Marinobufagenin enhances cardiac contractility in mice with ouabain-sensitive alpha1 Na+-K+-ATPase.
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 alpha Na(+)-K(+)-ATPase isoforms (alpha(1-4)) are sensitive to ouabain in most species, in rats and mice the ubiquitously expressed alpha(1) Na(+)-K(+)-ATPase is resistant to ouabain. We have previously shown that selective modification of the putative ouabain binding site of either the alpha(1) or alpha(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 alpha(1)-resistant/alpha(2)-resistant (alpha(1)(R/R)alpha(2)(R/R)), alpha(1)-sensitive/alpha(2)-resistant (alpha(1)(S/S)alpha(2)(R/R)), and alpha(1)-resistant/alpha(2)-sensitive mice (alpha(1)(R/R)alpha(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 alpha(1)(S/S)alpha(2)(R/R) compared with alpha(1)(R/R)alpha(2)(R/R) and wild-type mice. The increase in LVdP/dt(max) in alpha(1)(S/S)alpha(2)(R/R) mice was greater at higher concentrations of MBG compared with both alpha(1)(R/R)alpha(2)(R/R) and alpha(1)(R/R)alpha(2)(S/S) mice (P < 0.05). These results suggest that MBG interacts with the ouabain binding site of the alpha(1) Na(+)-K(+)-ATPase subunit and can thereby influence cardiac inotropy.
Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0576, USA.
Arshani N
AN
Wansapura
Valerie
V
Lasko
Zijian
Z
Xie
Olga V
OV
Fedorova
Alexei Y
AY
Bagrov
Jerry B
JB
Lingrel
John N
JN
Lorenz
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002018:Bufanolides / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D004280:Dobutamine / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D010042:Ouabain / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D002018:Bufanolides; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; C093896:marinobufagenin; D004280:Dobutamine; D010042:Ouabain; C401838:Atp1a2 protein, mouse; C497344:Atp1a1 protein, mouse; D000254:Sodium-Potassium-Exchanging ATPase