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(Circulation Research. 2002;91:90.)
© 2002 American Heart Association, Inc.

Report

Knockout Mice for Pharmacological Screening

Testing the Specificity of Na⁺-Ca²⁺ Exchange Inhibitors

Hannes Reuter, Scott A. Henderson, Tieyan Han, Toshio Matsuda, Akemichi Baba, Robert S. Ross, Joshua I. Goldhaber, Kenneth D. Philipson

From the Departments of Physiology and Medicine and the Cardiovascular Research Laboratories (H.R., S.A.H., T.H., R.S.R., J.I.G., K.D.P.), David Geffen School of Medicine at UCLA, Los Angeles, Calif, and the Laboratories of Medicinal Pharmacology (T.M.) and Molecular Neuropharmacology (A.B.), Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan. Present address for H.R. is the Laboratory of Muscle Research and Molecular Cardiology, University of Cologne, Cologne, Germany.

Correspondence to Dr Kenneth D. Philipson, Cardiovascular Research Laboratories, MRL 3-645, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1760. E-mail kphilipson{at}mednet.ucla.edu

Abstract

The role of the Na⁺-Ca²⁺ exchanger as a major determinant of cell Ca²⁺ is well defined in cardiac tissue, and there has been much effort to develop specific inhibitors of the exchanger. We use a novel system to test the specificity of two putative specific inhibitors, KB-R7943 and SEA0400. The drugs are applied to electrically stimulated heart tubes from control mouse embryos or embryos with the Na⁺-Ca²⁺ exchanger knocked out. We monitored effects of the drugs on Ca²⁺ transients. Both drugs depress the Ca²⁺ transients at low concentrations even in the absence of any Na⁺-Ca²⁺ exchanger. KB-R7943 and SEA0400 are not completely specific and should be used with caution as Na⁺-Ca²⁺ exchange inhibitors.

Key Words: Na⁺-Ca²⁺ exchange • inhibitors • genetically altered mice

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