Early Afterdepolarizations, Atrioventricular Block, and Ventricular Arrhythmias in Mice Lacking Kv1.4 and Expressing a Dominant-Negative Kv4 a Subunit
نویسندگان
چکیده
It was recently reported that the slow transient outward K current, Ito, s, that is evident in mouse left ventricular septal cells is eliminated in mice with a targeted deletion of the Kv1.4 gene (Kv1.4). The rapidly inactivating transient outward K current, Ito, f, in contrast, is selectively eliminated in ventricular myocytes isolated from transgenic mice expressing a dominant-negative Kv4 a subunit, Kv4.2W362F. Expression of Kv4.2W362F results in marked prolongation of action potentials and QT intervals. In addition, a slow transient outward K current, that is similar to Ito, s in wild-type mouse left ventricular septal cells, is evident in all Kv4.2W362F-expressing (left and right) ventricular cells. To test directly the hypothesis that upregulation of Kv1.4 a subunit underlies the appearance of this slow transient outward K current in Kv4.2W362F-expressing ventricular cells and to explore the functional consequences of elimination of Ito, f and Ito, s, mice expressing Kv4.2W362F in the Kv1.4 2/2 background (Kv4.2W362F3Kv1.4) were generated. Histological and echocardiographic studies revealed no evidence of structural abnormalities or contractile dysfunction in Kv4.2W362F3Kv1.4 mouse hearts. Electrophysiological recordings from the majority ('80%) of cells isolated from the right ventricle and left ventricular apex of Kv4.2W362F3Kv1.4 animals demonstrated that both Ito, f and Ito, s are eliminated; action potentials are prolonged significantly; and, in some cells, early afterdepolarizations were observed. In addition, in vivo telemetric ECG recordings from Kv4.2W362F3Kv1.4 animals revealed marked QT prolongation, atrioventricular block, and ventricular tachycardia. These observations demonstrate that upregulation of Kv1.4 contributes to the electrical remodeling evident in the ventricles of Kv4.2W362F-expressing mice and that elimination of both Ito, f and Ito, s has dramatic functional consequences. (Circ Res. 2000;87:73-79.)
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