Red Cell Sodium Content Research Articles

In vitro Interactions Between Oxygen and Carbon Dioxide Transport in the Blood of the Sea Lamprey (Petromyzon Marinus)

ABSTRACT In vitro experiments were carried out to examine the interactions between oxygen and carbon dioxide transport in the blood of the sea lamprey. Oxygen dissociation curves for whole blood obtained from quiescent lampreys had Hill numbers (NH) ranging from 1.52 to 1.89. The Bohr coefficient for whole blood was −0.17 when extracellular pH (pHe) was considered, but was much greater (−0.63) when red blood cell pH (pHi) was considered. The pHi was largely dependent on haemoglobin oxygen-saturation and the pH gradient across the red blood cell membrane was often reversed when was increased and/or was lowered. The magnitude of the increase in pHi associated with the Haldane effect ranged from 0.169 pH units at 2.9 kPa to 0.453 pH units at a of 0.2 kPa. Deoxygenated red blood cells had a much greater total CO2concentration than oxygenated red blood cells, but the nonbicarbonate buffer value for the red blood cells was unaffected by oxygenation. Plasma was not significantly different under oxygenated or deoxygenated conditions. Partitioning of CO2 carriage in oxygenated and deoxygenated blood supports recent in vivo observations that red blood cell CO2 carriage can account for much of the difference between arterial and venous blood. Together, the results also suggest that oxygen and carbon dioxide transport may not be tightly coupled in the blood of these primitive vertebrates. Finally, red cell sodium concentrations were dependent on oxygen and carbon dioxide tensions in the blood, suggesting that sodium-dependent ion transport processes may contribute to the unique strategy for gas transport in sea lamprey blood.

Clinical application of sodium-23 nuclear magnetic resonance for measurement of red cell sodium concentrations

Red cell sodium (RBC-Na+) concentrations were measured using 23Na nuclear magnetic resonance (NMR), without the destruction of erythrocyte membranes. Subjects were categorized into four groups: 20 normotensive subjects (NT group), 20 age-matched essential hypertensive patients (EHT group), 10 patients with primary aldosteronism (PA group), and 18 patients treated with digoxin (DIG group). Although RBC-Na+ concentrations were similar between the NT group (6.14±0.80 (Mean±SD) mmol/1) and the EHT group (5.92±0.99), they were significantly higher in both the PA group (7.55±0.88, p<0.001) and the DIG group (8.43±3.81, p<0.02). In the PA group, RBC-Na+ concentrations decreased significantly after resection of the adenoma, and there was an inverse relationship between serum potassium and RBC-Na+ concentrations (r=−0.65, p<0.01). In the DIG group, RBC-Na+ concentrations tended to increase in proportion to serum digoxin levels (r=0.53, p<0.05). These results support the view that RBC-Na+ concentrations are determined primarily by Na+/K+-pump activity of red cell membranes. This study showed also that Na+ NMR is an useful method determining intracellular Na+ concentrations.

Clinical application of sodium-23 nuclear magnetic resonance for measurement of red cell sodium concentrations

Red cell sodium (RBC-Na+) concentrations were measured using 23Na nuclear magnetic resonance (NMR), without the destruction of erythrocyte membranes. Subjects were categorized into four groups: 20 normotensive subjects (NT group), 20 age-matched essential hypertensive patients (EHT group), 10 patients with primary aldosteronism (PA group), and 18 patients treated with digoxin (DIG group). Although RBC-Na+ concentrations were similar between the NT group (6.14 +/- 0.80 (Mean +/- SD) mmol/l) and the EHT group (5.92 +/- 0.99), they were significantly higher in both the PA group (7.55 +/- 0.88, p less than 0.001) and the DIG group (8.43 +/- 3.81, p less than 0.02). In the PA group, RBC-Na+ concentrations decreased significantly after resection of the adenoma, and there was an inverse relationship between serum potassium and RBC-Na+ concentrations (r = -0.65, p less than 0.01). In the DIG group, RBC-Na+ concentrations tended to increase in proportion to serum digoxin levels (r = 0.53, p less than 0.05). These results support the view that RBC-Na+ concentrations are determined primarily by Na+/K+-pump activity of red cell membranes. This study showed also that Na+ NMR is an useful method determining intracellular Na+ concentrations.

