Nerve sprouting suppresses myocardial I(to) and I(K1) channels and increases severity to ventricular fibrillation in rat.

Nerve sprouting in healed myocardial infarction has been associated with increased incidences of ventricular tachyarrhythmia and sudden cardiac death. However, the underlying electrophysiological mechanisms are unclear. To investigate the linkage between nerve sprouting and potassium channel function, we developed a rat model of cardiac sympathetic nerve sprouting by chronic subcutaneous injection of 4-methylcatechol, a potent stimulator of nerve growth factor (NGF) synthesis. Cardiac sympathetic nerves were visualized by immunohistochemical staining. Myocardial necrotic injury was created by focal cold shock across intact diaphragm to mimic infarction. Transient outward current (I(to)) and inward rectifier current (I(K1)) of cardiomyocytes were recorded with the whole-cell patch clamp technique. We found that chronic 4-MC administration 1) increased cardiac NGF level and the density of cardiac sympathetic innervation; 2) decreased the expressions of Kv4.2, Kv channel-interacting protein 2 (KChIP2), Kir2.1, and the current densities of I(to) and I(K1); 3) reduced the phosphorylation of extracellular signal-regulated kinase 1/2 (pERK1/2); and 4) decreased heart rate variability and increased the susceptibility to ventricular fibrillation. Myocardial necrotic injury exerted similar effects as 4-methylcatechol, and 4-methylcatechol plus myocardial necrotic injury intensified the cardiac effects of 4-methylcatechol alone and decreased the phosphoralation of cAMP response element-binding protein (CREB). We conclude that nerve sprouting suppressed the expressions and functions of myocardial I(to) and I(K1) channels and increased the susceptibility to ventricular fibrillation. These effects are associated with decreased phosphorylation of ERK and CREB and reduced expression of KChIP2.