Status of the red cell Na,K-pump in hyper- and hypothyroidism

doi:10.1016/0026-0495(83)90151-8

Metabolism

Volume 32, Issue 1, January 1983, Pages 25-30

https://doi.org/10.1016/0026-0495(83)90151-8 Get rights and content

Abstract

To investigate the status of the sodium-potassium pump in cells of human subjects with abnormal thyroid function, we measured the number of pump units as well as the cation transport activity of the pump in erythrocytes from 23 hyperthyroid and 7 hypothyroid patients. It was found that the number of Na⁺-K⁺-ATPase units in erythrocytes (as measured by ouabain binding) was significantly reduced in hyperthyroidism (mean 36% below controls, p < 0.001). The rate of rubidium uptake by the same cells was also reduced, but to a smaller extent (mean 9%, p < 0.02). These changes were reversible with control of the hyperthyroidism. Hypothyroid individuals showed changes in erythrocyte Na⁺-K⁺ pump which were in the opposite direction to those seen in hyperthyroidism. It is concluded that thyroid hormone exerts a marked negative influence on the number of Na⁺-K⁺ pump units in one easily available human cell type. The direction of the effect suggests a complex relationship between thyroid hormone and the level of the Na,K-ATPase in any one tissue. Whatever the cellular mechanism responsible for the effects observed in the red cell, these changes should provide a measure of thyroid hormone action at a cellular level and this may prove useful in the study of thyroid hormone physiology in man.

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Mechanism of thyroid calorigenesis: Role of active sodium transport
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Cited by (41)

