Endogenous digitalis: pathophysiologic roles and therapeutic applications

Abstract

Endogenous 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.

Figure 1

Chemical structures of selected cardiotonic steroids. Ouabain belongs to the cardenolides, a class of cardiotonic steroids found in the common foxglove (Digitalis purpurea) and in other plants. The bufadienolides marinobufagenin and proscillaridin A are found in the cane toad (Bufo marinus) and sea squill (Urginea maritima), respectively. The image ‘Urginea maritima flowers’ by Júlio Reis is reproduced under the Creative Commons Attribution ShareAlike 2.5 License (http://creativecommons.org/licenses/by-sa/2.5/). The image of Bufo marinus is reproduced under the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/).

Figure 2

The two pathways via which binding of cardiotonic steroids to the Na⁺/K⁺-ATPase exerts genomic and non-genomic effects. In the classic ‘ionic’ pathway (left), inhibition of the pump function of the Na⁺/K⁺-ATPase by CTS results in an increase in cytosolic sodium concentration and a decrease in cytosolic potassium concentration. These changes induce an increase in cytosolic calcium level, which in turn activates a variety of pathways with genomic and non-genomic effects. The pump function of the caveolar Na⁺/K⁺-ATPase might be more sensitive to CTS than that of the noncaveolar Na⁺/K⁺-ATPase. The ‘signaling’ pathway (right) involves the association of Src with the Na⁺/K⁺-ATPase in a caveolar domain. Binding of CTS to the Na⁺/K⁺-ATPase activates Src, which in turn transactivates the EGFR and PLC, leading to a cascade that involves generation of ROS, activation of ERK through activation of MEK, activation of Akt (protein kinase B) via PI(3)K, stimulation of endocytosis and activation of PKC. These steps induce the genomic and non-genomic effects of CTS. Note that both the classic and signaling pathways allow intervention at the level of the binding of CTS to the Na⁺/K⁺-ATPase, by immunoneutralization or pharmacological antagonism; however, the signaling pathway presents several additional targets for interference, such as Src activation and transactivation of the EGFR, PLC activation, activation of MEK, generation of ROS and activation of PI(3)K. Modulation of the signaling pathway at the level of PKC, ERK and Akt might also be possible. Abbreviations: CTS, cardiotonic steroids; EGFR; epidermal growth factor receptor; ERK, extracellular regulated kinase; MEK, mitogen-activated protein kinase; Na⁺/K⁺-ATPase, sodium/potassium-transporting ATPase; PI(3)K, phosphoinositide-3 kinase; PKC, protein kinase C; PLC, phospholipase C; ROS, reactive oxygen species.

Figure 3

Interactions between brain endogenous ouabain, the central renin-angiotensin system, and circulating marinobufagenin in the pathogenesis of salt-sensitive hypertension. In salt-loaded Dahl salt-sensitive rats, sodium retention occurs because renal sodium transport is impaired. Sodium retention stimulates the release of endogenous ouabain in the hippocampus, hypothalamus and pituitary. Brain endogenous ouabain stimulates the RAS in the hypothalamus and pituitary, which activates the SNS. These events stimulate the RAS in the adrenal cortex, and activate adrenocortical production of marinobufagenin. Marinobufagenin, a natriuretic and a vasoconstrictor, induces natriuresis via inhibition of the renotubular Na⁺/K⁺-ATPase. Excessive release of marinobufagenin leads to inhibition of the Na⁺/K⁺-ATPase in vascular smooth muscle cells—which potentiates vasoconstriction—and in the heart—which increases cardiac contractility—causing hypertension. Abbreviations: Na⁺/K⁺-ATPase, sodium/potassium-transporting ATPase; RAS, renin-angiotensin system; SNS, sympathetic nervous system.