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  • Review Article
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Endogenous digitalis: pathophysiologic roles and therapeutic applications

Nature Clinical Practice Nephrology volume 4, pages 378–392 (2008)Cite this article

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.

Key Points

  • Several endogenous cardiotonic steroids, or digitalis-like factors, have been isolated and characterized in humans; of these, ouabain, from the cardenolide class, and marinobufagenin, from the bufadienolide class, are the most extensively studied

  • In addition to inhibiting the ion transport function of the sodium/potassium-transporting ATPase, binding of endogenous cardiotonic steroids to this sodium pump can activate signaling via the Src–epidermal growth factor receptor pathway

  • In Dahl salt-sensitive rats with salt-induced hypertension, endogenous ouabain acts as a neurohormone and stimulates the release of marinobufagenin, a natriuretic and vasoconstrictor

  • Endogenous cardiotonic steroids are implicated in congestive heart failure, pre-eclampsia and diabetes mellitus

  • Potential therapeutic approaches to targeting endogenous cardiotonic steroids include immunoneutralization, receptor antagonism and protein kinase C inhibition

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Figure 1: Chemical structures of selected cardiotonic steroids.
Figure 2: The two pathways via which binding of cardiotonic steroids to the Na+/K+-ATPase exerts genomic and non-genomic effects.
Figure 3: Interactions between brain endogenous ouabain, the central renin–angiotensin system, and circulating marinobufagenin in the pathogenesis of salt-sensitive hypertension.

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Acknowledgements

Supported in part by the Intramural Research Program of the National Institute on Aging, part of the NIH. We would like to thank Dr Olga V Fedorova for critical review of the manuscript and Ms Carol Woods for her excellent secretarial efforts.

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Authors and Affiliations

  1. AY Bagrov is an Investigator and Head of the Hypertension Unit at the Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD,

    Alexei Y Bagrov

  2. Chairman of the Department of Medicine and Professor of Medicine and Pharmacology at the University of Toledo College of Medicine, JI Shapiro is a Mercy Health Partners Education Professor, Toledo, OH, USA.,

    Joseph I Shapiro

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Bagrov, A., Shapiro, J. Endogenous digitalis: pathophysiologic roles and therapeutic applications. Nat Rev Nephrol 4, 378–392 (2008). https://doi.org/10.1038/ncpneph0848

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