Age-dependent response of the electrocardiogram to K⁺ channel blockers in mice

Developmental changes in electrocardiogram (ECG) and response to selective K⁺ channel blockers were assessed in conscious, unsedated neonatal (days 1, 7, 14) and adult male mice (>60 days of age). Mean sinus R-R interval decreased from 120 ± 3 ms in day 1 to 110 ± 3 ms inday 7, 97 ± 3 ms inday 14, and 81 ± 1 ms in adult mice (P < 0.001 by ANOVA; all 3 groups different from day 1). In parallel, the mean P-R interval progressively decreased during development. Similarly, the mean Q-T interval decreased from 62 ± 2 ms in day 1 to 50 ± 2 ms inday 7, 47 ± 8 ms inday 14 neonatal mice, and 46 ± 2 ms in adult mice (P < 0.001 by ANOVA; all 3 groups are significantly different fromday 1). Q-T_c was calculated as Q-$T/\sqrt{R­R}$ interval. Q-T_c significantly shortened from 179 ± 4 ms in day 1 to 149 ± 5 ms in day 7 mice (P < 0.001). In addition, the J junction-S-T segment elevation observed in day 1 neonatal mice resolved by day 14. Dofetilide (0.5 mg/kg), the selective blocker of the rapid component of the delayed rectifier (I_Kr) abolished S-T segment elevation and prolonged Q-T and Q-T_c intervals inday 1 neonates but not in adult mice. In contrast, 4-aminopyridine (4-AP, 2.5 mg/kg) had no effect onday 1 neonates but in adults prolonged Q-T and Q-T_c intervals and specifically decreased the amplitude of a transiently repolarizing wave, which appears as an r′ wave at the end of the apparent QRS in adult mice. In conclusion, ECG intervals and configuration change during normal postnatal development in the mouse. K⁺ channel blockers affect the mouse ECG differently depending on age. These data are consistent with the previous findings that the dofetilide-sensitiveI_Kr is dominant in day 1 mice, whereas 4-AP-sensitive currents, the transiently repolarizing K⁺ current, and the rapidly activating, slowly inactivating K⁺current are the dominant K⁺currents in adult mice. This study provides background information useful for assessing abnormal development in transgenic mice.