Referenced in: none

Automatically associated channels: Nav1.3 , Nav1.5 , Nav1.6

Title: Increased late sodium currents are related to transcription of neuronal isoforms in a pressure-overload model.

Authors: Yutao Xi, Geru Wu, Lin Yang, Ke Han, Yuan Du, Tingzhong Wang, Xinjun Lei, Xiaojun Bai, Aiqun Ma

Journal, date & volume: Eur. J. Heart Fail., 2009 Aug , 11, 749-57

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/19584134

Abstract
The late and persistent sodium current (I(Na)) has been identified as a target for anti-arrhythmia drugs in patients with heart failure (HF). However, the underlying mechanism of late I(Na) (I(NaL)) production remains uncertain. We hypothesized that transcriptional alteration among sodium channel (NaCh) isoforms may contribute to I(NaL) in failing cardiomyocytes.Pressure-overload rat models were created by 16-week constriction of the ascending aorta (HF). Haemodynamic and electrocardiographic variables were studied in sham operation and HF rats. Action potential (AP) and I(Na) were recorded using whole-cell patch-clamp techniques. The expression of various NaCh isoforms was evaluated by immunocytochemistry, RT-PCR, and western blot. The HF group exhibited left ventricular enlargement, systolic dysfunction, and prolongation of QTc intervals (P < 0.05). Current-clamp recording indicated that AP durations (APDs) were more sensitive to tetrodotoxin. Voltage-clamp recordings showed that I(NaL) was increased (-1.54 +/- 0.43 vs. -1.08 +/- 0.38 pA/pF, P < 0.01) in HF, but transient I(Na) (I(NaT)) density was decreased (-14.61 +/- 2.30 vs. -26.15 +/- 5.17 pA/pF, P < 0.01). Correspondingly, the relative mRNA levels of the neuronal isoforms SCN1a and SCN8a increased 2.5- and 2.7-fold, respectively; SCN3a did not change, whereas SCN5a decreased by approximately 60% in HF. Protein levels paralleled their mRNA expression.The up-regulated expression of the neuronal NaCh isoforms SCN1a and SCN8a could be one mechanism of I(NaL) production, which may contribute to prolongation of APD in the failing heart.