© 2000 American Heart Association, Inc.
Integrative Physiology |
Functional Consequences of Elimination of Ito, f and Ito, s
Early Afterdepolarizations, Atrioventricular Block, and Ventricular Arrhythmias in Mice Lacking Kv1.4 and Expressing a Dominant-Negative Kv4 
Subunit
From the Department of Molecular Biology and Pharmacology (W.G., H.L., J.M.N.), Washington University School of Medicine, St. Louis, Mo, and Cardiovascular Institute (B.L.), University of Pittsburgh Medical Center, Pittsburgh, Pa.
Correspondence to Dr Jeanne M. Nerbonne, Department of Molecular Biology and Pharmacology, Campus Box 8103, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110. E-mail: jnerbonn{at}pcg.wustl.edu
Abstract—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 
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 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-/- background (Kv4.2W362FxKv1.4-/-)
were generated. Histological and
echocardiographic studies revealed no evidence of
structural abnormalities or contractile dysfunction in
Kv4.2W362FxKv1.4-/- mouse hearts.
Electrophysiological recordings from the
majority (
80%) of cells isolated from the right
ventricle and left ventricular apex of
Kv4.2W362FxKv1.4-/- 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 Kv4.2W362FxKv1.4-/- 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.)
Key Words: transient outward K+ currents • early afterdepolarization • atrioventricular block • ventricular arrhythmia
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|
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|
|
|
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|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
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|
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|
|
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|
|
|
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