Endogenous and Exogenous Cardiac Glycosides and their Mechanisms of Action

doi:10.2165/00129784-200707030-00004

Paper

Endogenous and Exogenous Cardiac Glycosides and their Mechanisms of Action

Published 2007 · W. Schoner, G. Scheiner‐Bobis

American Journal of Cardiovascular Drugs

Q2 SJR score

205

Citations

14

Influential Citations

Full textSemantic Scholar

Abstract

Cardiac glycosides have been used for decades to treat congestive heart failure. The recent identification of cardiotonic steroids such as ouabain, digoxin, marinobufagenin, and telocinobufagin in blood plasma, adrenal glands, and hypothalamus of mammals led to exciting new perspectives in the pathology of heart failure and arterial hypertension. Biosynthesis of ouabain and digoxin occurs in adrenal glands and is under the control of angiotensin II, endothelin, and epinephrine released from cells of the midbrain upon stimulation of brain areas sensing cerebrospinal Na+ concentration and, apparently, the body’;s K+ content. Rapid changes of endogenous ouabain upon physical exercise may favor the economy of the heart by a rise of intracellular Ca2+ levels in cardiac and atrial muscle cells. According to the sodium pump lag hypothesis, this may be accomplished by partial inhibition of the sodium pump and Ca2+ influx via the Na+/Ca2+ exchanger working in reverse mode or via activation of the Na+/K+-ATPase signalosome complex, generating intracellular calcium oscillations, reactive oxygen species, and gene activation via nuclear factor-κB or extracellular signal-regulated kinases 1 and 2. Elevated concentrations of endogenous ouabain and marinobufagenin in the subnanomolar concentration range were found to stimulate proliferation and differentiation of cardiac and smooth muscle cells. They may have a primary role in the development of cardiac dysfunction and failure because (i) offspring of hypertensive patients evidently inherit elevated plasma concentrations of endogenous ouabain; (ii) such elevated concentrations correlate positively with cardiac dysfunction, hypertrophy, and arterial hypertension; (iii) about 40% of Europeans with uncomplicated essential hypertension show increased concentrations of endogenous ouabain associated with reduced heart rate and cardiac hypertrophy; (iv) in patients with advanced arterial hypertension, circulating levels of endogenous ouabain correlate with BP and total peripheral resistance; (v) among patients with idiopathic dilated cardiomyopathy, high circulating levels of endogenous ouabain and marinobufagenin identify those individuals who are predisposed to progressing more rapidly to heart failure, suggesting that endogenous ouabain (and marinobufagenin) may contribute to toxicity upon digoxin therapy.In contrast to endogenous ouabain, endogenous marinobufagenin may act as a natriuretic substance as well. It shows a higher affinity for the ouabain-insensitive α1 isoform of Na+/K+-ATPase of rat kidney tubular cells and its levels are increased in volume expansion and pre-eclampsia. Digoxin, which is synthesized in adrenal glands, seems to counteract the hypertensinogenic action of ouabain in rats, as do antibodies against ouabain, for example, (Digibind®) and rostafuroxin (PST 2238), a selective ouabain antagonist. It lowers BP in ouabain- and adducin-dependent hypertension in rats and is a promising new class of antihypertensive medication in humans.

Highly Cited

Study Snapshot

Cardiac glycosides, such as ouabain and digoxin, may play a role in the development of heart failure and arterial hypertension, and their use in treating these conditions may have potential benefits for patients with heart disease.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

Sign up to use Study Snapshot

Consensus is limited without an account. Create an account or sign in to get more searches and use the Study Snapshot.

Create an account

Paper

Endogenous and Exogenous Cardiac Glycosides and their Mechanisms of Action

Sign up to use Study Snapshot

References

Low-dose ouabain protects against excitotoxic apoptosis and up-regulates nuclear Bcl-2 in vivo

Low-dose ouabain protects against excitotoxic apoptosis in neurons by increasing nuclear Bcl-2 levels, potentially offering a therapeutic strategy against neuronal injury.

The Na(+)/K(+)-ATPase as [K(+)](o) sensor: Role in cardiovascular disease pathogenesis and augmented production of endogenous cardiotonic steroids.

