Chemical sympathetic denervation, suppression of myocardial transient outward potassium current, and ventricular fibrillation in the rat.
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.
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.
Juan
J
Bai
Chongyu
C
Ren
Wei
W
Hao
Rui
R
Wang
Ji-Min
JM
Cao
D000818:Animals; D015153:Blotting, Western; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis / Q000235:genetics; D006892:Hydroxydopamines; D051605:Kv Channel-Interacting Proteins / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D032342:Muscle Cells / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013563:Sympathectomy, Chemical; D013565:Sympatholytics; D014693:Ventricular Fibrillation / Q000503:physiopathology*
D017362:Cyclic AMP Response Element-Binding Protein; D006892:Hydroxydopamines; C496758:Kcnip2 protein, rat; D051605:Kv Channel-Interacting Proteins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D013565:Sympatholytics; D048049:Extracellular Signal-Regulated MAP Kinases; D009638:Norepinephrine