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

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 similar to 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.