Endogenous digitalis: pathophysiologic roles and therapeutic applications

Abstract

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.

Na,K-ATPase signal transduction triggers CREB activation and dendritic growth

“…Our results, which show that Na,K-ATPase, the receptor of ouabain, stimulates dendritic growth in rat cortical neurons, support such a biological function for ouabain. Concentrations of endogenous ouabain in the embryonic human brain during the course of development are unknown but are predicted to lie in the subnanomolar-to-nanomolar range, as previously reported (13,32). Indeed, nanomolar concentrations of ouabain stimulates neurite outgrowth in human neuroblastoma cells (Fig.…”

“…Evidence indicates that circulating levels of ouabain and ouabain-like factors are elevated during pregnancy and in newborn infants (13,32), thereby suggesting a developmental role for this signaling molecule. Our results, which show that Na,K-ATPase, the receptor of ouabain, stimulates dendritic growth in rat cortical neurons, support such a biological function for ouabain.…”

“…Previous reports indicate that Na,K-ATPase signal transduction stimulates proliferation in smooth muscle cells (11) and apoptosis in prostate cancer cells (12). Ouabain, an endogenously synthesized hormone (13,14), is Na,K-ATPase's ligand and forms a hormone-receptor complex capable of inducing mitogen-activated protein (MAP) kinase phosphorylation (15,16) and intracellular Ca 2ϩ signaling (17)(18)(19).…”

Subunit Isoform Selectivity in Assembly of Na,K-ATPase α-β Heterodimers

“…Considerable evidence exists for the presence of endogenous ouabain-like molecules in mammalian tissues that may serve to regulate Na,K-ATPase activity (3,14,51). Particularly, a signaling role of the Na ϩ /K ϩ -ATPase has been demonstrated in regulating synaptic plasticity and dendritic growth in cortical neurons (52).…”

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

“…[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.…”