Inhibitory effect of combinations of digoxin and endogenous cardiotonic steroids on Na+/K+-ATPase activity in human kidney membrane preparation

Touza, Natália Araújo; Pôças, Elisa Suzana Carneiro; Quintas, Luis Eduardo M.; Cunha-Filho, Geraldino; Santos, Maria Lucília dos; Noël, François

doi:10.1016/j.lfs.2010.10.027

Cited by 33 publications

(30 citation statements)

References 45 publications

(51 reference statements)

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“…The sodium-potassium ATPase is targeted by a variety of endogenous and exogenous cardiac glycosides and cardiotonic steroids, with increasing titres of the latter seen in disease states (17). Differing levels of endogenous cardiotonic steroids may partly explain the varied susceptibility to digoxin toxicity, including competition for molecular targets and conformational changes that lead to synergism or antagonism (18,19).…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Digoxin: The good and the bad

Ziff

Kotecha

2016

Trends in Cardiovascular Medicine

120

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After 230 years of use, digitalis remains an important and useful therapy for patients with atrial fibrillation, heart failure, and the 30-50 % of patients with both conditions. Although the combination of positive inotropic activity with negative chronotropic effects has been shown to reduce hospital admissions in heart failure, there is a distinct lack of robust trial data, particularly in patients with atrial fibrillation. We recently performed a comprehensive meta-analysis of all digoxin studies and demonstrated a neutral effect on mortality. This contradicts prior observational data that overlook the fact that digitalis is usually given as second-line therapy to the sickest patients. Use of these agents in clinical practice should take account of appropriate dose, serum concentration, drug interactions, and potential side effects. The aim of this review is to evaluate the evidence base for cardiac glycosides and provide a pragmatic guide to their advantages and disadvantages.

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Section: Mechanism Of Actionmentioning

confidence: 99%

Digoxin: The good and the bad

Ziff

Kotecha

2016

Trends in Cardiovascular Medicine

120

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“…From this point of view, it is of considerable concern that the limited number of past studies that have been done on digitalis sensitivities of the HKE have not been consistent in results and interpretations. 12 − 15 These studies have had several shortcomings owing to the legitimate difficulties of working with human tissues. First, nearly all of the previous work has been done on recombinant enzymes, 12 − 14 creating a real possibility that the different membrane environments of the recombinant enzymes may have influenced their digitalis sensitivities.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Digitalis Sensitivities of Na⁺/K⁺-ATPases from Human and Pig Kidneys

et al. 2017

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Digitalis drugs are selective inhibitors of the plasma membrane Na+/K+-ATPase. There are many studies on molecular mechanisms of digitalis interaction with purified pig kidney enzyme, with the tacit assumption that it is a good model of human kidney enzyme. However, previous studies on crude or recombinant human kidney enzymes are limited, and have not resulted in consistent findings on their digitalis sensitivities. Hence, we prepared comparably purified enzymes from human and pig kidneys and determined inhibitory constants of digoxin, ouabain, ouabagenin, bufalin, and marinobufagenin (MBG) on enzyme activity under optimal turnover conditions. We found that each compound had the same potency against the two enzymes, indicating that (i) the pig enzyme is an appropriate model of the human enzyme, and (ii) prior discrepant findings on human kidney enzymes were either due to structural differences between the natural and recombinant enzymes or because potencies were determined using binding constants of digitalis for enzymes under nonphysiological conditions. In conjunction with previous findings, our newly determined inhibitory constants of digitalis compounds for human kidney enzymes indicate that (i) of the compounds that have long been advocated to be endogenous hormones, only bufalin and MBG may act as such at kidney tubules, and (ii) beneficial effects of digoxin, the only digitalis with extensive clinical use, does not involve its inhibitory effect on renal tubular Na+/K+-ATPase.

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“…We were not able to detect the Na C /K C -ATPase a4 isoform at the protein level in Sertoli cells obtained from immature rats (15-day-old), similar to the findings of Woo et al (2000), and found that the Na C /K C -ATPase a1 present in these cells mediates a rapid ouabain-induced signaling cascade, which is to a great extent similar to the rapid signaling pathway triggered by testosterone and E 2 , and plays a role in Sertoli cell proliferation. Interestingly, differently from rodents, the Na C /K CATPase a1 isoform is sensitive to cardiotonic steroids as ouabain (Touza et al 2011).…”

Section: Ouabain Signaling In Rat Sertoli Cellsmentioning

confidence: 97%

Na+/K+-ATPase α1 isoform mediates ouabain-induced expression of cyclin D1 and proliferation of rat Sertoli cells

et al. 2012

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Novel roles for the interaction of cardiotonic steroids to Na H]thymidine, both of which were dependent on MAPK3/1 but not AKT intracellular cascade, as shown by pretreatment with MEK (MAP2K1/2) inhibitor U0126 and PI3K inhibitor wortmannin respectively. Moreover, the effect of ouabain on these proliferation parameters was completely prevented by phospho-cAMP response element-binding protein (CREB)/CREB-binding protein complex inhibitor KG501 and only partially by nuclear factor kB nuclear translocation inhibitor SN50. Pretreatment with estrogen receptor antagonist ICI 182 780 showed that MAPK3/1 activation by ouabain does not involve this receptor. The Na C /K C -ATPase a1 isoform, but not a4, was detected in Sertoli cells, suggesting that ouabain effects in Sertoli cells are mediated via a1. Taken together, these results show a rapid ouabain action in the Sertoli cells, which in turn can modulate nuclear transcriptional events essential for Sertoli cell proliferation in a critical period of testicular development. Our findings are important to understand the role of ouabain in the testis and its possible implications in male infertility. Reproduction (2012) 144 737-745

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Inhibitory effect of combinations of digoxin and endogenous cardiotonic steroids on Na+/K+-ATPase activity in human kidney membrane preparation

Cited by 33 publications

References 45 publications

Digoxin: The good and the bad

Digoxin: The good and the bad

Comparison of Digitalis Sensitivities of Na⁺/K⁺-ATPases from Human and Pig Kidneys

Na+/K+-ATPase α1 isoform mediates ouabain-induced expression of cyclin D1 and proliferation of rat Sertoli cells

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Inhibitory effect of combinations of digoxin and endogenous cardiotonic steroids on Na+/K+-ATPase activity in human kidney membrane preparation

Cited by 33 publications

References 45 publications

Digoxin: The good and the bad

Digoxin: The good and the bad

Comparison of Digitalis Sensitivities of Na+/K+-ATPases from Human and Pig Kidneys

Na+/K+-ATPase α1 isoform mediates ouabain-induced expression of cyclin D1 and proliferation of rat Sertoli cells

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Comparison of Digitalis Sensitivities of Na⁺/K⁺-ATPases from Human and Pig Kidneys