title: Nerve sprouting contributes to increased severity of ventricular tachyarrhythmias by upregulating iGluRs in rats with healed myocardial necrotic injury.
abstract: Sympathetic nerve sprouting in healed myocardial infarction (MI) has been associated with high incidences of lethal arrhythmias, but the underlying mechanisms are largely unknown. This study sought to test that sympathetic hyperinnervation and/or MI remodels the myocardial glutamate signaling and ultimately increases the severity of ventricular tachyarrhythmias. Myocardial necrotic injury (MNI) was created by liquid nitrogen freeze-thawing across an intact diaphragm to mimic MI. Cardiac sympathetic hyperinnervation was induced by chronic subcutaneous injection of 4-methylcatechol, a potent stimulator of nerve growth factor expression. The results showed that sympathetic hyperinnervation with or without MNI upregulated the myocardial expression of ionotropic glutamate receptors (iGluRs), including NMDA receptor (NMDAR) and AMPA receptor (AMPAR), and induced cardiomyocyte apoptosis. Intravenous infusion with either NMDA (12 mg/kg) or AMPA (15 mg/kg) triggered ventricular tachycardia and ventricular fibrillation in rats with healed MNI plus sympathetic hyperinnervation; these arrhythmias were prevented by respective antagonist of NMDAR or AMPAR. We conclude that MNI with sympathetic nerve sprouting upregulates the expression of NMDAR and AMPAR in the myocardium and this impact in turn enhances cardiac responses to stimulations of iGluRs and thus increases the incidence of ventricular tachyarrhythmias.
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, 5 Dong Dan San Tiao, Beijing 100005, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lü
authors.forename: Xue
authors.initials: X
authors.lastname: Gao
authors.forename: Jingli
authors.initials: J
authors.lastname: Gu
authors.forename: Lan
authors.initials: L
authors.lastname: Zhou
authors.forename: Shu
authors.initials: S
authors.lastname: Guo
authors.forename: Wei
authors.initials: W
authors.lastname: Hao
authors.forename: Zhuan
authors.initials: Z
authors.lastname: Zhou
authors.forename: Ji-Min
authors.initials: JM
authors.lastname: Cao
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009336:Necrosis; D051381:Rats; D017208:Rats, Wistar; D017470:Receptors, Glutamate / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D012720:Severity of Illness Index; D017180:Tachycardia, Ventricular / Q000473:pathology* / Q000503:physiopathology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D014693:Ventricular Fibrillation / Q000473:pathology* / Q000503:physiopathology; D014945:Wound Healing / Q000502:physiology*
chemical_list: D017470:Receptors, Glutamate