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This Article Full Text Full Text (PDF) All Versions of this Article: 295/2/H667    most recent 00111.2008v2 00111.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Maltsev, V. A. Articles by Undrovinas, A. PubMed PubMed Citation Articles by Maltsev, V. A. Articles by Undrovinas, A.

Molecular identity of the late sodium current in adult dog cardiomyocytes identified by Na_v1.5 antisense inhibition

¹Department of Internal Medicine, Henry Ford Hospital System, Detroit, Michigan; and ²Section of Cardiology, Department of Medicine, University of Chicago, Illinois

Submitted 1 February 2008 ; accepted in final form 2 June 2008

Late Na⁺ current (I_NaL) is a major component of the action potential plateau in human and canine myocardium. Since I_NaL is increased in heart failure and ischemia, it represents a novel potential target for cardioprotection. However, the molecular identity of I_NaL remains unclear. We tested the hypothesis that the cardiac Na⁺ channel isoform (Na_v1.5) is a major contributor to I_NaL in adult dog ventricular cardiomyocytes (VCs). Cultured VCs were exposed to an antisense morpholino-based oligonucleotide (Na_v1.5 asOligo) targeting the region around the start codon of Na_v1.5 mRNA or a control nonsense oligonucleotide (nsOligo). Densities of both transient Na⁺ current (I_NaT) and I_NaL (both in pA/pF) were monitored by whole cell patch clamp. In HEK293 cells expressing Na_v1.5 or Na_v1.2, Na_v1.5 asOligo specifically silenced functional expression of Na_v1.5 (up to 60% of the initial I_NaT) but not Na_v1.2. In both nsOligo-treated controls and untreated VCs, I_NaT and I_NaL remained unchanged for up to 5 days. However, both I_NaT and I_NaL decreased exponentially with similar time courses ( = 46 and 56 h, respectively) after VCs were treated with Na_v1.5 asOligo without changes in 1) decay kinetics, 2) steady-state activation and inactivation, and 3) the ratio of I_NaL to I_NaT. Four days after exposure to Na_v1.5 asOligo, I_NaT and I_NaL amounted to 68 ± 6% (mean ± SE; n = 20, P < 0.01) and 60 ± 7% (n = 11, P < 0.018) of those in VCs treated by nsOligo, respectively. We conclude that in adult dog heart Na_v1.5 sodium channels have a "functional half-life" of 35 h (0.69) and make a major contribution to I_NaL.

sodium channel functional half-life; antisense inhibition; patch clamp