© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
The functional effect of adenoviral Na+/Ca2+ exchanger overexpression in rabbit myocytes depends on the activity of the Na+/K+-ATPase
Herzzentrum Göttingen, Kardiologie und Pneumologie, Georg-August-Universität Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany
* Corresponding author. Tel.: +49-551-39-6349; fax: +49-551-39-9804. schiwolf{at}med.uni-goettingen.de
Objectives: 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. Methods and results: We investigated the Na+/K+-ATPase (NKA) inhibitor ouabain (0.5–16 µmol/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) µmol/l, P<0.05). When analyzing relaxation before contracture, the maximum relaxation velocity was reduced (0.15±0.04 vs. 0.27±0.04 µm/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 µmol/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.
KEYWORDS Calcium (cellular); Contractile function; Heart failure; Na/Ca-exchanger; Na/K-pump
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