Impaired NA+,K+ATPase activity in red blood cells in euthyroid women treated with levothyroxine after total thyroidectomy for Graves' disease
1998, Metabolism: Clinical and Experimental
In patients suffering from hyperthyroidism dependent on Graves' disease, a reduction in Na⁺,K⁺ATPase activity has been demonstrated in red blood cells (RBCs), as well as an inverse correlation between this enzymatic action and free triidothyronine (FT₃) levels. The restoration of normal FT₃ values also brings about a normalization of Na⁺,K⁺ATPase activity in erythrocytes. These results have made it possible to hypothesize that the thyroid hormones control Na⁺,K⁺ATPase activity and that this control is manifested by means of variations in the number of ouabain-binding sites. For this reason, the measurement of the activity of the Na/K pump can be considered as a further indicator of the peripheral effects of thyroid hormones. With a view to assess the relation between the course of treated hyperthyroidism and Na⁺,K⁺ATPase activity during antithyroid therapy and after surgical thyroidectomy followed by replacement therapy, we studied 24 patients affected by Graves' disease (group Graves [GG]). They were compared with 24 female Graves' patients who underwent total thyroidectomy for nontoxic and diffuse nodular goiter (NDNG) (group control [GC]) and with 24 normal healthy women (group normal [GN]). When Graves' hyperthyroidism was diagnosed, the Na⁺,K⁺ATPase activity in RBCs was impaired in all GG patients. Thionamide treatment restored the normal activity of the Na/K pump, accompanied by normalization of the number of ouabain-binding sites. One hundred eighty days after thyroidectomy, in conditions of clinical and biochemical euthyroidism due to replacement therapy with levothyroxine, the activity of Na⁺,K⁺ATPase in RBCs was once again reduced in GG, while appearing normal in GC and GN (1.77 ± 0.16 mmol Pi h⁻¹ · L⁻¹ RBCs v 2.09 ± 0.26 v 2.09 ± 0.24, P < .05). Different instrumental or biochemical parameters, such as glycemia, serum lipids, ions, serum alkaline phosphatase (AlPh), serum creatine phosphokinase (CPK), blood pressure, and heart rate, were evaluated and appeared normalized in GG and GC 180 days after surgery. We conclude that (1) in patients suffering from Graves' disease, subjected to total thyroidectomy followed by levothyroxine replacement therapy, there is a reduction in the activity of the Na⁺,K⁺ATPase on erythrocytes 6 months after the surgical approach; and (2) a similar alteration is not observed in patients subjected to thyroidectomy for NDNG. These findings allow the formulation of the hypothesis that (1) treatment with levothyroxine for 180 days after thyroidectomy in GG is not long enough to restore the normality of all the peripheral indicators of action of the thyroid hormones; and (2) levothyroxine replacement therapy is unable to guarantee euthyroidism in all the tissues in GG (eg, during hematopoiesis in the bone marrow).
Changes of erythrocyte ouabain maximum binding after birth in neonates - in relation to erythrocyte sodium and potassium concentrations
1995, Early Human Development
Erythrocyte ouabain maximum binding (V_max level) represents the number of molecules of Na-K ATPase on the erythrocyte membrane. Erythrocyte V_max levels and sodium potassium concentrations were studied in 38 mature and 57 premature infants, including 40 very low birth weight infants, 41 children and 16 adults, in order to clarify the development of erythrocyte Na-K ATPase related to mineral balance and thermogenesis. V_max levels were the highest (22.9 ± 8.9 nmol/l cells) for premature infants; correlated negatively with gestational age (r = −0.77, P < 0.01). V_max levels correlated positively with the ratio of erythrocyte potassium to sodium concentration ( $IC-K Na$ ) at <20 nmol/1 cells of V_max levels (r = 0.72, P < 0.01), but not at ≧20 nmol/l cells (r = 0.23). V_max levels in very low birth weight infants, especially <28 weeks postconception, decreased gradually with postnatal days. LnV_max levels correlated negatively with postconceptional age (r = −0.75, P < 0.01). Under 28 weeks postconception, V_max levels were high, but not correlated with $IC-K Na$ . It is probable that individual Na-K ATPase molecules may be less active, and the large numbers of Na-K ATPase molecules may compensate for the individual lower activity.
Stimulation of the Na+,K+-ATPase activity of K562 human erythroleukemia cells by triiodothyronine
1992, Life Sciences
The effect of triiodothyronine (T₃) on Na⁺,K⁺-ATPase activity of K562 human erythroleukemic cell was studied to understand why the erythrocyte sodium pump activity is decreased in hyperthyroidism. Na⁺,K⁺-ATPase activity of K562 cell lysates was assayed by measuring the release of inorganic phosphate (Pi) from ATP. Na⁺,K⁺-ATPase activity of K562 cell grown in the presence of T₃ for 48 hours was significantly higher than that of control (0.98±0.05 μmol Pi h⁻¹ mg protein⁻¹ vs 0.82±0.10 μmol Pi h⁻¹ mg protein⁻¹, p<0.05). The Na⁺,K⁺-ATPase activity could be stimulated in a time- and concentration-dependent manner; maximum stimulatory effect of T₃ was seen at a concentration of 10⁻⁷ mol/L. When an inducer [cytosine-β-D-arabino-furanoside (ARA-C)] was added to the culture medium, the K562 cells showed signs of differentiation and synthesised haemoglobin. At the same time, the Na⁺,K⁺-ATPase activity remained high. We conclude that T₃ stimulates Na⁺,K⁺-ATPase activity of K562 cells and in the presence of T₃ during differentiation, the enzyme activity remains high.
Ouabain-binding sites of reticulocytes from guinea pigs treated with triiodothyronine
1991, Metabolism
To understand the mechanism of reduced number of sodium pump units (ouabain-binding sites, OBS) of erythrocytes in hyperthyroidism, OBS of reticulocytes from guinea pigs injected with triiodothyronine (T₃) were measured. Reticulocytosis was induced in 16 guinea pigs by withdrawing 6 to 10 mL of blood for 5 days followed by 2 days rest. T₃ ( $50 μ g 100 g$ body weight) was injected into seven animals on days 4 and 6, and the remainder were injected with solvent for T₃. Reticulocyte-rich blood was withdrawn on day 8. Oxygen consumption determined 24 hours after the first injection of T₃ was 30% higher in the T₃-treated animals (P < .001). OBS of reticulocytes from control animals were sixfold higher than that of mature erythrocytes. Reticulocytes from T₃-treated guinea pigs had significantly lower OBS (P < .01) compared with controls. We conclude that the loss of OBS induced by thyroid hormones probably occurs during the formation of reticulocytes.
Erythrocyte sodium fluxes, ouabain binding sites, and Na+, K+-ATPase activity in hyperthyroidism
1990, Metabolism
Erythrocyte sodium pump activity, in contrast to other tissues, is decreased in hyperthyroidism. In order to examine whether the effect of thyroid hormones on erythrocytes is part of a generalized effect on other transport pathways, we measured sodium pump activity, Na⁺,K⁺-adenosine triphosphatase (ATPase) activity, ouabain binding sites, bumetanide-sensitive sodium potassium cotransport (SPC), sodium lithium countertransport (SLC), and ouabain- and bumetanide-insensitive passive efflux of sodium (sodium “leak”) in erythrocytes from 20 healthy subjects and 18 untreated hyperthyroid subjects. Sodium pump activity (ouabain-sensitive sodium efflux rate constant), Na⁺,K⁺-ATPase activity, and the number of ouabain binding sites were lower and the erythrocyte sodium content was higher in hyperthyroid subjects. The rate constants of erythrocyte SPC (P < .05), SLC (P < .001), and sodium “leak” (P < .05) were also significantly lower in hyperthyroidism. In 11 of the hyperthyroid subjects, sodium flux measurements were repeated after 20 weeks of treatment. Sodium pump activity, the number of ouabain binding sites, and the rate constant for SLC increased. These results suggest that the effect of thyroid hormones on the erythrocyte sodium pump is part of a generalized effect on membrane proteins, rather than a specific effect.
Erythrocytes from diabetics with neuropathy have fewer sodium pumps
1990, Diabetes Research and Clinical Practice
Erythrocytes from diabetics with neuropathy had fewer binding sites for ouabain and, therefore, fewer sodium pumps than did erythrocytes from diabetics without neuropathy or from age-matched controls (P < 0.001). Diabetics with neuropathy excreted in their urine significantly less C-peptide immunoreactivity (CPR) than those without neuropathy, which is a sign of lower endogenous insulin secretion levels. Significant positive correlations existed between the number of pumps and tibial motor nerve conduction velocity (MNCV) and urinary CPR in diabetics, and between urinary CPR and MNCV. This suggests that there is close correlation between the fall in the number of pumps in diabetics and diabetic neuropathy and insulin deficiency.

