Endogenous Ouabain

Murrell, Julie; Randall, Jeffrey; Rosoff, James S.; Zhao, Ji-Liang; Jensen, Roderick V.; Gullans, Steven R.; Haupert, Garner T.

doi:10.1161/circulationaha.105.554071

Cited by 71 publications

(32 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1F)]. HSD3B1 is involved in ouabain synthesis, as shown by the fact that its silencing reduces ouabain production in an adrenal medullary-derived cell line (10). A series of tag SNPs, representative of a region of genome with high linkage disequilibrium, is associated with BP variation (12).…”

Section: Resultsmentioning

confidence: 99%

“…Here, we have translated our experimental data to patients by (i) examining the choice of the gene variants predicting the rostafuroxin response with published [ (7)(8)(9)(10) and Supplementary Material] and new experimental data by testing whether the LSS gene variant (rs2254524) affects ouabain synthesis, and (ii) carrying out two clinical trials. For the first trial, we performed a double-blind crossover study (study 1) in newly discovered and never-treated patients, or previously treated patients after 1 month of washout, as described in detail elsewhere (11), and compared the effect of rostafuroxin on hypertension in patients with and without the gene variants of interest.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Adducin- and Ouabain-Related Gene Variants Predict the Antihypertensive Activity of Rostafuroxin, Part 2: Clinical Studies

et al. 2010

View full text Add to dashboard Cite

Twenty years of genetic studies have not contributed to improvement in the clinical management of primary arterial hypertension. Genetic heterogeneity, epistatic-environmental-biological interactions, and the pathophysiological complexity of hypertension have hampered the clinical application of genetic findings. In the companion article, we furnished data from rodents and human cells demonstrating two hypertension-triggering mechanisms-variants of adducin and elevated concentrations of endogenous ouabain (within a particular range)-and their selective inhibition by the drug rostafuroxin. Here, we have investigated the relationship between variants of genes encoding enzymes for ouabain synthesis [LSS (lanosterol synthase) and HSD3B1 (hydroxy-d-5-steroid dehydrogenase, 3b-and steroid d-isomerase 1)], ouabain transport {MDR1/ABCB1 [ATP-binding cassette, sub-family B (MDR/TAP), member 1]}, and adducin activity [ADD1 (adducin 1) and ADD3], and the responses to antihypertensive medications. We determined the presence of these variants in newly recruited, never-treated patients. The genetic profile defined by these variants predicted the antihypertensive effect of rostafuroxin (a mean placebo-corrected systolic blood pressure fall of 14 millimeters of mercury) but not that of losartan or hydrochlorothiazide. The magnitude of the rostafuroxin antihypertensive effect was twice that of antihypertensive drugs recently tested in phase 2 clinical trials. One-quarter of patients with primary hypertension display these variants of adducin or concentrations of endogenous ouabain and would be expected to respond to therapy with rostafuroxin. Because the mechanisms that are inhibited by rostafuroxin also underlie hypertensionrelated organ damage, this drug may also reduce the cardiovascular risk in these patients beyond that expected by the reduction in systolic blood pressure alone.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Adducin- and Ouabain-Related Gene Variants Predict the Antihypertensive Activity of Rostafuroxin, Part 2: Clinical Studies

et al. 2010

View full text Add to dashboard Cite

show abstract

“…Evidence is accumulating that most CTS are synthesised from cholesterol in the adrenal glands [37,38] and possibly hypothalamus [39] but the biosynthetic pathways for cardenolides and bufadienolides seem to differ. The trigger for biosynthesis initiation is complex, with serum concentrations of ouabain and marinobufagenin increasing in response to volume expansion [40], salt accumulation in the brain, adrenocorticotropic hormone, angiotensin II, vasopressin and phenylephrine [37,41].…”

