Endogenous ouabain is not ouabain.

T he concept of a circulating digitalis-like inhibitor of the sodium pump, Na + , K +-ATPase, evolved from studies performed in the 1960s. De Wardener et al 1 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 pump 3 —which is not a target of atrial natriuretic peptide and B-type natriuretic peptide. Essentially parallel studies were performed by Welt and colleagues 4 in ure-mia 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 hyperten-sion had, as a group, reduced activity of the sodium pump of leukocytes, with corresponding elevated values for intracel-lular sodium. 5 This finding proved to be reproducible in various laboratories, and once again the effect was transmissible by exposing normal cells to the plasma of hypertensives. It was also shown that there was a crude correlation between the elevated blood pressure and the depression of the activity of the sodium pump as measured by the efflux rate constant. 6 It was then clear that under certain conditions humans and other animals had the ability to secrete an inhibitor of the sodium pump and that this may well be of importance in the physiol-ogy/pathophysiology of salt overload, uremia, and essential hypertension. Long overdue is a review of De Wardener's third …