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^☆: Supported in part by a grant from the American Diabetes Association and grant #AM28082-01 from the National Institutes of Health.

¹: Dr. M. DeLuise is a C.J. Martin Fellow of the National Health and Medical Research Council of Australia.

²: Dr. Flier is the recipient of an National Institutes of Health Research Career Development Award #1 KO4 AM00856-01.

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Metabolism

Abstract

References (18)

Increased (Na⁺ + K⁺)ATPase concentrations in various tissues of rats caused by thyroid hormone treatment

J Biol Chem

Red cell ouabain binding sites, Na⁺ + K⁺-ATPase and intracellular Na⁺ as individual characteristics

Life Sciences

Mechanism of thyroid calorigenesis: Role of active sodium transport

Relationships between Na⁺-dependent respiration and Na⁺ + K⁺-adenosine triphosphatase activity in rat skeletal muscle

J Clin Invest

Dependence of renal (Na⁺ + K⁺)-adenosine triphosphatase activity on thyroid status

J Biol Chem

Thyroid thermogenesis

N Engl J Med

Time course of the effect of thyroid hormone on respiration and Na⁺ + K⁺-ATPase activity in rat liver

Thyroid thermogenesis in adult rat hepatocytes in primary monolayer culture. Direct action of thyroid hormone in vitro

J Gen Physiol

Alteration in intracellular sodium concentration and ouabain sensitive ATPase in erythrocytes from hyperthyroid patients

J Clin Endocrinol Metab

Cited by (41)

Impaired NA<sup>+</sup>,K<sup>+</sup>ATPase activity in red blood cells in euthyroid women treated with levothyroxine after total thyroidectomy for Graves' disease

Changes of erythrocyte ouabain maximum binding after birth in neonates - in relation to erythrocyte sodium and potassium concentrations

Stimulation of the Na<sup>+</sup>,K<sup>+</sup>-ATPase activity of K562 human erythroleukemia cells by triiodothyronine

Ouabain-binding sites of reticulocytes from guinea pigs treated with triiodothyronine

Erythrocyte sodium fluxes, ouabain binding sites, and Na<sup>+</sup>, K<sup>+</sup>-ATPase activity in hyperthyroidism

Erythrocytes from diabetics with neuropathy have fewer sodium pumps

Status of the red cell Na,K-pump in hyper- and hypothyroidism☆

Abstract

J Biol Chem

Life Sciences

Mechanism of thyroid calorigenesis: Role of active sodium transport

Relationships between Na+-dependent respiration and Na+ + K+-adenosine triphosphatase activity in rat skeletal muscle

J Clin Invest

Dependence of renal (Na+ + K+)-adenosine triphosphatase activity on thyroid status

J Biol Chem

Thyroid thermogenesis

N Engl J Med

Time course of the effect of thyroid hormone on respiration and Na+ + K+-ATPase activity in rat liver

Thyroid thermogenesis in adult rat hepatocytes in primary monolayer culture. Direct action of thyroid hormone in vitro

J Gen Physiol

Alteration in intracellular sodium concentration and ouabain sensitive ATPase in erythrocytes from hyperthyroid patients

J Clin Endocrinol Metab

Relationships between Na⁺-dependent respiration and Na⁺ + K⁺-adenosine triphosphatase activity in rat skeletal muscle

Dependence of renal (Na⁺ + K⁺)-adenosine triphosphatase activity on thyroid status

Time course of the effect of thyroid hormone on respiration and Na⁺ + K⁺-ATPase activity in rat liver