Isolation of a urinary digitalis-like factor indistinguishable from digoxin

doi:10.1016/S0006-291X(05)80898-8

Biochemical and Biophysical Research Communications

Volume 173, Issue 3, 31 December 1990, Pages 1093-1101

https://doi.org/10.1016/S0006-291X(05)80898-8 Get rights and content

A digitalis-like factor has been purified to apparent homogeneity from human urine based on the inhibitory effect on [³H]ouabain binding to intact human erythrocytes. The purification scheme involved large scale adsorption followed by preparative, semipreparative and analytical high-perormance liquid chromatography. The purified material showed a prominent digoxin-like immunoreactivity. The behaviour of the isolated substance was identical to that of authentic digoxin is three high-performance liquid chromatography and three thin-layer chromatography systems. Moreover, fast atom bombardment mass spectrum and proton nuclear magnetic resonance spectrum suggested that the purified material may be indistinguishable from digoxin.

References (14)

GotoA. et al.
Biochem. Biophys. Res. Commun.
(1988)
TamuraM. et al.
Biochem. Biophys. Res. Commun.
(1987)
HamlynJ.M. et al.
J. Biol. Chem.
(1989)
Castaneda-HernandezG.
Comp. Biochem. Physiol.
(1989)
HaddyF.J.
N. Eng. J. Med.
(1987)
PostonL.
Clin. Sci.
(1987)
HaberE. et al.
Hypertension
(1987)

There are more references available in the full text version of this article.

Cited by (126)

