, serum melatonin comes exclusively from the pineal. In view of the importance of this gland in biological rhythms, the unique shift to the left for melatonin following lithium treatment has important implications for the mechanisms, whereby lithium exerts its rhythm altering effects on biological systems.

Storage and survival of red blood cells with elevated sodium levels.

Approximately 25 percent of black blood donors have an elevated red blood cell (RBC) sodium (Nai) level compared with white donors. This elevation results in a significant increase in the mean Nai from black (9.00 +/- 2.96 mmoles/l RBC) as compared to white blood donors (7.04 +/- 1.48 mmoles/l RBC, p less than 0.001). Red blood cells from four black donors with mean Nai levels of 15 +/- 2.8 mmoles/l RBC were stored for 35 days in citrate-phosphate-dextrose-adenine and compared to that of four donors with normal levels of Nai. Serial measurements of red blood cell adenosine triphosphate, diphosphoglycerate, glucose-6-phosphate dehydrogenase, pyruvic kinase, lactate production rates, and intracellular cations showed no differences between the two donor groups. Furthermore, the mean 24-hour posttransfusion survival was not significantly different for the high Nai group (83.2 +/- 5.6%) as compared with the control group (82.3 +/- 6.9%). Based on this study, it is not necessary to eliminate individuals with an elevated red blood cell Nai level as blood donors.

Red blood cell sodium content and permeability changes in hemorrhagic shock

Recent studies of cellular function have demonstrated significant alterations of cell homeostasis during hemorrhagic shock. The progressive depolarization of cell membranes demonstrated in several organs has been attributed to failure of energy-dependent active ion transport. Similar changes in intracellular electrolyte composition have been observed in the red blood cells of some patients in late hemorrhagic shock and in other severely ill patients. The ready availability of isolated cells that do not require extracellular fluid space assessment makes the red blood cell an attractive model for investigating the factors controlling ion movements across the cell wall. It has been suggested that the red blood cell ion abnormalities may represent a generalized cellular response to severe illness. Red blood cell sodium concentration was measured in 145 patients during severe hemorrhagic shock. The direction and magnitude of changes in red blood sodium concentration was correlated with the time course of the shock state. The initial decrease in sodium content was a function of the diminished red blood cell membrane permeability due to a decrease in plasma bicarbonate levels. The subsequent red blood cell sodium uptake above the normal range, not associated with an increase in sodium influx, indicated an impairment of energy-dependent active transport. The observed high sodium concentrations associated with a potassium decrease in the red blood cell appeared to be only one manifestation of a generalized defect in cellular function and composition during severe hemorrhagic shock.

Origin of sodium ions appearing in the venous blood plasma during acute venous congestion and hemorrhagic hypotension: a study on kidneys and skeletal muscle of dogs.

We studied the origin of sodium ions which appeared in a higher concentration in the venous blood plasma obtained from the renal or femoral vein, than in the arterial blood plasma during acute renal venous congestion, acute venous congestion of hindlimbs and acute hemorrhagic hypotension. We measured the sodium concentration in the blood plasma as well as in hemolyzed blood obtained with sonication. In addition, sodium contents of the kidneys and skeletal muscle were determined. All experiments were performed on anesthetized mongrel dogs. Sodium contents of the kidneys and skeletal muscle of hindlimbs, in terms of milliequivalent per gram dry tissue weight, was decreased significantly 30-40 min after exposure of the kidneys and hindlimbs to acute venous congestion, or after exposure of hindlimbs to hemorrhagic hypotension, indicating a release of sodium ion into the blood stream. The sodium ion concentration became slightly higher in the venous blood than in the arterial blood, in terms of both blood plasma and hemolyzed blood, during 15-30 min of exposure of hindlimbs to local venous congestion or hemorrhagic hypotension, again indicating a release of sodium ion into the blood stream. However, acute renal vein congestion caused the sodium ion concentration to become slightly higher in the venous blood than in the arterial blood, only in terms of blood plasma, and not in terms of hemolyzed blood, indicating that red blood cell sodium is the origin of sodium ions which appeared in the renal venous plasma during acute renal vein congestion.

