Circulation Research. 2001
Published online before print April 27, 2001, doi: 10.1161/hh0901.090929
Published online before print April 27, 2001, doi: 10.1161/hh0901.090929
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© 2001 American Heart Association, Inc.
Article |
Targeted Replacement of Kv1.5 in the Mouse Leads to Loss of the 4-Aminopyridine–Sensitive Component of IK,slow and Resistance to Drug-Induced QT Prolongation
From the Cardiovascular Institute (B.L., X.-h.P., J.S.L., V.S., C.J.R.), University of Pittsburgh, Pittsburgh, Pa; Washington University School of Medicine (W.G., J.M.N.), St. Louis, Mo; Mount Sinai School of Medicine (D.A.L.), New York, NY; and University of Iowa College of Medicine and Department of Veterans Affairs (J.A.H.), Iowa City, Iowa.
Correspondence to Barry London, MD, PhD, Cardiovascular Institute, University of Pittsburgh, BST 1744, 200 Lothrop St, Pittsburgh, PA 15213. E-mail londonb{at}msx.upmc.edu
Abstract
Abstract—The
K+ channel mKv1.5 is thought to encode a
4-aminopyridine (4-AP)–sensitive component of the
current
IK,slow
in the mouse heart. We used gene targeting to replace mKv1.5 with the
4-AP–insensitive channel rKv1.1 (SWAP mice) and directly test the role
of Kv1.5 in the mouse ventricle. Kv1.5 RNA and protein were
undetectable, rKv1.1 was expressed, and Kv2.1 protein was upregulated
in homozygous SWAP hearts. The density of the
K+ current
IK,slow
(depolarizations to +40 mV, pA/pF) was similar in left
ventricular myocytes isolated from SWAP homozygotes (17±1,
n=27) and littermate controls (16±2, n=19). The densities and
properties of
Ipeak,
Ito,f,
Ito,s,
and Iss
were also unchanged. In homozygous SWAP myocytes, the 50-µmol/L
4-AP–sensitive component of
IK,slow
was absent (n=6), the density of the 20-mmol/L
tetraethylammonium-sensitive component of
IK,slow
was increased (9±1 versus 5±1,
P<0.05), and no 100- to
200-nmol/L 
-dendrotoxin–sensitive current was found (n=8).
APD90 in SWAP myocytes was similar to controls
at baseline but did not prolong in response to 30 µmol/L 4-AP.
Similarly, QTc (ms) was not prolonged in anesthetized SWAP mice
(64±2, homozygotes, n=9; 62±2, controls, n=9), and injection with
4-AP prolonged QTc only in controls (63±1, homozygotes; 72±2,
controls; P<0.05). SWAP mice
had no increase in arrhythmias during ambulatory telemetry
monitoring. Thus, Kv1.5 encodes the 4-AP–sensitive component of
IK,slow
in the mouse ventricle and confers sensitivity to 4-AP–induced
prolongation of APD and QTc. Compensatory upregulation of Kv2.1 may
explain the phenotypic differences between SWAP mice and the previously
described transgenic mice expressing a truncated dominant-negative
Kv1.1 construct.
Key Words: potassium channels • heart • genetically engineered mice • drug-induced long-QT syndrome • arrhythmias
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