Evaluation of zebrafish embryos as a model for assessing inhibition of hERG.
BACKGROUND
It has been proposed that the analysis of heart rate in zebrafish embryos can be used to assess the potential effects of compounds on hERG. The purpose of this study was to investigate the effect of compounds on the heart rate and atrioventricular dissociation in zebrafish. The compounds investigated were chosen based on the association or lack of association with QTc prolongation in the clinic.


METHODS
Three-day-old embryos were incubated in buffered embryo medium. On the day of the study, fish were placed in a petri dish containing 5.0 mL of embryo medium and 125 mg/L MS-222 anesthetic. Drugs to be tested were added to the medium from a stock solution to achieve the desired target concentration. Ten fish were incubated in each concentration of drug for 80 min. Beat rates of the atrium and ventricle were recorded after the incubation by counting beats of the respective chambers using standard brightfield stereomicroscopy.


RESULTS
All of the compounds associated with QT prolongation induced dissociation between the atrium and ventricular rates except D,L-sotalol and procainamide. The concentrations that induced dissociation tended to be higher than the hERG IC50. None of the negative control compounds caused atrioventricular dissociation at clinically efficacious concentrations.


CONCLUSIONS
In conclusion, the present data demonstrate that zebrafish can be utilized to assess the effects of chemicals on hERG. However, the practical use of this assay may be difficult because of the high concentrations that must be reached to see those pharmacological effects.
Mittelstadt
S W
SW
Abbott Laboratories, Dept. R46R, Abbott Park, IL 60064, United States. scott.mittelstadt@abbott.com
Hemenway
C L
CL
Craig
M P
MP
Hove
J R
JR
D000704:Analysis of Variance; D000818:Animals; D054537:Atrioventricular Block / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D000072237:ERG1 Potassium Channel; D004625:Embryo, Nonmammalian; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D008133:Long QT Syndrome / Q000139:chemically induced; D023421:Models, Animal; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000009:adverse effects; D012680:Sensitivity and Specificity; D015027:Zebrafish
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D026902:Potassium Channel Blockers