In Vivo Recording of the Adult Zebrafish Electrocardiogram - Zebrafish: Methods for Assessing Drug Safety and Toxicity - page 66

RR 1.05 with a QTc of 634 (R 2

best fit by the equation QT QTc 0.84) (Fig. 6.3).

¼ ¼

As the simpler linear equation QT 634 RR provided a nearly equivalent fit

¼

(R 2

0.83), we used this latter estimate for all subsequent analyses of zebrafish QT
duration.

¼

6.4 DRUG EFFECTS

Zebrafish were perfused with seven clinically relevant drugs, four of which prolong
the QT interval in humans (astemizole, haloperidol, pimozide, and terfenadine) and
three control drugs that do not prolong the QT interval (clonidine, penicillin, and
propranolol). Exposure to the known QT prolonging agents increased the QTc in each
case as follows: astemizole 18

9% (p 0.009), haloperidol 16 11% (p 0.019),

¼ ¼

pimozide 17 0.015). Drugs not

known to prolong cardiac repolarization did not significantly prolong the QTc
interval: clonidine 1

9% (p 0.005), and terfenadine 11 6% (p

¼ ¼

6% (p 0.5), penicillin -1 2% (p 0.46), and propranolol

¼ ¼

-6 0.054). All of the results are summarized in Fig. 6.4. The RR intervals

increased for each drug as follows: astemizole 16

6% (p

¼

6% (p ¼ 0.006), haloperidol

38 14% (p ¼ 0.004), pimozide 9 13% (p ¼ 0.19), terfenadine 18 15% (p ¼ 0.07),

clonidine 9 11% (p ¼ 0.11), penicillin 4 6% (p ¼ 0.12), and propranolol 19 18%

(p 0.04). Drug-induced QT prolongation was dose dependent as shown for astemi-

zole (Fig. 6.5) Typical QT prolongation responses are shown in Fig. 6.6 for the
cardiotoxic drugs tested.

¼

30

20

10

0

-10

-20

Figure 6.4 QT prolonging drugs astemizole, haloperidol, pimozide, and terfenadine all caused an
increase in the corrected QT interval. Control drugs clonidine, penicillin, and propranolol did not cause a
significant change in the QTc. Statistically significant differences (p < 0.05) are indicated by an asterisk.
(Figure adapted from Milan et al., 2006.)