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). Although all α Na+-K+-ATPase isoforms (α1-4) are sensitive to ouabain in most species, in rats and mice the ubiquitously expressed α1 Na+-K+-ATPase is resistant to ouabain. We have previously shown that selective modification of the putative ouabain binding site of either the α1 or α2 Na+-K+-ATPase 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 indexes 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. MBG at 0.025, 0.05, and 0.1 nmol·min−1·g body wt−1 significantly increased cardiac performance to a greater extent in α1S/Sα2R/R compared with α1R/Rα2R/R and wild-type mice. The increase in LVdP/d tmax in α1S/Sα2R/R mice was greater at higher concentrations of MBG compared with both α1R/Rα2R/R and α1R/Rα2S/S mice ( P < 0.05). These results suggest that MBG interacts with the ouabain binding site of the α1 Na+-K+-ATPase subunit and can thereby influence cardiac inotropy.
Cardiac Autonomic Dysfunction in Myasthenia Gravis and Relapsing-Remitting Multiple Sclerosis—A Pilot Study
