Marinobufagenin enhances cardiac contractility in mice with ouabain‐sensitive α1 Na,K‐ATPase (NKA)

Abstract

Endogenous Na+ pump inhibitors are thought to play important (patho)physiological roles, and occur in two different chemical forms in the mammalian circulation: cardenolides, such as ouabain, and bufadienolides, such as marinobufagenin (MBG). While all αNKA isoforms are sensitive to ouabain in most species, in rats and mice the ubiquitously expressed α1NKA is resistant to ouabain. We have previously shown that selective modification of the putative ouabain‐binding site of either the α1 or α2 NKA subunit in mice substantially alters the cardiotonic influence of exogenously applied cardenolides. To determine whether the ouabain‐binding site also interacts with MBG and if this interaction plays a functional role, we evaluated cardiovascular function in α1‐resistant/α2‐resistant (α1R/Rα2R/R), α1‐sensitive/α2‐resistant (α1S/Sα2R/R), and α1‐resistant/α2‐sensitive mice (α1R/Rα2S/S, wild type). Cardiovascular indices were evaluated in vivo by cardiac catheterization at baseline and during graded infusions of MBG. There were no differences in baseline measurements of targeted mice, indicating normal hemodynamics and cardiac function. As shown in the graph, MBG increased cardiac performance to a greater extent in α1S/Sα2R/R compared to α1R/Rα2R/R and wild type mice. These data indicate that MBG interacts with the ouabain‐binding site of the α1NKA subunit and can thereby influence cardiac inotropy.

C5′-Alkyl Substitution Effects on Digitoxigenin α-l-Glycoside Cancer Cytotoxicity

“…[12][13][14][15] More recently, Karlish demonstrated that inhibition of the R2isoform over the R1-Na þ /K þ ATPase isoform could induce cardiac contraction with minimal Ca 2þ overload and less cardiotoxicity. 16,17 These studies also suggest that an R2-selective cardiac glycoside could result from sugar modification, as the structural differences in these isoforms lie primarily in the extracellular carbohydrate binding loops. Thus, sugar modification could provide the potential for the discovery of new and safer digitoxin analogues with improved anticancer activity.…”

“…Digitoxin consists of digitoxigenin (pharmacophore) and the trisaccharide moiety, which are known to play a crucial role in both its cardiotoxicity and anticancer activity . Because digitoxin’s cardiotonic activity has been known for a much longer time, most structure activity relationship (SAR) studies have focused on the Na + /K + ATPase inhibition and examined the effect of modifying the carbohydrate portion of the cardiac glycosides. − More recently, Karlish demonstrated that inhibition of the α2-isoform over the α1-Na + /K + ATPase isoform could induce cardiac contraction with minimal Ca 2+ overload and less cardiotoxicity. , These studies also suggest that an α2-selective cardiac glycoside could result from sugar modification, as the structural differences in these isoforms lie primarily in the extracellular carbohydrate binding loops. Thus, sugar modification could provide the potential for the discovery of new and safer digitoxin analogues with improved anticancer activity.…”

Synthesis and Evaluation of the α-d-/α-l-Rhamnosyl and Amicetosyl Digitoxigenin Oligomers as Antitumor Agents

“…Although the detailed mechanism of anticancer activity is not fully understood, many apoptosis signals have been found to be affected by digitoxin at subcardiotoxic concentration in plasma . Studies also suggested that an α2-selective cardiac glycoside could result from sugar modification, because the structural differences in these isoforms primarily lie in the extracellular carbohydrate binding loops. , Thus, sugar modification opens the potential for discovery of new and safer digitoxin analogues with improved anticancer activity. In addition to the study of Na + /K + ATPase in myocardial cells, Thorson and co-workers demonstrated the potential for improving cytotoxicity against a wide range of human cancer cell lines by screening a library of digitoxin MeNO -neoglycoside analogues .…”