Erythrocyte sodium content and transport in borderline and mild hypertension

Sodium content and transport of red blood cells were examined in 98 male blood donors. Regarding their blood pressure they were classified into the following groups: (a) 57 normotensives, (RR less than 140/90 mm Hg); (b) 24 borderline hypertensives (140/90 less than or equal to RR less than 160/95 mm Hg); and (c) 17 hypertensives (RR greater than 160/100 mm Hg). Compared with the normotensives the borderline hypertensives have significantly reduced red cell sodium content. The ouabain-resistant net Na+ uptake and the relative Na+ uptake, as a measure of the Na+/K+ pump, were significantly increased. With rising blood pressures the measured values turn to normal, so that no difference exists between the normotensive and hypertensive groups. It is supposed that in the initial or even prehypertensive state a considerable enhancement of the pump activity occurs, simultaneously accompanied by less marked increases in sodium influx, leading to a reduced intracellular sodium content. In the course of hypertension, possibly caused by the formation of a pump inhibitor, the sodium content of red cells turns to normal or supernormal values.

The influence of potassium and bicarbonate on red blood cell sodium in the DOCA-hypertensive pig.

The effects of plasma potassium, and blood bicarbonate on red blood cell sodium were studied in vivo in seven pigs implanted subcutaneously with DOCA (100 mg/kg) impregnated in Silastic. Mean arterial pressure, red blood cell sodium, plasma sodium, plasma potassium, and blood bicarbonate were measured from 5 days pre-implant to 30 days post-implant. One day post-implant, the pigs had significant increases in mean arterial pressure and red cell sodium content, and a significant decrease in plasma potassium concentration. In KCl infusion studies when plasma potassium was raised an average of 2.13 +/- 0.17 mEq/L, red blood cell sodium fell 0.61 +/- 0.10 mEq/L cells. When blood bicarbonate was raised 6.9 mEq/L by infusing NaHCO3, red blood cell sodium increased 0.79 mEq/L cells. The changes in red blood cell sodium were rapid, occurring within one hour after either of these plasma electrolyte shifts. We conclude that either plasma potassium or blood bicarbonate, or both, can serve as regulators of red blood cell sodium content in vivo, and cause the elevated level of red blood cell sodium that we have found in the DOCA-hypertensive pig. If these plasma electrolyte changes cause a similar increase in intracellular sodium in vascular smooth muscle or in a blood pressure regulating center in the brain, they may play a role in producing the arterial pressure elevation of mineralocorticoid-induced hypertension.

The effect of oral digoxin on sodium excretion, renin-angiotensin-aldosterone system and blood pressure in normotensive subjects.

The effect of digoxin (0.25 mg t.d.s.) given orally for 5 days, on sodium excretion, plasma renin activity, plasma aldosterone and blood pressure has been studied in 6 normotensive subjects, on a constant sodium intake. Average serum digoxin level measured in 5 subjects on the 5th day of treatment was in the upper range of the therapeutic level (1.92 +/- 0.3 nmol/l). Red cell sodium content increased from 9.75 +/- 1.2 mmol/l of cells in the control period to 15.3 +/- 1.7 mmol/l of cells on the 5th day of digoxin treatment when measured in 4 of the 6 subjects. In spite of this evidence of inhibition of the red cell sodium pump, there was no detectable change in sodium excretion, blood pressure, plasma renin activity and aldosterone.

Erythrocyte lithium transport changes induced by deoxycorticosterone acetate treatment in pigs.

Ouabain-insensitive lithium efflux from lithium-loaded pig erythrocytes has sodium-dependent and sodium-independent components. Lithium effluxes into sodium (total efflux) and sodium-free (leak) media, sodium-dependent lithium efflux, defined as the difference between total and leak fluxes, and changes in red cell cation and water contents as well as blood pressure were assessed serially for 3 weeks in pigs implanted with Silastic strips impregnated with deoxycorticosterone acetate or with Silastic alone and maintained on a high salt diet (200 mEq/day). Significant differences developed between the groups in blood pressure, red cell sodium content, red cell water content, leak flux, and sodium-dependent lithium efflux (maximal difference: 648 +/- 60 vs 256 +/- 81 mumoles of lithium per liter of cells per hour, deoxycorticosterone acetate vs controls; p less than 0.01). Increased sodium-dependent lithium efflux paralleled a decrease of the diffusional leak component of lithium efflux; total lithium efflux was unchanged. Deoxycorticosterone acetate hypertension in pigs is a useful model in which to study factors modulating erythrocyte cation content and lithium transport in vivo. Changes in lithium transport characterized in red blood cells in this form of experimental hypertension may reflect generalized membrane phenomena.

