Endogenous ouabain is not ouabain.

Abstract

The concept of a circulating digitalis-like inhibitor of the sodium pump, Na+, K+-ATPase, evolved from studies performed in the 1960s. De Wardener et al1 addressed the question of whether a small increase in the glomerular filtration rate together with changes in the concentration of the more recently discovered hormone aldosterone could explain the natriuresis that generally followed salt (sodium) loading. In their studies, dogs had their renal blood flow reduced significantly by constricting the aorta above the renal arteries and were given supramaximal doses of fludrocortisone, a synthetic analogue of aldosterone, and vasopressin before being challenged with intravenous saline. Their ability to develop a natriuresis clearly demonstrated that a third factor (beyond changes in glomerular filtration rate and aldosterone concentrations) was involved in the natriuresis of salt loading. Subsequent experiments demonstrated that the responsible agent could be transmitted by the plasma of the volume-expanded animal.2 Although we may now ask whether in these experiments the effect was mediated, at least in part, by the release of atrial and B-type natriuretic peptide from the heart, it was nearly 2 decades before those hormones were discovered during which time it was demonstrated that the plasma of volume-expanded animals had the ability to inhibit the sodium pump3—which is not a target of atrial natriuretic peptide and B-type natriuretic peptide. Essentially parallel studies were performed by Welt and colleagues4 in uremia where inhibition of the sodium pump of erythrocytes was demonstrated along with the ability of uremic plasma to induce such a defect in normal erythrocytes. In 1975, it was shown that patients with essential hypertension had, as a group, reduced activity of the sodium pump of leukocytes, with corresponding elevated values for intracellular sodium.5 This finding proved to be reproducible in various laboratories, …