on March 3, 2003
Published online before print March 3, 2003, doi: 10.1161/01.CIR.0000061912.88753.87
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Submitted on December 31, 2002
From the Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston. * To whom correspondence should be addressed. E-mail: cmacrae{at}partners.org.
Background--Drug-induced QT prolongation and torsades de pointes remain significant and often unpredictable clinical problems. Current in vitro preclinical assays are limited by biological simplicity, and in vivo models suffer from expense and low throughput. Methods and Results--During a screen for the effects of 100 small molecules on the heart rate of the zebrafish, Danio rerio, we found that drugs that cause QT prolongation in humans consistently caused bradycardia and AV block in the zebrafish. Of 23 such drugs tested, 18 were positive in this initial screen. Poor absorption explained 4 of 5 false-negative results, as demonstrated by microinjection. Overall, 22 of 23 compounds that cause repolarization abnormalities were positive in this assay. Antisense "knockdown" of the zebrafish KCNH2 ortholog yielded bradycardia in a dose dependent manner confirming the effects of reduction of repolarizing potassium current in this model. Classical drug-drug interactions between erythromycin and cisapride, as well as cimetidine and terfenadine, were also reproduced. Conclusion--This simple high-throughput assay is a promising addition to the repertoire of preclinical tests for drug-induced repolarization abnormalities. The genetic tractability of the zebrafish will allow the exploration of heritable modifiers of such drug effects.
Revised on January 28, 2003
Accepted on February 3, 2003
Drugs That Induce Repolarization Abnormalities Cause Bradycardia in Zebrafish
David J. Milan MD,
Key words: drugs • electrophysiology • arrhythmia • genes
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