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 Ca²⁺ 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.

Keywords: Na/Ca exchange; calcium; endogenous ouabain; hypertension; sodium pump.

Fig. 1.

Block diagram (1977 version) of Ca²⁺ regulation in arterial smooth muscle myocytes used to explain the hypothesis that Na⁺ pumps, Na⁺/Ca²⁺ exchangers (NCX) and an endogenous ouabain-like compound (OLC) help regulate myocyte Ca²⁺ and arterial tone (29). Some key Na⁺ and Ca²⁺ transport pathways are shown: 1) ouabain-sensitive Na⁺ pump; 2) NCX operating in the Ca²⁺ extrusion mode, although we now know that NCX usually operates in the Ca²⁺ entry mode in arteries with tone (31, 319); 3) sarcoplasmic reticulum (SR) Ca²⁺ pump (SERCA). Most of the Na⁺ and Ca²⁺ entry is through plasma membrane voltage-gated channels (k₁ and k₂, respectively) and Ca²⁺ is released from the SR through ryanodine receptors or inositol trisphosphate receptors (k₃). This diagram anteceded the discovery of Na⁺ pump isoforms and PLasmERosomes. [Modified from Blaustein (29).]

Fig. 2.

Mean arterial pressure (MAP) is directly correlated with plasma Na⁺-K⁺-ATPase (NKA) inhibitory activity. Data are from 20 normotensive (green and blue circles) and 26 hypertensive (red circles) subjects. Green circles indicate discrete single plasma samples; red and blue circles indicate plasma samples drawn slowly over 6 hours (“integrated samples”). The regression line is a least-squares fit to the data; the correlation between MAP and % NKA inhibition is highly significant (r = 0.73; P < 0.0005). Details are given in Ref. . [Modified from Hamlyn et al. (123) with permission from Macmillan Publishers Ltd., copyright 1982.]

Fig. 3.

Molecular structures of ouabain (A), digoxin (B), marinobufagenin (C), and rostafuroxin (D). The sugars in ouabain and digoxin are indicated by “Rs.” [Reproduced from Schoner and Scheiner-Bobis (257).]

Fig. 4.

The centrally controlled, parallel sympathetic nerve and slow neurohumoral pathways that regulate both arterial and cardiac function, and participate in the pathogenesis of hypertension and heart failure (HF). Angiotensin II (Ang II) and high dietary salt (↑[Na⁺]) are convergent signals that act via hypothalamic Ang-type 1 receptors (AT₁R) to activate central nervous system (CNS) sympathetic pathways; the role of the kidneys in the retention of salt has been omitted for the sake of simplicity. The increased sympathetic nerve activity (SNA) promotes vasoconstriction and increases cardiac rate and contractile force. Prolonged stimulation of hypothalamic AT₁R also activates a novel neurohumoral pathway (box at top right) that includes aldosterone (Aldo), mineralocorticoid receptors (MR), epithelial Na⁺ channels (ENaC), endogenous ouabain (EO), and α2 Na⁺ pumps. This hypothalamic pathway feeds back (green line, “+”) to modulate Ang II-activated SNA and also promotes adrenal secretion of EO, triggered by, e.g., ACTH, adrenal SNA, and/or Ang II. The elevated plasma EO acutely inhibits α2 Na⁺ pumps in both the heart and arteries, and the rise in intracellular Na⁺ rapidly induces Na/Ca exchanger (NCX)-mediated Ca²⁺ gain, and cardiotonic and vasotonic effects. Prolonged plasma EO elevation also activates an α2 Na⁺ pump-associated protein kinase cascade (e.g., EGFR/Src/MEK/ERK-mediated) that increases cardiac and arterial NCX expression, and arterial sarcoplasmic reticulum (SR) Ca²⁺ pump (SERCA2) expression. In arteries with tone, NCX normally favors Ca²⁺ entry and helps to sustain cytosolic Ca²⁺ ([Ca²⁺]_CYT) above contraction threshold. The EO-induced NCX and SERCA2 upregulation enhances Ca²⁺ signaling and helps the very modestly increased SNA to increase vascular tone and resistance and elevate blood pressure. In the heart, NCX promotes Ca²⁺ extrusion during diastole, but prolonged α2 pump inhibition by EO reduces the Na⁺ gradient driving force so that [Na⁺]_CYT and diastolic [Ca²⁺]_CYT are both elevated; consequently, cardiac relaxation is slow and/or incomplete. Also, cardiac SERCA2 expression is usually reduced in HF (perhaps due to the high EO), as are SR Ca²⁺ stores and [Ca²⁺]_CYT transients, and systolic function is impaired. The diastolic dysfunction and attenuated cardiac contraction and stroke volume contribute to HF. These cellular mechanisms are discussed further in a recent review (31). [Modified from Blaustein et al. (31) with permission.]