© 1993 by European Society of Cardiology
Copyright © 1993, European Society of Cardiology
Characterisation of Na/K-ATPase, its isoforms, and the inotropic response to ouabain in isolated failing human hearts
University of Cincinnati, College of Medicine, Ohio, USA – Department of Molecular Genetics, Biochemistry and Microbiology: O I Shamraj, J B Lingrel; Department of Pharmacology and Cell Biophysics: I L Grupp, G Grupp; Department of Surgery: D Melvin; Ciba-Geigy Ltd, Basle, Switzerland – Department of Cardiovascular Research: N Gradoux, A De Pover; Medical Department, General Biometry: W Kremers.
Correspondence to Dr De Pover, at K-125.9.04, Ciba-Geigy Ltd, CH-4002 Basle, Switzerland.
Objective: The aim was to determine whether failing human hearts have increased sensitivity to the inotropic and toxic effects of ouabain, and to examine alterations in Na/K-ATPase that might explain the observed higher ouabain sensitivity. Methods: For contractility studies, a total of 57 trabeculae were isolated from two non- failing (death from head injury) and 10 terminally failing, explanted human hearts. After the experiment, each trabecula was inspected under the light microscope for morphological alterations consistent with heart failure. Samples for biochemical and molecular studies were obtained from five non-failing and 13 failing hearts. Total Na/K-ATPase was measured in desoxycholate treated homogenates and expressed per unit of tissue wet or dry weight, DNA, protein, or myosin. Interference from residual bound digoxin due to previous therapy was excluded. The expression of the three 
isoforms was studied at both the mRNA level using northern blots and the protein level by analysis of dissociation kinetics of the [3H]ouabain-enzyme complex. Results: Trabeculae showing morphological alterations and decreased contractility were sensitive to lower concentrations of ouabain (3-100 nM) than control trabeculae (100-1000 nM); the inotropic EC50 and the minimum toxic concentration were both reduced. [3H]Ouabain binding was significantly lower (p<<0.001) in failing than in non-failing hearts, at 293(SD 74) v 507(48) pmol·g–1 wet weight. No significant change was observed in maximum ATPase turnover rate, or in sensitivities to Na+, K+, vanadate, and dihydro-ouabain. All three isoforms were expressed at the mRNA level in both normal and failing hearts. Conclusions: This study shows conclusively, for the first time, that failing human hearts are more sensitive to ouabain. This may be at least partly due to a mean reduction of 42% (95% confidence interval, 26 to 56%) in the concentration of Na/K-ATPase (decrease in Na,K pump reserve), but not to an alteration in its catalytic properties or in its isoform composition.
Cardiovascular Research 1993;27:2229-2237
KEYWORDS cardiomyopathy; heart failure; ouabain; cardiac glycosides; Na/K-ATPase; Na/K-pump; ouabain binding; heart trabeculae; human
We thank Johanna von der Bel-Kahn MD for her help in the microscopic evaluation of the human beart trabeculae, and Robert Benia and Gilbert Newman for technical assistance. This work was supported in part by Grant POI HL22619 from thc National Institutes of Health.
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