Ouabain inhibitor rostafuroxin attenuates dextromethorphan-induced manic potential
2021, Food and Chemical Toxicology
Dextromethorphan (DM) abuse produces mania-like symptoms in humans. ERK/Akt signaling activation involved in manic potential can be attenuated by the inhibition of ouabain-like cardiac steroids. In this study, increased phosphorylations of ERK/Akt and hyperlocomotion induced by DM (30 mg/kg, i.p./day × 7) were significantly protected by the ouabain inhibitor rostafuroxin (ROSTA), suggesting that DM induces the manic potential. ROSTA significantly attenuated DM-induced protein kinase C δ (PKCδ) phosphorylation, GluN2B (i.e., MDA receptor subunit) expression, and phospho-PKCδ/GluN2B interaction. DM instantly upregulated the nuclear factor erythroid-2-related factor 2 (Nrf2)-dependent system. However, DM reduced Nrf2 nuclear translocation, Nrf2 DNA binding activity, γ-glutamylcysteine mRNA expression, and subsequent GSH/GSSG level and enhanced oxidative parameters following 1-h of administration. ROSTA, PKCδ inhibitor rottlerin, and GluN2B inhibitor traxoprodil significantly attenuated DM-induced alterations in Nrf2-related redox parameters and locomotor activity induced by DM in wild-type mice. Importantly, in PKCδ knockout mice, DM failed to alter the above parameters. Further, ROSTA and traxoprodil also failed to enhance PKCδ depletion effect, suggesting that PKCδ is a critical target for the anti-manic potential of ROSTA or GluN2B antagonism. Our results suggest that ROSTA inhibits DM-induced manic potential by attenuating ERK/Akt activation, GluN2B/PKCδ signalings, and Nrf2-dependent system.
Na,K-ATPase as a target for endogenous cardiotonic steroids: What's the evidence?
2021, Genes and Diseases
Citation Excerpt :
Other members of the cardiotonic steroid (CTS) superfamily, bufadienolides, were isolated from amphibians.6 A long-lasting search for endogenous CTS (ECTS) resulted in the purification from mammalian species compounds identical to ouabain,7–9 digoxin,10 bufalin,11 marinobufagenin (MBG),12,13 telocinobufagin14 and marinobufotoxin15 (structure of some endogenous cardiotonic steroids are presented in Fig. 1) Data on association of cardiovascular, renal and neuronal diseases with increased ECTS level and preventive actions of passive immunization by anti-ECTS antibodies allowed researchers to propose an implication of ECTS in the pathogenesis of these and other volume-expanded disorders (for comprehensive review, see16–21). Starting from early 90th the focus of investigations has been directed to the mechanisms by which ECTS may regulate various cellular functions.
With an exception of few reports, the plasma concentration of ouabain and marinobufagenin, mostly studied cardiotonic steroids (CTS) assessed by immunoassay techniques, is less than 1 nM. During the last 3 decades, the implication of these endogenous CTS in the pathogenesis of hypertension and other volume-expanded disorders is widely disputed. The threshold for inhibition by CTS of human and rodent α1-Na,K-ATPase is ∼1 and 1000 nM, respectively, that rules out the functioning of endogenous CTS (ECTS) as natriuretic hormones and regulators of cell adhesion, cell-to-cell communication, gene transcription and translation, which are mediated by dissipation of the transmembrane gradients of monovalent cations. In several types of cells ouabain and marinobufagenin at concentrations corresponding to its plasma level activate Na,K-ATPase, decrease the [Na⁺]_i/[K⁺]_i-ratio and increase cell proliferation. Possible physiological significance and mechanism of non-canonical Na⁺_i/K⁺_i-dependent and Na⁺_i/K⁺_i-independent cell responses to CTS are discussed.
Cardiac glycosides with target at direct and indirect interactions with nuclear receptors
2020, Biomedicine and Pharmacotherapy
Citation Excerpt :
The last of which is considered to be the main source of and storage area for endogenous ouabain [45,46]. Ouabain and other cardiac glycosides (e.g. digoxin [47], marinobufagenin [48], and 19-norbufalin [49]) are tentatively considered novel steroidal hormones that participate in the regulation of blood pressure [50–53]. Many low molecular weight compounds (e.g., steroid hormones, vitamin A derivatives, vitamin D, products of lipid metabolism, and xenobiotics) exert their biological activity by binding to transcription factors called nuclear receptors.
Cardiac glycosides are compounds isolated from plants and animals and have been known since ancient times. These compounds inhibit the activity of the sodium potassium pump in eukaryotic cells. Cardiac glycosides were used as drugs in heart ailments to increase myocardial contraction force and, at the same time, to lower frequency of this contraction. An increasing number of studies have indicated that the biological effects of these compounds are not limited to inhibition of sodium-potassium pump activity. Furthermore, an increasing number of data have shown that they are synthesized in tissues of mammals, where they may act as a new class of steroid hormones or other hormones by mimicry to modulate various signaling pathways and influence whole organisms. Thus, we discuss the interactions of cardiac glycosides with the nuclear receptor superfamily of transcription factors activated by low-weight molecular ligands (including hormones) that regulate many functions of cells and organisms. Cardiac glycosides of endogenous and exogenous origin by interacting with nuclear receptors can affect the processes regulated by these transcription factors, including hormonal management, immune system, body defense, and carcinogenesis. They can also be treated as initial structures for combinatorial chemistry to produce new compounds (including drugs) with the desired properties.
Endogenous cardiotonic steroids and cardiovascular disease, where to next?
2020, Cell Calcium
Ever since British Physician William Withering first described the use of foxglove extract for treatment of patients with congestive heart failure in 1785, cardiotonic steroids have been used clinically to treat heart failure and more recently atrial fibrillation. Due to their ability to bind and inhibit the ubiquitous transport enzyme sodium potassium pump, thus regulating intracellular Na⁺ concentration in every living cell, they are also an essential tool for research into the sodium potassium pump structure and function. Exogenous CTS have been clearly demonstrated to affect cardiovascular system through modulation of vagal tone, cardiac contraction (via ionic changes) and altered natriuresis. Reports of a number of endogenous CTS, since the 1980s, have intensified research into their physiologic and pathophysiologic roles and opened up novel therapeutic targets. Substantive evidence pointing to the role of endogenous ouabain and marinobufagenin, the two most prominent CTS, in development of cardiovascular disease has accumulated. Nevertheless, their presence, structure, biosynthesis pathways and even mechanism of action remain unclear or controversial. In this review the current state-of-the-art, the controversies and the remaining questions surrounding the role of endogenous cardiotonic steroids in health and disease are discussed.
A review of cardiac glycosides: Structure, toxicokinetics, clinical signs, diagnosis and antineoplastic potential
2019, Toxicon
Cardiac glycosides (CGs) are secondary compounds found in plants and amphibians and are widely distributed in nature with potential cardiovascular action. Their mechanism is based on the blockage of the heart's sodium potassium ATPase, with a positive inotropic effect. Some of the most well-known CGs are digoxin, ouabain, oleandrin, and bufalin. They have similar chemical structures: a lactone ring, steroid ring, and sugar moiety. Digoxin, ouabain, and oleandrin are classified as cardenolides, consisting of a lactone ring with five carbons, while bufalin is classified as bufodienolides, with a six-carbon ring. Small structural differences determine variations in the toxicokinetics and toxicodynamics of such substances. Most case reports of poisoning caused by CGs are associated with cardiovascular toxicity, causing a variety of arrhythmias and lesions in the heart tissue. Experimental studies also describe important similarities among different CGs, especially regarding species sensitivity. Recent studies furthermore focus on their antineoplastic potential, with controversial results. Data from research studies and case reports were reviewed to identify the main characteristics of the CGs, including toxicokinetics, toxicodynamics, clinical signs, electrocardiographic, pathological findings, antineoplastic potential and the main techniques used for diagnostic purposes.
Are endogenous cardenolides controlled by atrial natriuretic peptide
2016, Medical Hypotheses
Citation Excerpt :
Endogenous CTS are classified similar to exogenous compounds. Endogenous cardenolides consist of ouabain [1,23,24], digoxin [25] and their metabolites – dihydro-ouabain and dihydro-digoxin. Endogenous bufadienolides consist of marinobufagenin (MBG), telcinobufagin, proscillaridin A [26–29].
Endogenous cardenolides are digoxin-like substances and ouabain-like substances that have been implicated in the pathogenesis of hypertension and mood disorders in clinical and pre-clinical studies. Regulatory signals for endogenous cardenolides are still unknown. These endogenous compounds are believed to be produced by the adrenal gland in the periphery and the hypothalamus in the central nervous system, and constitute part of an hormonal axis that may regulate the catalytic activity of the α subunit of Na⁺/K⁺-ATPase. A review of literature suggests that there is great overlap in physiological environments that are associated with either elevations or reductions in the levels of atrial natriuretic peptide (ANP) and endogenous cardenolides. This suggests that these two factors may share a common regulatory signal or perhaps that ANP may be involved in the regulation of endogenous cardenolides.

View all citing articles on Scopus

View full text

Isolation of a urinary digitalis-like factor indistinguishable from digoxin

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Comp. Biochem. Physiol.

N. Eng. J. Med.

Clin. Sci.

Hypertension