Increase in the (Na+ + K+)-ATPase activity in heart muscle after chronic treatment with digitoxin or potassium deficient diet

Bluschke, V; Bonn, R.; Greeff, K.

doi:10.1016/0014-2999(76)90021-2

Cited by 59 publications

(16 citation statements)

References 5 publications

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“…Similar increases in Na,K-ATPase expression have been noted in vivo with administration of digoxin to experimental animals (13)(14)(15) and humans (16,17). A pretranslational mechanism has been implicated in the up-regulation of Na,KATPase activity based on the finding of either low K ϩ -or ouabain-mediated augmentation of Na,K-ATPase subunit mRNA contents in established cell lines such as Madin-Darby canine kidney and ARL-15 (18,19) and in primary cell cultures derived from adult rat kidney (20) and neonatal rat ventricle (21).…”

supporting

confidence: 53%

Regulation of Na,K-ATPase β1 Subunit Gene Transcription by Low External Potassium in Cardiac Myocytes

Zhuang¹,

Wendt²,

Gick³

2000

Journal of Biological Chemistry

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Expression of Na,K-ATPase activity is up-regulated in cells incubated for extended intervals in the presence of low external K ؉ . Our previous data showed that exposure of cardiac myocytes to low K ؉ increased the steadystate abundance of Na,K-ATPase ␤1 subunit mRNA. In the present study we determined that incubation of primary cultures of neonatal rat cardiac myocytes with low K ؉ augmented Na,K-ATPase ␤1 gene expression at a transcriptional level and that this effect required extracellular Ca 2؉ . The stimulatory effect of low K ؉ on Na,KATPase ␤1 gene transcription was not dependent on increased contractile activity of cardiac myocytes. Na,KATPase ␤1 5-flanking region deletion plasmids used in transient transfection analysis demonstrated that the region between nucleotides ؊62 to ؊42 of the ␤1 promoter contained a low K ؉ response element. Site-directed mutagenesis of a potential GC box core motif GCG in the ؊58/؊56 region of the ␤1 promoter decreased basal and low K ؉ -mediated transcription. Mutation of the core sequence of a putative GC box element located between nucleotides ؊101 and ؊99 further decreased the low K ؉ effect on ␤1 gene transcription. Electrophoretic mobility shift assays using oligonucleotides spanning the proximal and distal GC box elements of the ␤1 promoter showed enhanced binding of two complexes in response to low K ؉ . The inclusion of a consensus GC box sequence as a competitor in gel shift analysis reduced factor binding to the low K ؉ response elements. Antibodies to transcription factors Sp1 and Sp3 interacted with components of both DNA-binding complexes and binding of nuclear factors was abolished in gel shift studies using GC box mutants. Together these data indicate that enhanced binding of Sp1 and Sp3 to two GC box elements in the rat Na,K-ATPase ␤1 subunit gene promoter mediates ␤1 gene transcription up-regulation in neonatal rat cardiac myocytes exposed to low external K ؉ .

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supporting

confidence: 53%

Regulation of Na,K-ATPase β1 Subunit Gene Transcription by Low External Potassium in Cardiac Myocytes

Zhuang¹,

Wendt²,

Gick³

2000

Journal of Biological Chemistry

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“…They further suggested that as treatment continued there was an adaptive increase in the number of sodium pumps in the erythrocytes, so that the active pumps (free from digoxin) increased to normal. Similar adaptive increase in number of ouabain binding sites have been found in erythrocytes in patients with prolonged hypokalaemia (Erdman & Krawietz, 1977) and in cardiac muscle during long term digoxin treatment (Blusche, Bonn & Greef, 1976). However, in our patients during long term digoxin treatment the return of the erythrocyte sodium content to normal was associated with a significant increase of erythrocyte sodium flux, efflux rate constant and Na+K+ATPase activity to values greater than those in the controls.…”

Section: Discussionmentioning

confidence: 52%

The early and late effects of digoxin treatment on the sodium transport, sodium content and Na+K+‐ ATPase or erythrocytes.