Sex and race differences in sodium-lithium countertransport and red cell sodium concentration.

A total of 417 individuals from all four major sex-race groups were examined for the rate of sodium flux via the countertransport pathway and the sodium concentration within red cells. The age span was from early adolescence to retirement. Males of both races had sizable higher countertransport rates than did women (p less than 0.01), and a slight increase in sodium concentration (p greater than 0.05). Contrariwise, while whites or both sexes had higher countertransport than their black counterparts, sodium concentration was higher in blacks than whites (p less than 0.01). This pattern is not consistent with a direct relationship between both countertransport or sodium concentration and blood pressure which applies across both racial groups. Sex-race differences must be taken into account in any group comparisons of these variables.

Abnormal red cell sodium content and efflux in Japanese patients with essential hypertension.

Net sodium (Na) efflux and potassium (K) influx were determined in Na-loaded/K-depleted erythrocytes derived from 37 patients with essential hypertension and 25 age-matched normotensive subjects with no family history of hypertension, together with the measurement of basal red cell sodium and potassium contents. Intraerythrocyte sodium content was significantly higher in the essential hypertensives than in the normotensives (10.9 +/- 1.4 vs 10.0 +/- 1.2 mmol/L X cells, mean +/- SD, p less than 0.02), but potassium content was nearly equal between the two groups. Net Na efflux in the hypertensives was significantly reduced compared with that in the normotensives (4.57 +/- 0.70 vs 5.18 +/- 1.02 mmol/L X cells X hr, p less than 0.01), but both net K influx and net Na/K flux ratio were not significantly different between the two groups. Net Na efflux and K influx showed a significant inverse correlation with red cell sodium content (r = -0.64 and r = -0.56, respectively, p less than 0.001). These results suggest that the reduced net Na efflux with the increase of red cell sodium content may be related to the pathogenesis of essential hypertension. However, it is impossible to determine the genetic marker of essential hypertension by using the net Na/K flux ratio of Japanese subjects, although Garay et al. have reported that this index was abnormally low in the case of Europeans.

Effect of sodium intake on intraerythrocyte sodium concentration in normotensive subjects and patients with untreated mild hypertension.

The effect of changing sodium intake for 2 weeks was studied. Twelve normotensive subjects and five patients with mild essential hypertension were given two different levels of sodium intake for 2 weeks. Overall there was no significant rise in blood pressure but all patients with hypertension had a rise in blood pressure as they went from a low to a high sodium intake. Plasma sodium was not altered but red cell sodium concentration was higher on the high sodium intake. This effect was observed in both normotensive and hypertensive people. Alterations observed in cell sodium concentration provide support for the hypothesis that increased dietary intake of sodium may induce hypertension by causing changes in cellular transport systems.

Methodological assessment of assays for red cell sodium concentration and sodium-dependent lithium efflux

Assays for red cell sodium concentration and sodium-dependent lithium efflux were studied from a methodological point of view. The technical errors for sodium concentration—based on concurrent analysis of randomized blind duplicate samples —was 2.5% and for lithium efflux 6.4%. Based on repeated measures in the same individual, the assays were stable over time and reproducible; individual differences at a mean interval of 16 days were not significantly different. A wait of two hours from time of phlebotomy to analysis yielded a slight (3.8%) but significant fall in the sodium concentration; no further change was found at four hours. No change occurred in the lithium efflux over time. A standardized breakfast containing 664 mg sodium did not affect the measurements when fasting and three-hour postprandial levels were compared. The ratios of intra- to inter-individual variances were small—0.04 for red cell sodium concentration and 0.09 for sodium-stimulated lithium efflux. These assays appear to be reproducible and stable and can be applied in large scale field trials.

Pituitary resistance to thyroid hormone in cystinosis.

