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Increased late sodium currents are related to transcription of neuronal isoforms in a pressure‐overload model
Author(s) -
Xi Yutao,
Wu Geru,
Yang Lin,
Han Ke,
Du Yuan,
Wang Tingzhong,
Lei Xinjun,
Bai Xiaojun,
Ma Aiqun
Publication year - 2009
Publication title -
european journal of heart failure
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.149
H-Index - 133
eISSN - 1879-0844
pISSN - 1388-9842
DOI - 10.1093/eurjhf/hfp092
Subject(s) - pressure overload , sodium channel , medicine , gene isoform , heart failure , western blot , patch clamp , endocrinology , constriction , tetrodotoxin , immunocytochemistry , cardiology , sodium , electrophysiology , chemistry , cardiac hypertrophy , biochemistry , organic chemistry , gene
Aims 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. Methods and results 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 ~60% in HF. Protein levels paralleled their mRNA expression. Conclusion 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.