Identification and characterization of a ouabain-like compound from human plasma.

Abstract

The plasma membrane sodium-potassium pumps that regulate intracellular sodium in most animal cells have specific, high-afimity receptors for the digitalis glycosides and their aglycones. This has fostered speculation that there is an endogenous ligand. We have purified and structurally identified by mass spectroscopy an endogenous substance from human plasma that binds with high affinity to this receptor and that is indistinguishable from the cardenolide ouabain. This human ouabain-like compound (OLC) displaces [3H]ouabain from its receptor, inhibits Na,K-ATPase and ouabain-sensitive 86Rb+ uptake, and has cardiotonic actions quantitatively similar to commercial ouabain. Immunoreactive OLC was detected in the plasma of many mammals, and high concentrations were found in the adrenals. The circulating OLC may modulate intracellular Na' and affect numerous Na' gradientdependent processes including intracellular Ca2' and pH homeostasis in many tissues. Furthermore, altered circulating levels of OLC may be associated with the pathogenesis of certain forms of hypertension.

Na/K-ATPase Tethers Phospholipase C and IP3 Receptor into a Calcium-regulatory Complex

“…Because there is sufficient evidence that ouabain and marinobufagenin are likely the endogenous cardiotonic steroids, our findings brings about an interesting question as to whether this mode of regulation is relevant to in vivo physiology. To this end, several laboratories have reported that endogenous ouabain and marinobufagenin are circulated at sub-nM to nM concentrations in normal individuals and that volume expansion can significantly increase their concentrations (Hamlyn et al, 1991;Fedorova et al, 2002;Bauer et al, 2005). Thus, it is conceivable that the described regulation may be relevant to in vivo physiopathology if future in vivo studies confirm our in vitro experiments.…”

Na + pump low and high ouabain affinity α subunit isoforms are differently distributed in cells

“…This could be the rationale for colocalization of high ouabain affinity Na ϩ pumps and Na ϩ ͞Ca 2ϩ exchangers in these PM areas. This might reveal how an endogenous ouabain isomer (12,(37)(38)(39), which circulates at nanomolar concentrations (40) and is present in the brain (38,39), could, by modulating the activity of these high ouabain affinity Na ϩ pumps (28,37), play a role in many physiological, and even pathophysiological, processes (12). Finally, this may also explain why the isoformspecific features of the ouabain binding regions of ␣2 and ␣3 have been so well conserved during the evolution of higher animals (4,10).…”

Selective association of endogenous ouabain with subclinical organ damage in treated hypertensive patients

“…[1][2][3] Previous studies have shown that EO is mostly produced in the adrenal cortex and circulating EO activate the sympathetic nervous system. 3,4 Their results suggested that these activations can be inhibited with b-blocker, angiotensin converting enzyme inhibitor and digoxin immune fab (antigen-binding fragments), Digi-Bind.…”