title: Nerve sprouting suppresses myocardial I(to) and I(K1) channels and increases severity to ventricular fibrillation in rat.
abstract: 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.
authors.affiliation: Department of Physiology and Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, PR China.
authors.forename: Chongyu
authors.initials: C
authors.lastname: Ren
authors.forename: Fuzhen
authors.initials: F
authors.lastname: Wang
authors.forename: Guang
authors.initials: G
authors.lastname: Li
authors.forename: Qing
authors.initials: Q
authors.lastname: Jiao
authors.forename: Juan
authors.initials: J
authors.lastname: Bai
authors.forename: Dejie
authors.initials: D
authors.lastname: Yu
authors.forename: Wei
authors.initials: W
authors.lastname: Hao
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Ji-Min
authors.initials: JM
authors.lastname: Cao
mesh_terms: D000818:Animals; D002396:Catechols / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D051605:Kv Channel-Interacting Proteins / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000150:complications*; D020932:Nerve Growth Factor / Q000819:agonists; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051672:Shal Potassium Channels / Q000187:drug effects / Q000378:metabolism; D017779:Sympathetic Fibers, Postganglionic / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014693:Ventricular Fibrillation / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D002396:Catechols; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C496758:Kcnip2 protein, rat; C489461:Kir2.1 channel; D051605:Kv Channel-Interacting Proteins; D018696:Neuroprotective Agents; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D051672:Shal Potassium Channels; C018599:4-methylcatechol; D020932:Nerve Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases