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This Article Full Text Full Text (PDF) All Versions of this Article: 287/4/H1435    most recent 00397.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (14) Citing Articles via Google Scholar Google Scholar Articles by Bölck, B. Articles by Schwinger, R. H. G. Search for Related Content PubMed PubMed Citation Articles by Bölck, B. Articles by Schwinger, R. H. G.

Na⁺/Ca²⁺ exchanger overexpression impairs frequency- and ouabain-dependent cell shortening in adult rat cardiomyocytes

¹Laboratory of Muscle Research and Molecular Cardiology, Department for Internal Medicine III, University of Cologne, 50924 Cologne; ²Deutsches Herzzentrum der Technischen Universität München, 81675 München; and ³Institute of Medical Statistics, Informatics, and Epidemiology; University of Cologne, 50924 Cologne, Germany

Submitted 3 May 2003 ; accepted in final form 18 May 2004

The Na⁺/Ca²⁺ exchanger (NCX) may influence cardiac function depending on its predominant mode of action, forward mode or reverse mode, during the contraction-relaxation cycle. The intracellular Na⁺ concentration ([Na⁺]_i) and the duration of the action potential as well as the level of NCX protein expression regulate the mode of action of NCX. [Na⁺]_i and NCX expression have been reported to be increased in human heart failure. Nevertheless, the consequences of altered NCX expression in heart failure are still a matter of discussion. We aimed to characterize the influence of NCX expression on intracellular Ca²⁺ transport in rat cardiomyocytes by adenoviral-mediated gene transfer. A five- to ninefold (dose dependent) overexpression of NCX protein was achieved after 48 h by somatic gene transfer (Ad.NCX.GFP) versus control (Ad.GFP). NCX activity, determined by Na⁺ gradient-dependent ⁴⁵Ca²⁺-uptake, was significantly increased. The protein expressions of sarco(endo)plasmic reticulum Ca²⁺-ATPase, phospholamban, and calsequestrin were unaffected by NCX overexpression. Fractional shortening (FS) of isolated cardiomyocytes was significantly increased at low stimulation rates in Ad.NCX.GFP. After a step-wise enhancing frequency of stimulation to 3.0 Hz, FS remained unaffected in Ad.GFP cells but declined in Ad.NCX.GFP cells. The positive inotropic effect of the cardiac glycoside ouabain was less effective in Ad.NCX.GFP cells, whereas the positive inotropic effect of -adrenergic stimulation remained unchanged. In conclusion, NCX overexpression results in a reduced cell shortening at higher stimulation frequencies as well as after inhibition of sarcolemmal Na⁺-K⁺-ATPase, i.e., in conditions with enhanced [Na⁺]_i. At low stimulation rates, increased NCX expression enhances both intracellular systolic Ca²⁺ and contraction amplitude.

adenovirus; gene transfer; calcium cycling; sarcoplasmic reticulum; contractility

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