Age-dependent effects on cisapride-induced QTc prolongation in the isolated guinea pig heart.
BACKGROUND
The isolated guinea pig heart preparation has been suggested as a suitable small animal model for investigating potential for QTc prolongation. The purpose of this study was to investigate the effect of age on electrophysiological parameters measured in the isolated guinea pig heart preparation. In addition, the effect of a compound known to prolong the QT interval (cisapride) was investigated in both young and adult guinea pigs.


METHODS
Male guinea pigs were divided into 2 groups (n=6). One group of guinea pigs was between 3 and 4 weeks old (young) and the other group was between 16 and 17 weeks old (adult). Concentrations (0, 1, 5, and 50 ng/mL; 2, 11, and 110 nM) of cisapride were perfused for 15 min from low to high concentration. Measurements of PR, QRS, RR and QT intervals were typically made on 5 consecutive electrocardiogram complexes during the last minute of each concentration. The QT interval was corrected for changes in heart rate using the cube root formula of Fridericia (QTcF).


RESULTS
Adult guinea pigs had significantly longer RR and QTcF intervals when compared to young animals. Cisapride prolonged QTcF in both young and adult animals at the same concentrations (5 ng/mL and 50 ng/mL). The maximal change in QTcF at 50 ng/mL was similar in young (44+/-3 ms) and adult animals (40+/-1 ms).


CONCLUSIONS
In summary, the present study demonstrated that there was an increase in the RR and QTcF intervals with age in isolated guinea pig hearts. However, this age difference does not appear to impact the sensitivity of the assay to drug-induced QTcF prolongation.
Mittelstadt
S W
SW
Procter and Gamble Pharmaceuticals, Miami Valley Innovation Center, 11810 E. Miami River Rd. Cincinnati, OH 45252, USA. mittelstadt.sw@pg.com
Adams
N A
NA
Spruell
R D
RD
D000375:Aging / Q000502:physiology*; D000465:Algorithms; D000818:Animals; D000897:Anti-Ulcer Agents / Q000633:toxicity*; D020117:Cisapride / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male
D000897:Anti-Ulcer Agents; D020117:Cisapride