title: The Na+-Ca2+ exchanger is essential for the action of cardiac glycosides.
abstract: The widely accepted model to explain the positive inotropic effect of cardiac glycosides invokes altered Na+-Ca2+ exchange activity secondary to Na+ pump inhibition. However, proof of this model is lacking and alternative mechanisms have been proposed. We directly tested the role of the Na+-Ca2+ exchanger in the action of the glycoside ouabain using Na+-Ca2+ exchanger knockout mice. Ablation of the exchanger is embryonic lethal, but contractility can be studied in embryonic heart tubes at day 9.5 postcoitum. Heart tubes isolated from homozygous Na+-Ca2+ exchanger knockout mice (NCX-/-) display surprisingly normal Ca2+ transients. Removal of extracellular Na+ induces Ca2+ overload in wild-type heart tubes but does not alter the Ca2+ transients of NCX-/- heart tubes. Similarly, ouabain, at levels causing Ca2+ overload in wild-type heart tubes, has no effect on NCX-/- heart tubes. We conclude that in embryonic mouse myocytes the Na+-Ca2+ exchanger is absolutely required for the effect of cardiac glycosides on Ca2+(i).
authors.affiliation: Department of Physiology, UCLA School of Medicine, Los Angeles, Calif 90095-1760, USA.
authors.forename: Hannes
authors.initials: H
authors.lastname: Reuter
authors.forename: Scott A
authors.initials: SA
authors.lastname: Henderson
authors.forename: Tieyan
authors.initials: T
authors.lastname: Han
authors.forename: Robert S
authors.initials: RS
authors.lastname: Ross
authors.forename: Joshua I
authors.initials: JI
authors.lastname: Goldhaber
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Philipson
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002301:Cardiac Glycosides / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D022062:Electrophysiologic Techniques, Cardiac; D006321:Heart / Q000187:drug effects* / Q000196:embryology / Q000502:physiology; D006579:Heterozygote; D006720:Homozygote; D066298:In Vitro Techniques; D017136:Ion Transport / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D009200:Myocardial Contraction / Q000187:drug effects*; D010042:Ouabain / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*
chemical_list: D002301:Cardiac Glycosides; D002316:Cardiotonic Agents; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D010042:Ouabain; D012964:Sodium; D002118:Calcium