The pump, the exchanger, and the holy spirit: origins and 40-year evolution of ideas about the ouabain-Na⁺ pump endocrine system

Abstract

Two prescient 1953 publications set the stage for the elucidation of a novel endocrine system: Schatzmann's report that cardiotonic steroids (CTSs) are all Na pump inhibitors, and Szent-Gyorgi's suggestion that there is an endogenous "missing screw" in heart failure that CTSs like digoxin may replace. In 1977 I postulated that an endogenous Na pump inhibitor acts as a natriuretic hormone and simultaneously elevates blood pressure (BP) in salt-dependent hypertension. This hypothesis was based on the idea that excess renal salt retention promoted the secretion of a CTS-like hormone that inhibits renal Na pumps and salt reabsorption. The hormone also inhibits arterial Na pumps, elevates myocyte Na and promotes Na/Ca exchanger-mediated Ca gain. This enhances vasoconstriction and arterial tone-the hallmark of hypertension. Here I describe how those ideas led to the discovery that the CTS-like hormone is endogenous ouabain (EO), a key factor in the pathogenesis of hypertension and heart failure. Seminal observations that underlie the still-emerging picture of the EO-Na pump endocrine system in the physiology and pathophysiology of multiple organ systems are summarized. Milestones include: 1) cloning the Na pump isoforms and physiological studies of mutated pumps in mice; 2) discovery that Na pumps are also EO-triggered signaling molecules; 3) demonstration that ouabain, but not digoxin, is hypertensinogenic; 4) elucidation of EO's roles in kidney development and cardiovascular and renal physiology and pathophysiology; 5) discovery of "brain ouabain", a component of a novel hypothalamic neuromodulatory pathway; and 6) finding that EO and its brain receptors modulate behavior and learning.

Endogenous Ouabain and Related Genes in the Translation from Hypertension to Renal Diseases

“…The presence of EO was finally demonstrated with mass spectrometry, nuclear magnetic resonance (NMR) and chromatography, confirming its existence and its identicalness to the plant-derived ouabain [ 27 , 28 ]. Furthermore, it was possible to identify the most important production site of EO in the adrenal cortex [ 29 , 30 ]. All this evidence led to the identification in mammals of numerous endogenous cardiotonic steroids as cardenolides and bufodienolides (as marinobufagenine) [ 31 ].…”

“…EO might be actually considered as a growth-promoting hormone. Indeed, many authors showed that EO is involved in pro-hypertrophic and pro-fibrotic pathways that lead to cardiac remodeling with a negative impact on both cardiac structures and cardiovascular functions [ 30 , 44 ]. The authors also tried to understand how EO might perform the role of a signal transducer.…”

Predictability in the evolution of Orthopteran cardenolide insensitivity

“…In fact, cardenolides have been used medicinally for hundreds of years as common treatments for conditions such as congestive heart failure and cardiac arrhythmias [18]. A growing number of studies have implicated the regulation of Na + , K + -ATPase by putatively endogenous cardenolides in signalling pathways linked to a variety of pathologies including hypertension and cancer [19,20].…”

Ouabain - A gift from paradise

“…It has been asserted that "ouabain is a key factor in the pathogenesis of hypertension and heart failure" [11]. The concept of "endogenous ouabain" (EO) originated in the late 1970s when it was postulated that an endogenous inhibitor of vascular Na/K ATPase might be a natriuretic hormone (NH) causing hypertension [12].…”

“…These results confirm that there is no endogenous ouabain in human plasma. In a series of publications Mordecai P. Blaustein, who strongly advocates the EO concept, vigorously denies the results of Vogeser's laboratory [11,18,19]. With dubious claims and even unfounded accusations ("edited their raw data", "scientific misconduct") he tries to discredit Vogeser's method.…”