Effect of chronic lithium treatment on twenty four hour variation in plasma and red blood cell lithium and sodium concentrations, drinking behavior, body weight, kidney weight, and corticosterone levels

This study tested the hypothesis that lithium alters the phase relationships of various 24-hour rhythms. Six point 24-hour patterns were measured throughout a 12 hour light/12 hour dark cycle from separate groups of individually housed adult male wistar rats maintained for six weeks on ad lib water and either 1) Normal lab chow, 2) Lab chow supplemented with 50mM/KG of lithium chloride, or 3) Lab chow supplemented with 50mM/KG of sodium chloride. Plasma lithium levels were 0.7–1.0 mEq/1. The sodium diet had no effect on any of the variables measured relative to normal controls. Plasma but not red blood cell lithium levels demonstrated a 24-hour rhythm with higher levels during darkness. Serum and red blood cell sodium levels did not differ among the diets and showed no 24-hour variation. Lithium treated rats weighed signficantly less than controls and had significantly heavier kidneys per 100 grams of body weight than controls. Resting plasma corticosterone levels demonstrated the expected 24-hour pattern in all groups, however, the lithium group evidenced higher levels during the middle of the dark hours than either control group. Water consumption also demonstrated a 24-hour rhythm. Lithium animals consumed far greater quantities of water than controls and this behaviour became increasingly exaggerated over the duration of the study. The data are interpreted as suggesting that lithium broadens the peak of twenty four hour rhythms such that normal elevation in these measures appear earlier and last longer.

Zinc concentrations in plasma and erythrocytes in digitalized patients.

Determination of zinc, sodium, potassium and magnesium in plasma and red blood cells were performed in 31 controls and 63 patients treated with digitalis. In digitalized patients sodium and zinc concentrations in red blood cells were significantly increased. The intraerythrocyte magnesium and potassium levels as well as all investigated electrolytes in plasma remained within the normal range. There was a close relationship between the increase of sodium and zinc content in red blood cells, indicating alterations in transmembrane transport mechanisms induced by digitalis therapy.

Red blood cell sodium, potassium, and ATP levels during hemorrhagic shock

The effects of hemorrhagic shock and whole blood transfusions on red blood cell (RBC) Na +, K +, and ATP levels have been studied using two shock models. Group A animals were bled to a pressure of 40 mm Hg, following which no further blood was removed or returned. The blood pressure of these rats increased to approximately 70 mm Hg within 30 min and remained at that level for 2 hr. Group B animals were bled to a pressure of 40 mm Hg and maintained at that level for 2 hr. No significant changes in RBC Na + or K + levels were found in Group A animals subjected to shock. However, small but significant changes in RBC cations were observed in Group B animals subjected to hemorrhagic shock. In Group B, ATP levels decreased from 1.51 to 1.27 mmole/liter RBC. In another study (Group C), rats were subjected to shock as in Group B but were transfused with rat's whole blood which had been stored in cold ACD buffer for 6 days instead of their own shed blood. RBC Na + of Group C increased from 3.5 ± 0.1 to 8.4 ± 0.7, and K + decreased from 100.3 ± 2.3 to 85.0 ± 2.1. The RBC Na + of stored blood itself increased by 288 and 355% at 3 and 6 days cold storage, respectively. These results indicate that (1) severe hemorrhagic shock produces small changes in RBC Na + and K + levels; and (2) large changes in RBC cation levels which have been reported previously in man may be due to the additional effect of transfusion of stored blood.

Red blood cell sodium and potassium after hydrochlorothiazide

In six of seven healthy males 6 days of hydrochlorothiazide (HCT), 50 mg twice daily, without potassium supplements resulted in a rise in red blood cell (RBC) sodium concentration. Serum potassium concentration fell in all subjects. Four days after discontinuing HCT, intracellular sodium and extracellular potassium concentrations had normalized. Throughout the evaluation period the course of mean relative intracellular sodium was almost a mirror image of mean relative extracellular potassium. Thus, either the decline of serum potassium or of HCT (because of its inhibitory effect on Na-K-ATPase activity) might have diminished Na-K-ATPase-dependent active RBC sodium efflux with a resultant rise in erythrocyte sodium concentration. RBC potassium and serum sodium concentrations were not affected by short-term exposure to HCT.