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This Article Full Text Full Text (PDF) All Versions of this Article: 296/6/H1833    most recent 00285.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Wansapura, A. N. Articles by Lorenz, J. N. Search for Related Content PubMed PubMed Citation Articles by Wansapura, A. N. Articles by Lorenz, J. N.

Marinobufagenin enhances cardiac contractility in mice with ouabain-sensitive ₁ Na⁺-K⁺-ATPase

Departments of ¹Molecular and Cellular Physiology and ²Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati; ³Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio; and ⁴Laboratory of Cardiovascular Science, National Institute on Aging, Baltimore, Maryland

Submitted 24 March 2009 ; accepted in final form 13 April 2009

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 Na⁺-K⁺-ATPase isoforms (_1-4) are sensitive to ouabain in most species, in rats and mice the ubiquitously expressed ₁ Na⁺-K⁺-ATPase is resistant to ouabain. We have previously shown that selective modification of the putative ouabain binding site of either the ₁ or 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 ₁-resistant/₂-resistant (₁^R/R₂^R/R), ₁-sensitive/₂-resistant (₁^S/S₂^R/R), and ₁-resistant/₂-sensitive mice (₁^R/R₂^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 ₁^S/S₂^R/R compared with ₁^R/R₂^R/R and wild-type mice. The increase in LVdP/dt_max in ₁^S/S₂^R/R mice was greater at higher concentrations of MBG compared with both ₁^R/R₂^R/R and ₁^R/R₂^S/S mice (P < 0.05). These results suggest that MBG interacts with the ouabain binding site of the ₁ Na⁺-K⁺-ATPase subunit and can thereby influence cardiac inotropy.

cardiotonic steroids; sodium-potassium-adenosinetriphosphatase isoforms