Altered extracellular K(+) handling contributes to hypertension by modulating the interaction of endogenous cardiotonic steroids with Na(+)/K(+)-ATPase, potentially playing a role in cardiovascular disease pathogenesis.

Ouabain induces cell proliferation through calcium-dependent phosphorylation of Akt (protein kinase B) in opossum kidney proximal tubule cells.

Ouabain increases cell proliferation in opossum kidney proximal tubule cells through calcium-dependent phosphorylation of Akt and calcium-dependent calcium entry, without inhibiting Na(+)-K(+)-ATPase-mediated ion transport.

Signaling pathways involving the sodium pump stimulate NO production in endothelial cells.

Ouabain activates a signaling pathway in endothelial cells, leading to increased nitric oxide production, suggesting the sodium pump plays a role in vascular tone regulation.

Role of dietary salt in hypertension.

Restricting dietary sodium intake can lower blood pressure and reduce the need for antihypertensive medication in some individuals with hypertension.

Activation of brain renin-angiotensin-aldosterone system by central sodium in Wistar rats.

Chronic increase in CSF sodium levels in Wistar rats may increase hypothalamic aldosterone and activate brain pathways involving mineralocorticoid receptors and ouabain-like compounds, leading to increases in cardiovascular regulation and hypertension.

Local subplasma membrane Ca2+ signals detected by a tethered Ca2+ sensor

The jS/ER and adjacent plasma membrane may communicate through Ca2+ signals confined to the tiny junctional space between the two membranes.

Distinct Role of the N-terminal Tail of the Na,K-ATPase Catalytic Subunit as a Signal Transducer*

The N-terminal tail of the Na,K-ATPase catalytic subunit acts as a signal transducer, triggering anti-apoptotic calcium signals and activating NF-B in cells.

Central and peripheral renin-angiotensin systems in ouabain-induced hypertension.

Ouabain-induced hypertension involves the brain renin-angiotensin system, with increased hypothalamic ANG II content and decreased central AT1 receptor and ACE densities contributing to the central hypertensive mechanism.

Citations

Nanosurgery and bioengineered structural regenerative protocols for the treatment of human knee meniscal tears: a double-blind randomized controlled study of a novel regenerative method

The novel nanosurgery and bioengineering treatment method is highly effective and standardized, offering rapid recovery for patients compared to less structured treatments.

The cystogenic effects of ouabain in autosomal dominant polycystic kidney disease require cell caveolae.

Ouabain accelerates cyst progression in autosomal dominant polycystic kidney disease (ADPKD) by enhancing NKA signaling through cell caveolae.

Role of Na+-K+ ATPase Alterations in the Development of Heart Failure

Na+-K+ ATPase alterations, affecting its activity and function, contribute to the progression of heart failure by causing intracellular calcium overload, cardiac arrhythmias, and depression in cardiac function.

Enhanced Drug Classification Using Machine Learning with Multiplexed Cardiac Contractility Assays.

Machine learning using multiplexed cardiac contractility assays can accurately classify unknown compounds' mechanistic actions with 86.2 % predictive accuracy, enhancing future clinical trial success.

Na+/K+-ATPase: More than an Electrogenic Pump

The sodium pump plays a crucial role in maintaining an electrochemical gradient and also functions as a receptor for cardiac glycosides, influencing cell-cell contacts, proliferation, differentiation, and adhesion.

New Insights on the Role of Marinobufagenin from Bench to Bedside in Cardiovascular and Kidney Diseases

Marinobufagenin (MBG) plays a role in various human diseases, including chronic kidney disease, cardiovascular diseases, and sex and gender medicine, and could be used as a diagnostic biomarker or therapeutic target in the future.

MULTIFUNCTIONAL MODIFIED CARBON NANOTUBES AS POTENTIAL ANTI-TUMOR DRUG DELIVERY

A novel dual drug delivery system using multi-walled carbon nanotubes and folic acid shows potential in delivering specific and effective antitumoral activity, reducing tumor cell viability at safe concentrations.