NDLI: Marinobufagenin enhances cardiac contractility in mice with ouabain-sensitive $α

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Wansapura, Arshani N. Lasko, Valerie Xie, Zijian Fedorova, Olga V. Bagrov, Alexei Y. Lingrel, Jerry B. Lorenz, John N.
Description	Country affiliation: United States Author Affiliation: Wansapura AN ( Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0576, USA.)
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). Although all α $Na^{+}-K^{+}-ATPase$ isoforms $(α_{1-4})$ are sensitive to ouabain in most species, in rats and mice the ubiquitously expressed $α_{1}$ $Na^{+}-K^{+}-ATPase$ is resistant to ouabain. We have previously shown that selective modification of the putative ouabain binding site of either the $α_{1}$ or $α_{2}$ $Na^{+}-K^{+}-ATPase$ 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 $α_{1}-resistant/α_{2}-resistant$ $(α_{1}^{R/R}α_{2}^{R/R}),$ $α_{1}-sensitive/α_{2}-resistant$ $(α_{1}^{S/S}α_{2}^{R/R}),$ and $α_{1}-resistant/α_{2}-sensitive$ mice $(α_{1}^{R/R}α_{2}^{S/S},$ 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 $α_{1}^{S/S}α_{2}^{R/R}$ compared with $α_{1}^{R/R}α_{2}^{R/R}$ and wild-type mice. The increase in $LVdP/dt_{max}$ in $α_{1}^{S/S}α_{2}^{R/R}$ mice was greater at higher concentrations of MBG compared with both $α_{1}^{R/R}α_{2}^{R/R}$ and $α_{1}^{R/R}α_{2}^{S/S}$ mice (P < 0.05). These results suggest that MBG interacts with the ouabain binding site of the $α_{1}$ $Na^{+}-K^{+}-ATPase$ subunit and can thereby influence cardiac inotropy.
File Format	HTM / HTML
ISSN	03636135
e-ISSN	15221539
DOI	10.1152/ajpheart.00285.2009
Journal	AJP: Heart and Circulatory Physiology
Issue Number	6
Volume Number	296
Language	English
Publisher	American Physiological Society
Publisher Date	2009-06-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Physiology Discipline Cardiology Bufanolides Pharmacology Enzyme Inhibitors Myocardial Contraction Drug Effects Sodium-potassium-exchanging Atpase Metabolism Animals Binding Sites Cardiotonic Agents Dobutamine Enzyme Activation Physiology Mice Mice, Inbred Strains Mice, Mutant Strains Ouabain Chemistry Genetics Ventricular Function, Left Research Support, N.i.h., Extramural Research Support, N.i.h., Intramural
Alternative Title	Marinobufagenin enhances cardiac contractility in mice with ouabain-sensitive alpha1 Na+-K+-ATPase
Content Type	Text
Resource Type	Article
Subject	Physiology Physiology (medical) Cardiology and Cardiovascular Medicine

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