Endogenous digitalis-like factors: an overview of the history

Abstract

The sodium pump is a ubiquitous cell surface enzyme, a Na, K ATPase, which maintains ion gradients between cells and the extracellular fluid (ECF). The extracellular domain of this enzyme contains a highly conserved binding site, a receptor for a plant derived family of compounds, the digitalis glycosides. These compounds inhibit the enzyme and are used in the treatment of congestive heart failure and certain cardiac arrhythmias. The highly conserved nature of this enzyme and its digitalis receptor led to early suggestions that endogenous regulators might exist. Recent examination of this hypothesis emerged from research in two separate areas: the regulation of ECF volume by a natriuretic hormone (NH), and the regulation of peripheral vascular resistance by a circulating inhibitor of vascular Na, K ATPase. These two areas merged with the hypothesis that NH and the vascular Na, K ATPase inhibitor were in fact the same entity, and that it played a causative role in the pathophysiology of certain types of hypertension. The possibility that multiple endogenous digitalis-like factors (EDLFs) exist emerged from efforts to characterize the circulating enzyme inhibitory activity. In this review, the development of this field from its beginnings is traced, the current status of the structure of EDLFs is briefly discussed, and areas for future development are suggested.

Keywords: bufodienolides; cardenolides; digitalis-like factor; marinobufagenin; natriuretic hormone; ouabain.

Figure 1

The concept of an endogenous digitalis-like factor (EDLF) that inhibits Na, K ATPase in a manner similar to the cardiac glycosides developed from two lines of investigation (see text), the response of renal sodium excretion to extracellular fluid volume expansion, and the regulation of peripheral vascular resistance in hypertension. Research on the identity of EDLF indicates that mammalian species synthesize two classes of steroids that are either identical to, or analogs of those found in plants (cardenolides) and toads (bufodienolides). Evidence suggests that one or more of these compounds may be involved in the pathophysiology of various hypertensive disorders, chronic renal failure, and congestive heart failure.