Aging-related changes of QT and RR intervals in conscious guinea pigs.
BACKGROUND
Although guinea pigs are suitable for in vivo QT assessment of newly discovered drugs at the pre-clinical stage because of the similarity of the ion channels between the guinea pig heart and the human, there is limited data available regarding the characteristics of QT interval in conscious guinea pigs. Aging is one of several factors which have been shown to affect the QT interval in humans and animals. In the present study, we examined the influence of age on QT and RR intervals in conscious guinea pigs.


METHODS
Electrocardiograms were recorded from female Hartley guinea pigs at the age of 6 weeks (young; n=6) and 23 months (old; n=4) via a telemetry system. The QT and RR intervals were measured during daytime and nighttime, and following intravenous bolus injection of E-4031 (0.1 mg/kg) or terfenadine (4 mg/kg). Comparisons were made to determine group differences in: (1) the normal values of the QT and RR intervals, (2) the best-fit QT-correction formula, (3) the circadian rhythm of QT and RR intervals, and (4) drug effects on repolarization.


RESULTS
The normal values of QT and RR intervals in the old group were significantly longer than those in the young group. The best-fit formula for correcting QT interval was a modified Bazett's formula for both young and old groups. The old group did not show the nocturnal variation of either QT or RR interval. Terfenadine caused significantly greater QTc prolongation in the old group compared to the young.


CONCLUSIONS
Aging affects resting QT and RR intervals in conscious female guinea pigs, a factor which should be considered when examining the effects of compounds on cardiac repolarization. Also, the present study suggests a possibility that age can affect QTc prolongation induced by some IKr blockers.
Shiotani
Motohiro
M
Drug Safety Research & Development, Pfizer Global Research & Development Nagoya Laboratories, Pfizer Japan Inc., 5-2 Taketoyo, Aichi 470-2393, Japan. mshio@mail.goo.ne.jp
Harada
Takuma
T
Abe
Junko
J
Hamada
Yoshimasa
Y
Horii
Ikuo
I
D000375:Aging / Q000502:physiology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D002317:Cardiovascular Agents / Q000494:pharmacology; D002940:Circadian Rhythm; D015716:Electrocardiography, Ambulatory / Q000295:instrumentation; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D039563:Histamine H1 Antagonists, Non-Sedating / Q000494:pharmacology; D008133:Long QT Syndrome; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013686:Telemetry; D016593:Terfenadine / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D002317:Cardiovascular Agents; D039563:Histamine H1 Antagonists, Non-Sedating; D010880:Piperidines; D011725:Pyridines; C063968:E 4031; D016593:Terfenadine