Is ouabain the endogenous digitalis?

T he possibility that an endogenous ligand might exist for the cardiac glycoside binding site on the Na+,K+-ATPase (i.e., the "sodium pump") has been a source of much speculation, resulting in intensive efforts over the past decade by many laboratories to identify an "endogenous digitalis-like hormone."'1-6 Several arguments have been propounded in support of this hypothesis. The first and perhaps most compelling is the fact that the binding site for cardiac glycosides is highly conserved throughout the phylogeny of eukaryotes. The possibility that the conservation of the specific protein conformation responsible for binding of cardiac glycosides merely ensures successful ion translocation, having by design nothing to do with the binding of a putative cardiac glycoside-like autacoid, is unsatisfying. This explanation, for example, ignores the rationale followed in the identification of the endogenous opioids, which clearly act at receptors that also bind compounds derived from plants, although this example may be less relevant than it appears for reasons to be discussed below. Other explanations aside from a circulating digitalis-like hormone have been elaborated to explain the conservation of the cardiac glycoside binding site on the sodium pump, although these remain purely speculative.6 The second major reason for the continuing interest in an endogenous digitalis is the hypothesis that such a hormone, if it were to exist, could have important effects on sodium homeostasis and systemic vascular resistance. Neither of these actions, ironically, has anything to do with the usual indications for administration of digoxin to patients, i.e., its antiarrhythmic and positive inotropic actions on the heart, although the article by