Role of endogenous digitalis-like factors in the clinical manifestations of severe preeclampsia: a systematic review

Abstract

Endogenous digitalis-like factor(s), originally proposed as a vasoconstrictor natriuretic hormone, was discovered in fetal and neonatal blood accidentally because it cross-reacts with antidigoxin antibodies (ADAs). Early studies using immunoassays with ADA identified the digoxin-like immuno-reactive factor(s) (EDLF) in maternal blood as well, and suggested it originated in the feto-placental unit. Mammalian digoxin-like factors have recently been identified as at least two classes of steroid compounds, plant derived ouabain (O), and several toad derived bufodienolides, most prominent being marinobufagenin (MBG). A synthetic pathway for MBG has been identified in mammalian placental tissue. Elevated maternal and fetal EDLF, O and MBG have been demonstrated in preeclampsia (PE), and inhibition of red cell membrane sodium, potassium ATPase (Na, K ATPase (NKA)) by EDLF is reversed by ADA fragments (ADA-FAB). Accordingly, maternal administration of a commercial ADA-antibody fragment (FAB) was tested in several anecdotal cases of PE, and two, small randomized, prospective, double-blind clinical trials. In the first randomized trial, ADA-FAB was administered post-partum, in the second antepartum. In the post-partum trial, ADA-FAB reduced use of antihypertensive drugs. In the second trial, there was no effect of ADA-FAB on blood pressure, but the fall in maternal creatinine clearance (CrCl) was prevented. In a secondary analysis using the pre-treatment maternal level of circulating Na, K ATPase (NKA) inhibitory activity (NKAI), ADA-FAB reduced the incidence of pulmonary edema and, unexpectedly, that of severe neonatal intraventricular hemorrhage (IVH). The fall in CrCl in patients given placebo was proportional to the circulating level of NKAI. The implications of these findings on the pathophysiology of the clinical manifestations PE are discussed, and a new model of the respective roles of placenta derived anti-angiogenic (AAG) factors (AAGFs) and EDLF is proposed.

Cardiac Glycosides as Immune System Modulators

“…[ 23 , 24 , 25 , 26 ], but also animals, e.g., in the skin of particular amphibians such as toads ( Bufa bufa and others) [ 27 , 28 ]. Besides, there are equivalents of CGs also in humans, referred to as digitalis-like factors [ 29 , 30 ]. CGs from all plants, animals, and humans have a conserved structure, which is composed of a steroid core, a lactone ring, and a sugar moiety.…”

Canrenone Restores Vasorelaxation Impaired by Marinobufagenin in Human Preeclampsia

“…Several papers which point out that spironolactone and canrenone act as a mixed agonist/antagonist of CTS and Na/K-ATPase were summarized by Semplicini et al [ 23 ]. The recent discovery of sodium pump signaling functions has added a new dimension to the study of CTS and fibrosis, that is, demonstrated the significance of the Na/K-ATPase “signaling mechanism” [ 24 ].…”

Spiral Steroid (SS) Phosphodiesters: Role in Pregnancy

“…Buckalew evaluated the role of endogenous ouabain in severe pre-eclampsia [7]. Bagrov investigated novel therapeutic target for endogenous ouabain [8]. Altogether, there are over 1000 publications in which, investigators have used an immunoassay for ouabain to monitor cardiotonic glycosides to diagnose human disease.…”