Journal
CIRCULATION RESEARCH
Volume 88, Issue 9, Pages 940-946Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/hh0901.090929
Keywords
potassium channels; heart; genetically engineered mice; drug-induced long-QTF syndrome; arrhythmias
Funding
- NHLBI NIH HHS [K08 HL03908, HL58030] Funding Source: Medline
- PHS HHS [R01 34161] Funding Source: Medline
Ask authors/readers for more resources
The K+ channel mKv1.5 is thought to encode a 4-aminopyridine (4-AP)-sensitive component of the current I-K,I-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 wore undetectable, rKv1.1 was expressed, and Kv2.1 protein was upregulated in homozygous SWAP hearts, The density of the K+ current I-K,I-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 I-peak, I-to,I-f, I-to,I-s, and I-ss were also unchanged. In homozygous SWAP myocytes, the 50-mu mol/L 4-AP-sensitive component of I-K,I-slow was absent (n=6), the density of The 20-mmol/L tetraethylammonium-sensitive component of I-K,I-slow was increased (9 +/-1 versus, 5 +/-1, P <0.05), and no 100- to 200-nmol/L alpha -dendrotoxin-sensitive current was found (n=8). APD(90) in SWAP myocytes was similar to controls at baseline but did not prolong in response to 30 mu mol/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 I-K,I-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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available