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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

The Na⁺-Ca²⁺ exchanger (NCX) is the major Ca²⁺ efflux mechanism in cardiac muscle.^1,2 Mediating cellular Ca²⁺ efflux is a role of special importance in cardiomyocytes because substantial transsarcolemmal Ca²⁺ fluxes occur with each contraction. The Na⁺-Ca²⁺ exchanger also plays a role in inotropic responses and is upregulated in many studies of hypertrophy and heart failure. The exact roles of the Na⁺-Ca²⁺ exchanger are difficult to study because of the multiplicity of Ca²⁺ flux pathways in cardiomyocytes and the lack of specific inhibitors.

In the present study, we investigate the specificity of two recently described Na⁺-Ca²⁺ exchange inhibitors. The first, KB-R7943,^3,4 inhibits Na⁺-Ca²⁺ exchange activity with an IC₅₀ in the low micromolar range. The inhibitory mechanism of KB-R7943 has been investigated,^3,5 and amino acids of the exchanger involved in binding KB-R7943 have been identified.⁶

In some studies,^3,5,7 although not all,^8–10 the action of KB-R7943 was more potent on the reverse mode (Ca²⁺ influx) than the forward mode (Ca²⁺ efflux) of exchange. Despite this inconsistency, KB-R7943 has been used as a specific inhibitor of reverse-mode Na⁺-Ca²⁺ exchange^11,12 and has implied a role for reverse-mode exchange in arrhythmogenicity.^7,13 Relatively potent effects of KB-R7943 on other transporters and channels have been described. KB-R7943 binds to the norepinephrine transporter,¹⁴ blocks or binds to NMDA, K⁺, Na⁺, and Ca²⁺ channels,^14,15 and blocks the nicotinic acetylcholine receptor.¹⁶

The second drug that we investigate is SEA0400,^14,17 described as the most potent known inhibitor of Na⁺-Ca²⁺ exchange with an IC₅₀ of 20 nmol/L.¹⁴ SEA0400 reduced Ca²⁺-induced damage in cultured astrocytes¹⁴ and improved functional recovery after myocardial ischemia (T. Matsuda and A. Baba, unpublished observation, 2002), implicating a role for Na⁺-Ca²⁺ exchange in these processes. Moreover, SEA0400 had no effects on several ion channels and transporters and seems to have excellent specificity.

Four laboratories^18–21 have found that knockout of the mouse Na⁺-Ca²⁺ exchanger, NCX1, is embryonic lethal by 11 days postcoitum (dpc). NCX1 is the only isoform of the exchanger in myocardium, and it might be expected that excitation-contraction coupling would fail in the absence of exchange activity. Koushik et al,¹⁹ however, found normal Ca²⁺ transients in heart tubes from 9.5-dpc NCX^-/- embryos. We reproduced this finding and used the NCX1 knockout model to identify the importance of the Na⁺-Ca²⁺ exchanger in the response of myocardium to ouabain.²¹

In this investigation, we use heart tubes from NCX^-/- mice to examine the specificity of KB-R7943 and SEA0400. Any effects of drugs on Ca²⁺ transients in NCX^-/- heart tubes must be due to modulation of something other than Na⁺-Ca²⁺ exchange.

Materials and Methods

Production of Na⁺-Ca²⁺ exchanger knockout mice has been described.²¹ All experiments were performed under approved institutional animal protocols. As before, the heart tubes from embryos at 9.5 dpc were loaded with fura 2, and Ca²⁺ transients were measured by fluorescence in a flow-through chamber on an inverted microscope. Heart tubes were paced at 1 Hz at 35°C.

The heart tubes were from embryos that are NCX^{- /-}, NCX^+/-, or NCX^+/+. However, in several series of experiments, the hemizygous knockouts and wild-type embryos had identical properties. Therefore, we combined data obtained with NCX^{+ /-} and NCX^+/+ heart tubes into one group representing NCX1-containing heart tubes and refer to this group as NCX+.

KB-R7943 and SEA0400 were kind gifts from Kanebo and Taisho Pharmaceutical, respectively.

Results

Stock solutions of KB-R7943 and SEA0400 were in DMSO, and we tested whether DMSO by itself altered Ca²⁺ transients. Figure 1 shows that 0.1% DMSO had no effects on Ca²⁺ transients in heart tubes from NCX^-/- embryos. Figure 1 also demonstrates the excellent stability of the system. No changes were observed in Ca²⁺ transients over the 10-minute period in DMSO.

View larger version (19K): [in this window] [in a new window]   Figure 1. Effects of DMSO on Ca2+ transients of heart tubes from NCX-/- embryos. Data are expressed as the percentage of control values before the application of 0.1% DMSO. Ca2+ indicates difference between systolic and diastolic Ca2+ levels; TPT, time to peak transient. Data are mean±SEM; n= 5.

