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Whither digitalis? What we can still learn from cardiotonic steroids about heart failure and hypertension
Mordecai P Blaustein1,2, Stephen S Gottlieb2, John M Hamlyn1
1Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland.
Insights
Endogenous ouabain (EO) and its Na+,K+-ATPase (NKA) receptor influence cardiovascular function, impacting heart failure and hypertension. Understanding EO's role may revive digoxin therapy for heart failure.
Area of Science:
- Cardiovascular Physiology
- Endocrinology
- Pharmacology
Background:
- The Na+,K+-ATPase (NKA) pump and its endogenous ligand, endogenous ouabain (EO), are crucial for cardiovascular regulation.
- Cardiotonic steroids (CTS), including digitalis preparations like digoxin, have a long history in heart failure (HF) treatment.
- Previous HF trials using digoxin did not account for the influence of endogenous CTS on treatment efficacy.
Purpose of the Study:
- To explore the role of endogenous ouabain (EO) and its interaction with the Na+,K+-ATPase (NKA) receptor in cardiovascular pathophysiology.
- To investigate the differential effects of digoxin and ouabain on blood pressure, cardiac function, and signaling pathways.
- To elucidate the neuromodulatory role of EO in regulating sympathetic drive and its implications for hypertension and HF.
Main Methods:
- Utilizing EO assays, ouabain-resistant NKA mutations, and immunoneutralization techniques to study EO and NKA interactions.
- Employing rodent models to assess the long-term cardiovascular effects of ouabain and digoxin administration.
- Analyzing the impact of the NKA α2 CTS binding site and EO on blood pressure regulation and cardiac remodeling in hypertension and post-myocardial infarction models.
Main Results:
- Digoxin antagonizes ouabain's action at therapeutic concentrations, suggesting complex interactions within the NKA system.
- Prolonged ouabain treatment induces hypertension in rodents, while digoxin lowers blood pressure in the same model.
- EO and the NKA α2 isoform play a critical role in regulating sympathetic drive, blood pressure elevation, and cardiac dysfunction in various cardiovascular disease models.
Conclusions:
- Endogenous CTS, particularly EO, significantly impact the pathophysiology of hypertension and heart failure.
- The distinct signaling pathways modulated by NKA-bound ouabain and digoxin lead to disparate long-term cardiovascular outcomes.
- Further understanding of endogenous CTS mechanisms may necessitate a re-evaluation of digoxin's therapeutic potential in heart failure management.
Abstract:
Cloning of the "Na+ pump" (Na+,K+-ATPase or NKA) and identification of a circulating ligand, endogenous ouabain (EO), a cardiotonic steroid (CTS), triggered seminal discoveries regarding EO and its NKA receptor in cardiovascular function and the pathophysiology of heart failure (HF) and hypertension. Cardiotonic digitalis preparations were a preferred treatment for HF for two centuries, but digoxin was only marginally effective in a large clinical trial (1997). This led to diminished digoxin use. Missing from the trial, however, was any consideration that endogenous CTS might influence digitalis' efficacy. Digoxin, at therapeutic concentrations, acutely inhibits NKA but, remarkably, antagonizes ouabain's action. Prolonged treatment with ouabain, but not digoxin, causes hypertension in rodents; in this model, digoxin lowers blood pressure (BP). Furthermore, NKA-bound ouabain and digoxin modulate different protein kinase signaling pathways and have disparate long-term cardiovascular effects. Reports of "brain ouabain" led to the elucidation of a new, slow neuromodulatory pathway in the brain; locally generated EO and the α2 NKA isoform help regulate sympathetic drive to the heart and vasculature. The roles of EO and α2 NKA have been studied by EO assay, ouabain-resistant mutation of α2 NKA, and immunoneutralization of EO with ouabain-binding Fab fragments. The NKA α2 CTS binding site and its endogenous ligand are required for BP elevation in many common hypertension models and full expression of cardiac remodeling and dysfunction following pressure overload or myocardial infarction. Understanding how endogenous CTS impact hypertension and HF pathophysiology and therapy should foster reconsideration of digoxin's therapeutic utility.
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