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Am J Physiol Heart Circ Physiol (May 27, 2004). doi:10.1152/ajpheart.00397.2003
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Submitted on May 2, 2003
Accepted on May 18, 2004

Na+/Ca2+ Exchanger Overexpression Impairs Frequency- and Ouabain-Dependent Cell-Shortening in Adult Rat Cardiomyocytes

Birgit Bolck1, Gotz Munch1, Peter Mackenstein1, Martin Hellmich2, Ingo Hirsch1, Hannes Reuter1, Nadja Hattebuhr1, Hans-Jorg Weig3, Martin Ungerer3, Klara Brixius1, and Robert H.G. Schwinger1*

1 Laboratory of Muscle Reseach and Molecular Cardiology, Department for Internal Medicine III, University of Cologne, Cologne, Germany
2 Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany
3 Deutsches Herzzentrum, Technische Universitaet Muenchen, Munich, Germany

* To whom correspondence should be addressed. E-mail: Robert.Schwinger{at}medizin.uni-koeln.de.

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 sodium concentration ([Na+]i), 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 an 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 5-9 fold (dose-dependent) overexpression of the 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. Protein expression of SERCA, 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. Following step-wise enhancing frequency of stimulation to 3.0 Hz, FS remained unaffected in Ad.GFP, but declined in Ad.NCX.GFP cells. The positive inotropic effect of the cardiac glycoside ouabain was less effective in Ad.NCX.GFP; whereas the positive inotropic effect of {beta}-adrenergic stimulation remained unchanged. In conclusion, NCX overexpression results in a reduced cell shortening at higher stimulation frequencies as well as after inhibition of the 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.




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