Typical effects of KB-R7943 (5 µmol/L, 5 minutes) on Ca²⁺ transients in embryonic heart tubes are shown in Figure 2A and are summarized in Figure 2B. In NCX+ heart tubes, KB-R7943 had substantial effects on diastolic Ca²⁺, Ca²⁺, and relaxation time. However, even in the absence of the Na⁺-Ca²⁺ exchanger, KB-R7943 significantly reduced Ca²⁺ by 34±8%. Continued exposure to KB-R7943 further reduced the Ca²⁺ transients. After 10 minutes of exposure to KB-R7943 (Figure 2C), Ca²⁺ was largely eliminated for both the NCX+ and NCX^-/- heart tubes.

View larger version (18K): [in this window] [in a new window]   Figure 2. Effects of KB-R7943 on Ca2+ transients in embryonic heart tubes. A, Responses of heart tubes from an NCX+ and an NCX-/- embryo to 5 µmol/L KB-R7943 for 5 minutes. Data are expressed as the ratio of fluorescence intensity at 510 nm with excitation at 335 and 405 nm. Summary of effects of KB-R7943 (5 µmol/L) applied for 5 (B) or 10 minutes (C). Data expressed as percent change compared with properties before drug application, n=3 to 5. *P< 0.05.

Effects of SEA0400 (0.1 µmol/L) on the Ca²⁺ transients of embryonic heart tubes are shown in Figure 3A and are summarized in Figure 3B. The effects are similar to those obtained with KB-R7943, although achieved with much lower concentrations. Both drugs elevated diastolic Ca²⁺ and reduced Ca²⁺ in NCX+ heart tubes and reduced Ca²⁺ in NCX^-/- heart tubes.

View larger version (21K): [in this window] [in a new window]   Figure 3. Effects of SEA0400 on Ca2+ transients in embryonic heart tubes. A, Responses of heart tubes from an NCX+ and an NCX-/- embryo to 0.1 µmol/L SEA0400 for 5 minutes. B, Summary of effects of SEA0400 (0.1 µmol/L) applied for 10 minutes. Data expressed as percent change compared with properties before drug application, n=4 to 6. *P<0.05.

The voltage of the field stimulation needed to be increased to maintain Ca²⁺ transients after application of both drugs. This occurred with both NCX+ and NCX^{- /-} heart tubes. The voltage typically would need to be increased from 30 to 40 or 50 V after 3 minutes of drug exposure.

Discussion

The usefulness in physiological settings of the Na⁺-Ca²⁺ exchange inhibitors KB-R7943 and SEA0400 requires specificity. We compared the effects of the drugs on Ca²⁺ transients in embryonic heart tubes of control and Na⁺-Ca²⁺ exchanger knockout mice. If a drug affects the Ca²⁺ transient in the absence of exchanger, it is certainly not a specific inhibitor of the exchanger. We have recently used this approach to demonstrate that the presence of the exchanger is required to elicit a response to ouabain or to removal of external Na⁺.²¹

KB-R7943 and SEA0400 both depress Ca²⁺ transients even in the absence of the Na⁺-Ca²⁺ exchanger. This depressant effect clearly occurs by a mechanism not involving Na⁺-Ca²⁺ exchange. KB-R7943 has already been noted to have multiple other effects,^14–16 but SEA0400 had seemed promising as a specific exchange inhibitor.^14,17

The differences between the effects of the drugs on myocardium containing or lacking the exchanger is informative. Both drugs elevate diastolic Ca²⁺ only in the presence of the exchanger. Diastolic Ca²⁺ in NCX^{- /-} hearts was unaffected. The difference is likely related to a direct inhibitory effect of the drugs on the exchanger. Acute inhibition of the exchanger apparently blocks a component of Ca²⁺ efflux and the Ca²⁺ transient never fully relaxes. The fact that both drugs required the field stimulation to be increased for maintenance of Ca²⁺ transients suggests that ion channels involved in tissue excitation are being affected.

In summary, KB-R7943 and SEA0400 are not specific inhibitors of the Na⁺-Ca²⁺ exchanger. Although we observe a lack of specificity, we have not determined the other actions of these drugs on embryonic heart tubes. KB-R7943 and SEA0400 may have uses in Na⁺-Ca²⁺ exchange research but should be used with caution.

Acknowledgments

This research was supported by the NIH (HL 48509), the American Heart Association, Western States Affiliate (9950748Y), Koeln Fortune, Deutsche Forschungsgemeinschaft (1496/1-1), and the Laubisch Foundation.

Received May 28, 2002; revision received June 13, 2002; accepted June 13, 2002.

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