Cumberbatch¹,

Zareian²,

Davidson³

et al. 1981

Brit J Clinical Pharma

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1 Erythrocyte sodium content, sodium transport (ouabain sensitive sodium flux Eos, and ouabain sensitive efflux rate constant ERCO) sodium, potassium activated ouabain sensitive adenosine triphosphatase (Na+K+ATPase) and plasma digoxin were measured in patients during acute digitalisation and in patients who were on long-term digoxin treatment.2 In the six patients who were studied during digitalisation, the ERCo,, and Na+K+ATPase activity decreased and erythrocyte sodium content increased during days 2-4 of treatment, but there was no change in E0,.3 In 39 patients on long term digoxin therapy (2-119 months) the erythrocyte sodium content was normal, but the erythrocyte Na+K+ATPase activity was higher than the control group. When the results from these 39 patients were divided according to the duration of treatment it was found that the erythrocyte sodium content was higher in patients treated for 2-4 months than in patients treated for longer periods and the erythrocyte Na+K+ATPase activity increased with duration of treatment. In eight patients (duration of treatment >29 months) in whom ERCO and Eo, were measured, ERC.s and Eos were higher than the control group. 4 The results suggest that the effects of digoxin on erythrocytes which occur during acute digoxin treatment do not persist in the long term.5 The possible explanation for the higher ERC0s, Eos and Na+K+ATPase activity in patients treated with digoxin for more than 2 months is discussed.

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“…twice daily for up to 4 weeks, myocardial (Na + + K + ) -ATPase and digoxin binding sites were unchanged, however [24]. The extremely high doses used by Bluschke et al [3] might have caused the observed increases in (Na + + K +)-ATPase and thus, in spite of the negative findings of Ku et al [24], adaptive or compensatory cell membrane changes might be possible. Ford et al [22] and Aronson et al [1] reported that the number of 3H-digoxin binding sites, the active 86Rb+-uptake, and the intracellular electrolyte concentrations changed in human erythrocytes in the course of chronic glycoside treatment concomitantly with a decrease and even a loss of digitalis effects as measured by the systolic time intervals.…”

Section: Discussionmentioning

confidence: 83%

“…Recently, however, several experimental findings have suggested that cell membrane changes occur in chronic treatment with cardiac glycosides. Bluschke et al [3] and Bonn and Greeff [6] reported increased myocardial (Na + + K+)-ATPase activity in guinea pigs treated with digitoxin (0.3 mg/kg s.c.) for 24 days. In dogs treated with digoxin (8-12 ng/kg i.v.)…”

Section: Discussionmentioning

confidence: 99%

Influence of digitalis and diuretics on ouabain binding sites on human erythrocytes

1984

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It has been reported that during chronic treatment with digitalis, the number of digitalis binding sites is increased in human erythrocytes [22]. From this finding a tachyphylaxis for cardiac glycosides has been postulated. We reinvestigated this problem in several groups of patients. The number of 3H-ouabain binding sites per erythrocyte in control persons (group I) was 214 +/- 60, n = 43 (means +/- SD). The dissociation constant (KD) was 1.8 +/- 0.5 nM. Thirteen patients (group II) taking cardiac glycosides only, for at least 6 months, had 281 +/- 99 (p less than 0.05) ouabain binding sites per single red cell, KD = 1.8 +/- 0.7 nM. Group III (34 patients) took digitalis for more than 6 months and diuretics for at least 3 months (352 +/- 126 (p less than 0.001), KD = 1.6 +/- 0.6). Twenty-three of these (group IV) were taking a combination with "K+-saving" diuretics (336 +/- 194 (p less than 0.01), KD = 1.6 +/- 0.5) and (group V, 11 patients) a combination with "K+-losing" diuretics (462 +/- 133 (p less than 0.001), KD = 1.4 +/- 0.4). Nine patients (group VI) had a chronic hypokalemia, mainly due to taking furosemide (437 +/- 98 (p less than 0.001), KD = 1.5 +/- 0.4). Four control persons took 50 mg hydrochlorothiazide daily for more than 4 months without measurable K+-losses and without changes in ouabain binding sites. It is concluded from these findings that diuretic treatment with chronic hypokalemia in addition to digitalis is accompanied by a significant increase in ouabain binding sites in human red cells.(ABSTRACT TRUNCATED AT 250 WORDS)

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Increase in the (Na+ + K+)-ATPase activity in heart muscle after chronic treatment with digitoxin or potassium deficient diet

Cited by 59 publications

References 5 publications

Regulation of Na,K-ATPase β1 Subunit Gene Transcription by Low External Potassium in Cardiac Myocytes

Regulation of Na,K-ATPase β1 Subunit Gene Transcription by Low External Potassium in Cardiac Myocytes

The early and late effects of digoxin treatment on the sodium transport, sodium content and Na+K+‐ ATPase or erythrocytes.

Influence of digitalis and diuretics on ouabain binding sites on human erythrocytes

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