Characterization of mice with a combined suppression of I-to and I-K,I-slow

Cardiac-specific expression of a truncated Kv1.1 polypeptide (Kv1DN) attenu ates the slow inactivating outward K+ current (I-Kslow), increases action p otential duration (APD) and Q-T intervals, and induces spontaneous ventricu lar arrhythmias. Expression of the pore mutant of Kv4.2 (Kv4DN) eliminates the fast component of the transient outward current (I-to) and prolongs APD s and Q-T intervals markedly; however, no arrhythmias are seen in Kv4DN mic e, suggesting that APD and Q-T prolongation are not per se proarrhythmic. T o test this hypothesis, the Kv1DN and Kv4DN lines were crossbred to produce animals (Kv1/Kv4DN) expressing both transgenes in an identical genetic bac kground. Whole cell voltage-clamp recordings from left ventricular apex cel ls confirmed that in Kv1/Kv4DN left ventricular apex cells, both components (fast and slow) of It. and the 4-aminopyridine-sensitive component of I-K. slow are eliminated, resulting in marked APD prolongation compared with wil d-type, Kv1DN, or Kv4DN cells. Telemetric electrocardiogram monitoring (n = 10 mice/group) revealed a significant prolongation of Q-Tc and P-R interva ls in Kv1/Kv4DN animals compared with Kv1DN or Kv4DN animals. Spontaneous a rrhythmias were observed mainly in Kv1DN mice. Thus the attenuation of fast I-to. in addition to in Kv1/Kv4DN mice causes significant prolongation of APD and Q-T intervals and attenuation of spontaneous arrhythmias.