Section: Cardiotonic Steroidsmentioning

confidence: 99%

“…The mechanisms that govern hypertension development have not yet been fully elucidated; however, evidence is accumulating that in response to high salt intake, CTS are secreted by the brain [39] as well as the adrenal glands [37,38] and that this leads to both central and peripheral blood pressure elevation and consequent salt excretion. Specifically, high salt intake elevates both plasma and cerebrospinal fluid Na + [71,72], and this induces the secretion of CTS by the adrenals and the hypothalamus.…”

Section: Cts and Disease Pathogenesismentioning

confidence: 99%

The Role of Cardiotonic Steroids in the Pathogenesis of Cardiomyopathy in Chronic Kidney Disease

Pavlović¹

2014

Nephron Clin Pract

View full text Add to dashboard Cite

Cardiotonic steroids (CTS) are a new class of hormones that circulate in the blood and are divided into two distinct groups, cardenolides, such as ouabain and digoxin, and bufadienolides, such as marinobufagenin, telocinobufagin and bufalin. They have the ability to bind and inhibit the ubiquitous transport enzyme sodium potassium pump, thus regulating intracellular Na⁺ concentration in every living cell. Although digoxin has been prescribed to heart failure patients for at least 200 years, the realization that CTS are endogenously produced has intensified research into their physiological and pathophysiological roles. Over the last two decades, substantial evidence has accumulated demonstrating the effects of endogenously synthesised CTS on the kidneys, vasculature and the heart. In this review, the current state of art and the controversies surrounding the manner in which CTS mediate their pathophysiological effects are discussed. Several potential therapeutic strategies have emerged as a result of our increased understanding of the role CTS play in health and disease.

show abstract

“…42,43,55 The adrenal cortex and hypothalamus are considered to be the sites of ouabain production in mammals. [55][56][57] Adrenocorticotropic hormone, angiotensin II, vasopressin, and phenylephrine stimulate the release of ouabain from the adrenal cortex in vitro. 58,59 Evidence suggests that digoxin is an endogenous cardiotonic steroid 60,61 that might be an endogenous antagonist of endogenous ouabain; 16,62 however, the extensive variability in the detection of digoxin-like immunoreactive material by highly specific commercial digoxin immunoassays in digoxin-naive populations 38-41,63 argues against this idea.…”

Section: Subtypes Of Endogenous Cardiotonic Steroids Endogenous Cardementioning

confidence: 99%

Endogenous digitalis: pathophysiologic roles and therapeutic applications

2008

View full text Add to dashboard Cite

SUMMARYEndogenous digitalis-like factors, also called cardiotonic steroids, have been thought for nearly half a century to have important roles in health and disease. The endogenous cardiotonic steroids ouabain and marinobufagenin have been identified in humans, and an effector mechanism has been delineated by which these hormones signal through the sodium/potassium-transporting ATPase. These findings have increased interest in this field substantially. Although cardiotonic steroids were first considered important in the regulation of renal sodium transport and arterial pressure, subsequent work has implicated these hormones in the control of cell growth, apoptosis and fibrosis, among other processes. This Review focuses on the role of endogenous cardiotonic steroids in the pathophysiology of essential hypertension, congestive heart failure, end-stage renal disease and pre-eclampsia. We also discuss potential therapeutic strategies that have emerged as a result of the increased understanding of the regulation and actions of cardiotonic steroids.

show abstract

Endogenous Ouabain

Abstract: Our findings support the possibility that a unique steroid biosynthetic circuit exists in Milan rat brain, functioning independently from adrenal, which could account for the overproduction of the hypothalamic ouabain-like compound in this species.

Cited by 71 publications

References 24 publications

Adducin- and Ouabain-Related Gene Variants Predict the Antihypertensive Activity of Rostafuroxin, Part 2: Clinical Studies

Adducin- and Ouabain-Related Gene Variants Predict the Antihypertensive Activity of Rostafuroxin, Part 2: Clinical Studies

The Role of Cardiotonic Steroids in the Pathogenesis of Cardiomyopathy in Chronic Kidney Disease

Endogenous digitalis: pathophysiologic roles and therapeutic applications

Contact Info

Product

Resources

About