Drugs that induce repolarization abnormalities cause bradycardia in zebrafish.
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.


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.


CONCLUSIONS
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.
Milan
David J
DJ
Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston 02129, USA.
Peterson
Travis A
TA
Ruskin
Jeremy N
JN
Peterson
Randall T
RT
MacRae
Calum A
CA
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D001919:Bradycardia / Q000139:chemically induced* / Q000209:etiology / Q000503:physiopathology; D027682:Cation Transport Proteins; D004347:Drug Interactions; D004553:Electric Conductivity; D051638:Ether-A-Go-Go Potassium Channels; D006327:Heart Block / Q000139:chemically induced; D006339:Heart Rate / Q000187:drug effects*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D015027:Zebrafish
D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D016376:Oligonucleotides, Antisense; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated