The alpha2 isoform of Na,K-ATPase mediates ouabain-induced cardiac inotropy in mice.
Inhibition of Na,K-ATPase activity by cardiac glycosides is believed to be the major mechanism by which this class of drugs increases heart contractility. However, direct evidence demonstrating this is lacking. Furthermore it is unknown which specific alpha isoform of Na,K-ATPase is responsible for the effect of cardiac glycosides. Several studies also suggest that cardiac glycosides, such as ouabain, function by mechanisms other than inhibition of the Na,K-ATPase. To determine whether Na,K-ATPase, specifically the alpha2 Na,K-ATPase isozyme, mediates ouabain-induced cardiac inotropy, we developed animals expressing a ouabain-insensitive alpha2 isoform of the Na,K-ATPase using Cre-Lox technology and analyzed cardiac contractility after administration of ouabain. The homozygous knock-in animals were born in normal Mendelian ratio and developed normally to adulthood. Analysis of their cardiovascular function demonstrated normal heart function. Cardiac contractility analysis in isolated hearts and in intact animals demonstrated that ouabain-induced cardiac inotropy occurred in hearts from wild type but not from the targeted animals. These results clearly demonstrate that the Na,K-ATPase and specifically the alpha2 Na,K-ATPase isozyme mediates ouabain-induced cardiac contractility in mice.
Dostanic
Iva
I
Department of Molecular Genetics, University of Cincinnati, College of Medicine, Cincinnati, Ohio 45267, USA.
Lorenz
John N
JN
Schultz
Jo El J
Jel J
Grupp
Ingrid L
IL
Neumann
Jonathan C
JC
Wani
Maqsood A
MA
Lingrel
Jerry B
JB
D000483:Alleles; D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D004280:Dobutamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006027:Glycosides / Q000737:chemistry; D006321:Heart / Q000187:drug effects; D006439:Hemodynamics; D006720:Homozygote; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D008957:Models, Genetic; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009200:Myocardial Contraction / Q000502:physiology*; D010042:Ouabain / Q000378:metabolism / Q000494:pharmacology*; D020033:Protein Isoforms; D000254:Sodium-Potassium-Exchanging ATPase / Q000737:chemistry* / Q000502:physiology*; D014018:Tissue Distribution
D006027:Glycosides; D020033:Protein Isoforms; D004280:Dobutamine; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase