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Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2724-8.

Regulation of sodium channel gene expression by class I antiarrhythmic drugs and n - 3 polyunsaturated fatty acids in cultured neonatal rat cardiac myocytes.

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1
Department of Medicine, Harvard Medical School and Massachusetts General Hospital, Boston 02114, USA.

Abstract

Previous studies have shown that chronic administration of class I antiarrhythmic drugs, which have definite inhibitory action on the fast Na+ channel, result in up-regulation of cardiac Na+ channel expression, and suggest that this effect may contribute to their deleterious effects during chronic administration. Recent studies have shown that the antiarrhythmic effects of free n - 3 polyunsaturated fatty acids (PUFA) are associated with an inhibition of the Na+ channel. Whether the PUFA when used chronically will mimic the effect of the class I drugs on the expression of the Na+ channel is not known. To answer this question, we determined the level of mRNA encoding cardiac Na+ channels and the number of the Na+ channels per cell in cultured neonatal rat cardiac myocytes after supplementation of the cells with the n - 3 PUFA eicosapentaenoic acid (EPA), the class I drug mexiletine, or both EPA and mexiletine for 3-4 days. The number of sodium channels was assessed with a radioligand binding assay using the sodium channel-specific toxin [3H]batrachotoxinin benzoate ([3H]BTXB). The supplementation of myocytes with mexiletine (20 microM) induced a 4-fold increase in [3H]BTXB specific binding to the cells. In contrast, chronic treatment with EPA (20 microM) alone did not significantly affect [3H]BTXB binding. However, the combination of EPA with mexiletine produced a 40-50% reduction in the [3H]BTXB binding, compared with that seen with mexiletine alone. RNA isolated from cardiac myocytes was probed with a 2.5-kb cRNA transcribed with T7 RNA polymerase from the clone Na-8.4, which encodes nucleotides 3361-5868 of the alpha-subunit of the R(IIA) sodium channel subtype. The changes in the level of mRNA encoding sodium channel alpha-subunit were correlated with comparable changes in sodium channel number in the cultured myocytes, indicating that regulation of transcription of mRNA or its processing and stability is primarily responsible for the regulation of sodium channel number. These data demonstrate that chronic EPA treatment not only does not up-regulate the cardiac sodium channel expression but also reduces the mexiletine-induced increase in the cardiac sodium channel expression.

PMID:
9122264
PMCID:
PMC20157
[Indexed for MEDLINE]
Free PMC Article
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