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(Circulation. 1999;99:2105-2112.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Reduced Sodium Pump 
1, 3, and ß1-Isoform Protein Levels and Na+,K+-ATPase Activity but Unchanged Na+-Ca2+ Exchanger Protein Levels in Human Heart Failure
From Klinik III für Innere Medizin der Universität zu Köln (Germany) (R.H.G.S., K.F., J.M.-E., K.B., E.E.) and the Departments of Physiology and Biophysics, University of Southern California School of Medicine, Los Angeles (J.W., A.A.M.).
Correspondence to Priv-Doz DrMed Robert H.G. Schwinger, Laboratory of Muscle Research and Molecular Cardiology, Klinik III für Innere Medizin der Universität zu Köln, Joseph-Stelzmannstr. 9, D-50924 Köln, Germany. E-mail Robert.Schwinger{at}medizin.uni-koeln.de
Background-Cardiac glycosides initiate an increase in force of contraction by inhibiting the sarcolemmal sodium pump (Na+,K+-ATPase), thereby decreasing Ca2+ extrusion by the Na+-Ca2+ exchanger, which increases the cellular content of Ca2+. In patients with heart failure the sensitivity toward cardiac glycosides is enhanced.
Methods and Results-Because the inotropic effect of cardiac
glycosides may be a function of the sodium pump and
Na+-Ca2+ exchanger (NCE) expression levels, the
present study aimed to investigate protein expression of both
transporters (immunoblot with specific antibodies against
the sodium pump catalytic 
1-, 2-,
3-, and glycoprotein
ß1-isoforms and against NCE) in left ventricle from
failing (heart transplantations, New York Heart Association class IV,
n=21) compared with nonfailing (donor hearts, NF, n=22) human
myocardium. The density of 3H-ouabain–binding
sites (Bmax) and the Na+,K+-ATPase
activity were also measured. In NYHA class IV, protein levels of
Na+,K+-ATPase 1- (0.62±0.06 of
control), 3- (0.70±0.09), and ß1-
(0.61±0.04) but not 2-isoforms were significantly
reduced (P<0.01), whereas levels of NCE (0.92±0.13 of
control) and calsequestrin (0.98±0.06) remained unchanged. Both
Na+,K+-ATPase activity (NF: 1.9±0.29; NYHA
class IV: 1.1±0.17 µmol ATP/min per milligram of protein) and
the 3H-ouabain binding sites (Bmax NF:
15.9±1.9 pmol/mg protein; NYHA class IV: 9.7±1.5) were reduced in
NYHA class IV and correlated significantly to each other
(r2=0.73; P<0.0001), as did
ß1-subunit expression. In left ventricular
papillary muscle strips from NYHA class IV compared with nonfailing
tissue the Na+-channel modulator BDF 9198 exerted an
increase in force of contraction with unchanged effectiveness but
enhanced potency.
Conclusions-The enhanced sensitivity of failing human myocardium toward cardiac glycosides may be, at least in part, attributed to a reduced protein expression and activity of the sarcolemmal Na+,K+-ATPase without a change in Na+-Ca2+ exchanger protein expression.
Key Words: sodium • heart failure • myocardium • receptors
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