The Na + -Ca 2+ Exchanger Is Essential for the Action of Cardiac Glycosides

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Abstract
The widely accepted model to explain the positive inotropic effect of cardiac glycosides invokes altered Na + -Ca 2+ exchange activity secondary to Na + pump inhibition. However, proof of this model is lacking and alternative mechanisms have been proposed. We directly tested the role of the Na + -Ca 2+ exchanger in the action of the glycoside ouabain using Na + -Ca 2+ exchanger knockout mice. Ablation of the exchanger is embryonic lethal, but contractility can be studied in embryonic heart tubes at day 9.5 postcoitum. Heart tubes isolated from homozygous Na + -Ca 2+ exchanger knockout mice (NCX −/− ) display surprisingly normal Ca 2+ transients. Removal of extracellular Na + induces Ca 2+ overload in wild-type heart tubes but does not alter the Ca 2+ transients of NCX −/− heart tubes. Similarly, ouabain, at levels causing Ca 2+ overload in wild-type heart tubes, has no effect on NCX −/− heart tubes. We conclude that in embryonic mouse myocytes the Na + -Ca 2+ exchanger is absolutely required for the effect of cardiac glycosides on Ca 2+ i .