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

Abstract

The widely accepted model to explain the positive inotropic effect of cardiac glycosides invokes altered Na⁺-Ca²⁺ 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⁺-Ca²⁺ exchanger in the action of the glycoside ouabain using Na⁺-Ca²⁺ 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⁺-Ca²⁺ exchanger knockout mice (NCX^−/−) display surprisingly normal Ca²⁺ transients. Removal of extracellular Na⁺ induces Ca²⁺ overload in wild-type heart tubes but does not alter the Ca²⁺ transients of NCX^−/− heart tubes. Similarly, ouabain, at levels causing Ca²⁺ overload in wild-type heart tubes, has no effect on NCX^−/− heart tubes. We conclude that in embryonic mouse myocytes the Na⁺-Ca²⁺ exchanger is absolutely required for the effect of cardiac glycosides on Ca²⁺_i.