Circulating digitalis-like factors

Abstract

The ability of extracts of mammalian plasma and tissue to mimic the biologic activities of the digitalis glycosides has suggested the existence of endogenous regulators for Na, K ATPase. Purification of plasma extracts has identified several classes of circulating lipids with digitalis-like activity including free fatty acids, lysophospholipids, and arachidonic acid metabolites of the lipoxygenase pathway. Circulating steroids with digitalis-like activity include dehydroepiandrosterone sulfate and hydrocortisone. Evidence for other, more unique compounds has also been published although their structure has not yet been determined. Analysis of tissue suggests that hypothalamus contains a unique, low molecular digitalis-like factor (DLF) which also circulates in plasma. Some studies suggest that the hypothalamic factor is also present in other parts of the brain and in the adrenal. Some of these endogenous DLF may function as modulators of cardiovascular function by regulating renal sodium excretion and peripheral vascular resistance in both physiological and pathophysiological situations.

Natriuretic Hormone: Current Status

“…Lipids with digitalis-like activity are easily distin guishable by their dose-response curves, which are steeper than those of ouabain [8], and by their solubility in organic solvents. However, some studies which re ported digitalis-like activity were performed on lipidcontaining extracts where dose-response curves were not performed [e.g.…”

“…These com pounds inhibit Na-K-ATPase and ouabain binding to the digitalis receptor; along with several other lipids, they appear to have DLI (table 1). These lipids are active in assays for digitalis-like activity in the same concentra tions as those found in plasma [8]. The question has been raised, therefore, as to whether there are any novel DLFs in plasma or tissue which function as natriuretic hor mone or as regulators of Na-K-ATPase in tissues other than the kidney.…”

“…This latter observation led to the demonstration of plasma's ability to inhibit the activity of membrane-bound Na-K-ATPase preparations in vitro [7] and to the suggestion that natriuretic hormone might be an endogenous digi talis-like substance. Subsequently, numerous laborato ries demonstrated that plasma (and certain tissues) con tained other digitalis-like activities such as cross-reactiv ity with antidigoxin antibodies, inhibition of ouabain binding, and inhibition of ouabain-suppressible sodiumpotassium transport [8]. These activities have formed the basis for semiquantitative assays used to purify the factor (or factors) responsible.…”

“…Despite these difficul ties, many have pursued this approach and have identi fied several known endogenous compounds with digital is-like activities. In addition, evidence for the existence of more novel factors and for the physiological and pathophysiological relevance of these compounds con tinues to mount [8].…”

“…The role of these fac tors in the several pathophysiological states in which they have been implicated will not be discussed. Several such summaries of that subject have been published recently or are in press [8][9][10][11].…”