Key result
Chemical sympathectomy with 6-OHDA in rats decreased myocardial Ito channel activities and downregulated selective Kv channel subunits, increasing susceptibility to ventricular fibrillation.
Raises possibility of sympathetic influences on ventricular repolarization in models; leaves open applicability to human arrhythmia management.
Sympathetic denervation is frequently observed in heart disease. To investigate the linkage of sympathetic denervation and cardiac arrhythmia, we developed a rat model of chemical sympathectomy by subcutaneous injections of 6-hydroxydopamine (6-OHDA). Cardiac sympathetic innervation was visualized by means of a glyoxylic catecholaminergic histofluorescence method. Transient outward current (Ito) of ventricular myocytes was recorded with the whole-cell configuration of the patch clamp technique. We observed that sympathectomy (i) decreased cardiac sympathetic nerve density and norepinephrine level, (ii) reduced the protein expression of Kv4.2, Kv1.4, and Kv channel-interacting protein 2 (KChIP2), (iii) decreased current densities and delayed activation of Ito channels, (iv) reduced the phosphorylation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) and cAMP response element-binding protein (CREB), and (v) increased the severity of ventricular fibrillation induced by rapid pacing. Three weeks after 6-OHDA injections, which allowed time for sympathetic regeneration, we found cardiac sympathetic nerve density, norepinephrine levels, expression levels of Kv4.2 and KChIP2 proteins, and I(to) densities were partially normalized and ventricular fibrillation severity was decreased. We conclude that chemical sympathectomy downregulates the expression of selective Kv channel subunits and decreases myocardial I(to) channel activities, contributing to the elevated susceptibility to ventricular fibrillation.
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Bai et al. (2008) studied Sympathetic denervation and cardiac arrhythmia. Chemical sympathectomy by subcutaneous injections of 6-hydroxydopamine (6-OHDA) was evaluated on Cardiac sympathetic nerve density, norepinephrine level, protein expression of Kv4.2, Kv1.4, KChIP2, Ito current densities, and severity of ventricular fibrillation. Chemical sympathectomy with 6-OHDA in rats decreased myocardial Ito channel activities and downregulated selective Kv channel subunits, increasing susceptibility to ventricular fibrillation.
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