Eleven children with nephropathic cystinosis without clinical features of hyperthyroidism or hypothyroidism had elevated serum levels of immunoreactive TSH. The mean TSH level (+/- SE) was 37.4 +/- 12.3 microM/ml. Serial determinations of thyroid function during 1 yr were: mean (+/- SE) serum T4, 10.8 +/- 0.7 microgram/dl; free T4, 2.1 +/- 0.2 ng/dl; and T3, 239 +/- 6 ng/dl. After 500 microgram TRH iv, the peak TSH level exceeded 100 microU/ml in 6 of 10 patients, whereas T3 responses were variable. Studies of parameters influenced by thyroid hormone, including red cell sodium content, serum cholesterol, and 24-h urinary hydroxylysine excretion, were consistent with euthyroidism. On the other hand, the mean pulse wave arrival time was significantly reduced, consistent with hyperthyroidism. Three control patients, 2 with Lowe's syndrome and 1 with benign cystinosis, had normal thyroid studies. Eight of the patients were given either exogenous L-T4 or T3 in doses which were increased at weekly intervals. The serum TSH concentrations were suppressed to normal only after elevation of serum levels of thyroid hormones and with high exogenous thyroid replacement doses. The data suggest abnormal pituitary resistance to feedback by thyroid hormone in patients with cystinosis. We believe this to be the first description of the association of a heritable metabolic disease with such pituitary resistance.

Red cell sodium and potassium contents in liver cirrhosis

Red cell sodium and potassium contents were investigated in 57 patients with histologically proven liver cirrhosis and were compared with 13 controls without clinical evidence of liver disease. Patients with normal serum electrolytes (and without digoxin treatment) had normal red cell sodium content indicating no influence of the cirrhosis per se on the sodium-potassium pump or membrane permeability for sodium. Red cell potassium content was elevated, possibly as a consequence of subclinical hemolysis and a relatively young cell population. Hypokalemia was correlated to increased red cell sodium. Hyponatremia was correlated to low red cell sodium indicating reduced influx due to a decreased concentration gradient. According to the concept of the “sick cell syndrome,” membrane failure and cellular gain of sodium and loss of potassium can lead to hyponatremia. Our findings of normal or low red cell sodium contents provide evidence against this mechanism as explanation for the often severe hyponatremia in terminal liver failure. The abnormalities found in the red cells could be attributed to secondary complications to the cirrhosis.

Abnormal cation composition and transport in erythrocytes from hypertensive patients.

Red cell sodium and potassium were determined in 100 untreated subjects with uncomplicated essential hypertension and compared with the values from 908 healthy normotensive control subjects. Red cell sodium concentration (expressed as mmol/l of erythrocytes) was significantly higher in hypertensive than in normotensive subjects. Red cell potassium concentration (in mmol/l of erythrocytes) was not significantly different in the two groups. Passive efflux of red cell potassium into buffered isotonic sucrose solution determined in eight hypertensive and nine normotensive subjects showed a lower potassium efflux rate in the hypertensive subjects. Comparison of active sodium efflux in sixteen hypertensive and fourteen normotensive subjects showed that ouabain-sensitive active sodium efflux was higher in red cells of normotensive than in those of hypertensive subjects.

A simple technique for the measurement of ouabain-sensitive sodium transport in red cells

A new, simple and non-radioactive technique is described for the measurement of ouabain-sensitive sodium transport in red cells, which is an alternative to the more complex standard technique using radioactive sodium. The new technique is based on the observation that when excess ouabain is added to blood, the sodium content of the red cells rises, due to complete inhibition of ouabain-sensitive sodium efflux while influx remains unchanged. The rate of increase of red cell sodium is therefore a measure of ouabain-sensitive sodium efflux ( Einos). This estimate of Eos, when expressed as a fraction of the original red cell sodium concentration, gives a measure of the ouabain-sensitive, efflux rate constant (ERC os). In healthy persons, ERC os obtained with this new technique agrees closely with that obtained with the standard radioactive technique. In hypokalaemic patients the ERC os estimated by the new technique was less than that obtained with the standard technique, but this difference disappeared as the patients became normokalaemic. We suggest that this difference arises because the new technique measures only net ouabain-sensitive sodium transport whereas the standard technique also measures the ouabain-sensitive Na : Na exchange which is present in patients with hypokalaemia.

