title: The functional effect of adenoviral Na+/Ca2+ exchanger overexpression in rabbit myocytes depends on the activity of the Na+/K+-ATPase.
abstract: OBJECTIVE
  The functional consequences of Na+/Ca2+ exchanger (NCX) overexpression in heart failure have been controversially discussed. NCX function strongly depends on intracellular sodium which has been shown to be increased in heart failure.
  
  
  RESULTS
  We investigated the Na+/K+-ATPase (NKA) inhibitor ouabain (0.5-16 micromol/l) in electrically stimulated, isotonically contracting adult rabbit cardiocytes overexpressing NCX after adenoviral gene transfer (Ad-NCX-GFP, 48 h culture time). Myocytes transfected with adenovirus encoding for green fluorescent protein (Ad-GFP) served as a control. Contractions were analyzed by video-edge detection. In the Ad-NCX-GFP group, the maximum inotropic response was significantly reduced by 50.7% (P<0.05). This was a result of an enhanced susceptibility to contracture after exposure to the drug (median concentration (25-75%): 4 (4-8) vs. 8 (6-16) micromol/l, P<0.05). When analyzing relaxation before contracture, the maximum relaxation velocity was reduced (0.15+/-0.04 vs. 0.27+/-0.04 microm/s, P<0.05) and the time from peak shortening to 90% of relaxation was increased (298+/-39 vs. 185+/-15 ms, P<0.05). No differences in systolic and diastolic parameters were observed with the Na+ channel modulator BDF9198 (1 micromol/l).
  
  
  CONCLUSIONS
  Inhibition of NKA by ouabain induces a combined diastolic and systolic dysfunction in NCX overexpressing rabbit myocytes. This may be the consequence of cytoplasmic Ca2+ overload due to inhibition of forward mode or induction of reverse mode Na+/Ca2+ exchange. In end-stage failing human myocardium and during digitalis treatment this mechanism may be of major importance.
authors.affiliation: Herzzentrum Göttingen, Kardiologie und Pneumologie, Georg-August-Universität Göttingen, Robert-Koch-Strasse 40, 37075, Göttingen, Germany. schiwolf@med.uni-goettingen.de <schiwolf@med.uni-goettingen.de>
authors.forename: W
authors.initials: W
authors.lastname: Schillinger
authors.forename: A
authors.initials: A
authors.lastname: Ohler
authors.forename: S
authors.initials: S
authors.lastname: Emami
authors.forename: F
authors.initials: F
authors.lastname: Müller
authors.forename: C
authors.initials: C
authors.lastname: Christians
authors.forename: P M L
authors.initials: PM
authors.lastname: Janssen
authors.forename: H
authors.initials: H
authors.lastname: Kögler
authors.forename: N
authors.initials: N
authors.lastname: Teucher
authors.forename: B
authors.initials: B
authors.lastname: Pieske
authors.forename: T
authors.initials: T
authors.lastname: Seidler
authors.forename: G
authors.initials: G
authors.lastname: Hasenfuss
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005822:Genetic Vectors; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010042:Ouabain / Q000494:pharmacology; D011817:Rabbits; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000502:physiology*; D014162:Transfection
chemical_list: D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D015222:Sodium Channels; D019831:Sodium-Calcium Exchanger; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase