Chemical sympathetic denervation, suppression of myocardial transient outward potassium current, and ventricular fibrillation in the rat

Author:

Bai Juan12,Ren Chongyu12,Hao Wei12,Wang Rui12,Cao Ji-Min12

Affiliation:

1. Department of Physiology and Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005, P.R. China.

2. Department of Biology, Lakehead University, Thunder Bay, ON P7B 5E1, Canada.

Abstract

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 Ito 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 Ito channel activities, contributing to the elevated susceptibility to ventricular fibrillation.

Publisher

Canadian Science Publishing

Subject

Physiology (medical),Pharmacology,General Medicine,Physiology

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