Endogenous cardiac glycosidelike compounds.

The possibility that endogenous inhibitors of the sodium pump exist and bind to the cardiac glycoside binding site on Na+,K+-adenosine triphosphatase (ATPase) has been a source of much controversy. Although numerous hormones and inorganic ions that modulate Na+,K+-ATPase activity have been described, most of these affect the sodium pump indirectly by varying the intracellular sodium concentration or by increasing the number of enzyme units. None of these endogenous compounds has been shown conclusively to modulate sodium pump activity by binding to the cardiac glycoside binding site on Na+,K+-ATPase. However, the near-universal presence of three high-affinity binding sites on the alpha-subunit of the enzyme has engendered much speculation that endogenous ligands for these receptors must exist. In addition, none of the hormones known to indirectly affect sodium pump activity in vivo has been shown to modulate Na+,K+-ATPase activity in response to extracellular volume expansion or to play a role in the pathogenesis of hypertension or chronic renal failure, conditions in which a circulating inhibitor of Na+,K+-ATPase has been implicated. This report presents a condensed history of the search for endogenous inhibitors of Na+,K+-ATPase and describes recent advances in the field. Despite progress in identifying and characterizing compounds that could affect Na+,K+-ATPase activity in vivo, definitive proof for the existence of endogenous ligands for the cardiac glycoside binding site remains elusive.