Endogenous ouabain in cardiovascular function and disease

Manunta, Paolo; Ferrandi, Mara; Bianchi, Giuseppe; Hamlyn, John M.

doi:10.1097/hjh.0b013e32831cf2c6

Cited by 90 publications

(86 citation statements)

References 105 publications

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“…In our study, the levels of EO were lower than in some studies in literature using other immunoassay methods (enzyme-linked immunosorbent assay, EIA), which are, however, not comparable with our results because of the use of different antibody and methods. 3 Some papers have shown a modified nighttime blood pressure pattern in healthy persons and Abbreviations: BMI, body mass index; E/A, the ratio between the early and late peak flow velocity; EO, endogenous ouabain; GFR, glomerular filtration rate; IMT, intima media thickness; LVMI, left ventricular mass index; MAP, mean arterial blood pressure; PWV, pulse wave velocity; TPR, total peripheral resistance.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…[1][2][3] Previous studies have shown that EO is mostly produced in the adrenal cortex and circulating EO activate the sympathetic nervous system. 3,4 Their results suggested that these activations can be inhibited with b-blocker, angiotensin converting enzyme inhibitor and digoxin immune fab (antigen-binding fragments), Digi-Bind. 5,6 The increased level of EO may have direct and indirect (via marinobufagenin) vasoconstrictor (hypertensive) effects by blocking sodium/potassium pump (Na þ /K þ -ATPase), consecutively increasing intracellular calcium level by the activation of the sodium-calcium exchanger, but this effect of EO is not homogenous, that is different Na þ /K þ -ATPase isoforms respond differently to EO.…”

Section: Introductionmentioning

confidence: 99%

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Selective association of endogenous ouabain with subclinical organ damage in treated hypertensive patients

et al. 2010

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According to previous studies endogenous ouabain (EO) closely correlates with high blood pressure, congestive heart failure and kidney disease in humans. Our aims were to analyse associations between plasma, urinary EO level and various markers of cardiovascular damage in treated hypertensive patients. Forty-one adult patients with hypertension and/or diabetes mellitus (DM) and/or chronic kidney disease (CKD) were studied. We assessed plasma and urinary EO, pro-brain natriuretic peptide and catecholamines, profile of ambulatory blood pressure monitor and cardiovascular status by echocardiography and echo-tracking. The highest level of plasma EO (19.7 ± 9.5 pmol l -1 ) was measured in hypertensive patients with DM and CKD. The nighttime mean arterial blood pressure independently correlated with the level of plasma EO (P ¼ 0.004), while independent predictor of the b-stiffness of carotid artery was the urinary EO (P ¼ 0.011). Elevated level of EO was associated with nighttime blood pressure and subclinical organ damage in treated hypertensive patients, suggesting possible role of EO in the pathogenesis of impaired diurnal blood pressure rhythm and arterial stiffness.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Selective association of endogenous ouabain with subclinical organ damage in treated hypertensive patients

et al. 2010

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“…In this context, we have contributed to unraveling the role of a polymorphism of the cytoskeletal protein adducin and high levels of endogenous ouabain (EO) in hypertension and glomerular podocyte damage, both in animal models and in patients (Bianchi et al, 1994;Bianchi, 2005;Manunta et al, 2009;Ferrandi et al, 2010a,b). These studies have shown that mutant a-adducin and ouabain activate Src tyrosine kinase and the Src-dependent Na,K-ATPase phosphorylation and its signaling network, associated with an overall increase of renal tubular sodium reabsorption and blood pressure (BP) (Ferrandi et al, 2010a).…”

