In vivo recording of adult zebrafish electrocardiogram and assessment of drug-induced QT prolongation.
In the last decade the zebrafish has become a major model organism for the study of development and organogenesis. To maximize the experimental utility of this organism, it will be important to establish methods for adult phenotyping. We previously proposed that the embryonic zebrafish may be useful in high-throughput screening for drug-induced cardiotoxicity. We now describe a method for the reproducible recording of the adult zebrafish ECG and illustrate its application in the investigation of QT-prolonging drugs. Zebrafish ECGs were obtained by inserting two needle electrodes through the ventral epidermis. Fish were perfused orally, and motion artifacts were eliminated with a paralytic dose of mu-conotoxin GIIIB. Test compounds were delivered via the perfusion system. Without a means of hydration and oxygenation, the fish succumb rapidly. The use of a perfusion system allowed stable recording for > 6 h. Baseline conduction intervals were as follows: PR, 66 ms (SD 14); QRS, 34 ms (SD 11); QT, 242 ms (SD 54); and R-R, 398 ms (SD 77). The known QT-prolonging agents astemizole, haloperidol, pimozide, and terfenadine caused corrected QT increases of 18% (SD 9), 16% (SD 11), 17% (SD 9), and 11% (SD 6), respectively. The control drugs clonidine, penicillin and propranolol did not prolong the corrected QT interval. In conclusion, perfusion and muscular paralysis allows stable, low-noise recording of zebrafish ECGs. Agents known to cause QT prolongation in humans caused QT prolongation in fish in each case. The development of rigorous tools for the phenotyping of adult zebrafish will complement the high-throughput assays currently under development for embryonic and larval fish.
Milan
David J
DJ
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Jones
Ian L
IL
Ellinor
Patrick T
PT
MacRae
Calum A
CA
D000375:Aging; D000818:Animals; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000379:methods*; D005260:Female; D008133:Long QT Syndrome / Q000139:chemically induced / Q000175:diagnosis* / Q000503:physiopathology*; D008297:Male; D013045:Species Specificity; D015027:Zebrafish / Q000502:physiology*