Red cell sodium concentration as an indicator of cellular injury in clinical shock.

Red cell sodium concentration has been found to be elevated in shock. The significance of this change relative to survival and the possible sources for this increase were examined. Twenty patients in shock had red cell sodium levels compared to shock-related variables and to conditions known to increase red cell sodium levels in vitro. There was no difference noted in red cell sodium elevations between survivors and nonsurvivors. There was a highly significant correlation with transfusions of banked blood and a significant correlation with the administration of digitalis. There was no correlation with the type, duration, or severity of shock. Changes in the sodium gradients across red cell membranes in clinical shock are not good indicators of the general cellular injury of shock.

The effect of mild hyperventilation on red cell sodium.

Control subjects voluntarily overbreathed to produce end-tidal PCO2 levels similar to those found in patients suffering from neurotic or endogenous non-retarded depression. Red cell sodium content was found to decrease during overbreathing in all the subjects. The changes were similar to those usually reported for depressed patients. The results imply that red cell sodium levels are in part dependent on respiratory behaviour. They suggest a need for considerable caution in interpreting red cell sodium values from psychiatric patients.

Hereditary Stomatocytosis With Hemolytic Anemia in the Dog

Abstract An autosomal recessive mutant (symbol, dan) in the dog causes chondrodysplastic dwarfism and mild anemia as pleiotropic effects. The anemia is characterized by stomatocytosis, macrocytosis, low MCHC, increased osmotic fragility, shortened red cell survival, reticulocytosis, erythroid hyperplasia, and increased iron turnover. Minor changes can be detected in the red cells of heterozygous carriers of the dan gene, but red cell survival is normal and chondrodysplasia is not present. Red cell sodium concentration and water content are increased in anemic dogs and to a lesser degree in carriers. Glutathione deficiency is present. The disorder described here resembles a number of human hemolytic anemias with stomatocytosis, glutathione deficiency, and disordered red cell cation and water content, and further study of the dan mutant, together with investigations of the hereditary human conditions, will elucidate the maintenance of normal red cell cation balance.

The effect of hypokalaemia and of digoxin therapy on red cell sodium and potassium content. Some clinical aspects.

Red cells from patients with hypokalaemia were found to have gained sodium and lost potassium. Below a threshold of about 3.5-3.75 mmol potassium/l plasma, an increase in red cell sodium developed quite sharply, and an inverse relation to the red cell sodium concentration was clearly present. The onset of this relation was defined as the threshold of hypokalaemia and identified as the minimum concentration of potassium in plasma required to cause a measurable increase in red cell sodium. So determined, the limit for hypokalaemia agreed well with the generally accepted lower limit for plasma potassium derived statistically. The effect of digoxin treatment was also studied, and in 21 patients, after 10 days of treatment, an increase in red cell sodium concentration from 7.1 ± 1.5 to 11.9 ± 3.8 mmol/1 red cells and a decrease in red cell potassium concentration from 99.6 ± 3.7 to 95.3 ± 4. 9 mmol/l red cells were found. It is consistent with the hypokalaemia - digitalis glycoside interaction that this effect...

Diurnal variations of protein and electrolyte concentrations and of acid-base status in plasma and red cells of normal man.

Venous blood was sampled in 3-h intervals from 5 men and 4 women under conditions of normal daily activity during 24 h (Series I). Hematocrit, hemoglobin concentration in blood and red cells, sodium, potassium, magnesium and chloride concentrations in plasma and red cells, protein, calcium and inorganic phosphate concentrations and standard bicarbonate in plasma, pH in blood and red cells, pCO2 in blood were measured or calculated. Most concentration curves showed biphasic patterns with night minima which were significant for hemoglobin, hematocrit and pH in blood, protein, sodium, calcium and standard bicarbonate in plasma, potassium and pH in red cells. Inorganic phosphate in plasma alone exhibited a definite day minimum. A second series (6 subjects) with measurements made only between 06.00 and 12.00 showed changes similar to those in Series I with an additional small increase of red cell sodium concentration at noon. In a third series, where 6 subjects remained in a recumbent position up to midday, the morning increase of [Hb], Hct, pH and standard bicarbonate was clearly reproducible.