Section: Introductionmentioning

confidence: 99%

Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

Ferrandi

Molinari

Rastaldi

et al. 2014

J Pharmacol Exp Ther

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Glomerulopathies are important causes of morbidity and mortality. Selective therapies that address the underlying mechanisms are still lacking. Recently, two mechanisms, mutant b-adducin and ouabain, have been found to be involved in glomerular podocytopathies and proteinuria through nephrin downregulation. The main purpose of the present study was to investigate whether rostafuroxin, a novel antihypertensive agent developed as a selective inhibitor of Src-SH2 interaction with mutant adducinand ouabain-activated Na,K-ATPase, may protect podocytes from adducin-and ouabain-induced effects, thus representing a novel pharmacologic approach for the therapy of podocytopathies and proteinuria caused by the aforementioned mechanisms. To study the effect of rostafuroxin on podocyte protein changes and proteinuria, mice carrying mutant b-adducin and ouabain hypertensive rats were orally treated with 100 mg/kg per day rostafuroxin. Primary podocytes from congenic rats carrying mutant a-adducin or b-adducin (NB) from Milan hypertensive rats and normal rat podocytes incubated with 10 29 M ouabain were cultured with 10 29 M rostafuroxin. The results indicated that mutant b-adducin and ouabain caused podocyte nephrin loss and proteinuria in animal models. These alterations were reproduced in primary podocytes from NB rats and normal rats incubated with ouabain. Treatment of animals, or incubation of cultured podocytes with rostafuroxin, reverted mutant b-adducin-and ouabain-induced effects on nephrin protein expression and proteinuria. We conclude that rostafuroxin prevented podocyte lesions and proteinuria due to mutant b-adducin and ouabain in animal models. This suggests a potential therapeutic effect of rostafuroxin in patients with glomerular disease progression associated with these two mechanisms.

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“…18 Studies from the Blaustein laboratory, 19 on wild-type and mice heterozygous (+/À) for null mutations in the genes coding for the a1 or a2 subunit of the Na + pump, have shown that ouabain raises blood pressure and myogenic tone by reducing a2 subunit Na + pump activity and enhancing Ca ++ entry via the Na + /Ca ++ exchanger. In parallel studies from the Lingrel laboratory 20 the a2-subunit gene sequence was minimally mutated to make the protein ouabainresistant.…”

Section: Illuminatementioning

confidence: 99%

Aldosterone, hypertension and heart failure: insights from clinical trials

Funder¹

2010

Hypertens Res

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Two clinical trials will be reviewed, RALES 1 and ILLUMINATE. 2 In RALES, low-dose spironolactone in addition to standard of care, produced a 30% improvement in survival in progressive heart failure, commonly assumed to reflect deleterious effects of aldosterone, with spironolactone competing with aldosterone for cardiac mineralocorticoid receptors. Recent evidence, however, points to cortisol rather than aldosterone as the hormone activating cardiac mineralocorticoid receptors, under conditions of tissue damage, and spironolactone as acting by mechanisms other than receptor blockade. ILLUMINATE compared the effects of torcetrapib, a cholesterol ester transport protein inhibitor, in combination with atorvastatin vs. atorvastatin alone, and was terminated after excess mortality was found in the torcetrapib arm. Subjects receiving torcetrapib showed effects consistent with increased aldosterone secretion, subsequently confirmed on patient samples and in vitro. In animal experiments, the pressor effect of torcetrapib was abolished by adrenalectomy but not by administration of trilostane, an inhibitor of aldosterone secretion. Although aldosterone (and probably cortisol) excess is involved in the off-target effects of torcetrapib, they may also involve secretion of endogenous oubain from the adrenal glomerulosa. This possibility may explain the enigma of aldosterone being homeostatic in chronic sodium deficiency, but deleterious in the presence of inappropriate sodium levels.

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Endogenous ouabain in cardiovascular function and disease

Cited by 90 publications

References 105 publications

Selective association of endogenous ouabain with subclinical organ damage in treated hypertensive patients

Selective association of endogenous ouabain with subclinical organ damage in treated hypertensive patients

Rostafuroxin Protects from Podocyte Injury and Proteinuria Induced by Adducin Genetic Variants and Ouabain

Aldosterone, hypertension and heart failure: insights from clinical trials

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