Circulation Research. 2002;90:305-308
Published online before print January 3, 2002, doi: 10.1161/hh0302.104562
Published online before print January 3, 2002, doi: 10.1161/hh0302.104562
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© 2002 American Heart Association, Inc.
Cellular Biology |
The Na+-Ca2+ Exchanger Is Essential for the Action of Cardiac Glycosides
From the Departments of Physiology (H.R., S.A.H., T.H., R.S.R., K.D.P.) and Medicine (R.S.R., J.I.G., K.D.P.) and the Cardiovascular Research Laboratories (H.R., S.A.H., T.H., R.S.R., J.I.G., K.D.P.), UCLA School of Medicine, Los Angeles, Calif.
Correspondence to Dr Kenneth D. Philipson, Cardiovascular Research Laboratories, MRL 3-645, UCLA School of Medicine, Los Angeles, CA 90095-1760. E-mail kphilipson{at}mednet.ucla.edu
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.
Key Words: Na+-Ca2+ exchange • cardiac glycosides • genetically altered mice
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