title: A preliminary experimental study on the cardiac toxicity of glutamate and the role of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor in rats.
abstract: BACKGROUND
  Monosodium L-glutamate (MSG) is a food flavour enhancer and its potential harmfulness to the heart remains controversial. We investigated whether MSG could induce cardiac arrhythmias and apoptosis via the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor.
  
  
  METHODS
  Myocardial infarction (MI) was created by ligating the coronary artery and ventricular arrhythmias were monitored by electrocardiogram in the rat in vivo. Neonatal rat cardiomyocytes were isolated and cultured. Cell viability was estimated by 3-(4,5)-dimethylthiahiazo(-z-yl)-3,5-di-phenytetrazoliumromide (MTT) assay. Calcium mobilization was monitored by confocal microscopy. Cardiomyocyte apoptosis was evaluated by acridine orange staining, flow cytometry, DNA laddering, reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting.
  
  
  RESULTS
  MSG (i.v.) decreased the heart rate at 0.5 g/kg and serious bradycardia at 1.5 g/kg, but could not induce ventricular tachyarrhythmias in normal rats in vivo. In rats with acute MI in vivo, however, MSG (1.5 g/kg, i.v.) induced ventricular tachyarrhythmias and these arrhythmias could be prevented by blocking the AMPA and N-methyl-d-aspartate (NMDA) receptors. Selectively activating the AMPA or NMDA receptor induced ventricular tachyarrhythmias in MI rats. At the cellular level, AMPA induced calcium mobilization, oxidative stress, mitochondrial dysfunction and apoptosis in cultured cardiomyocytes, especially when the AMPA receptor desensitization were blocked by cyclothiazide. The above toxic cellular effects of AMPA were abolished by AMPA receptor blockade or by H2O2 scavengers.
  
  
  CONCLUSIONS
  MSG induces bradycardia in normal rats, but triggers lethal tachyarrhythmias in myocardial infarcted rats probably by hindering AMPA receptors. AMPA receptor overstimulation also induces cardiomyocyte apoptosis, which may facilitate arrhythmia.
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 100005, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Lan
authors.initials: L
authors.lastname: Zhou
authors.forename: Hai-Fei
authors.initials: HF
authors.lastname: Xu
authors.forename: Li
authors.initials: L
authors.lastname: Yan
authors.forename: Fan
authors.initials: F
authors.lastname: Ding
authors.forename: Wei
authors.initials: W
authors.lastname: Hao
authors.forename: Ji-Min
authors.initials: JM
authors.lastname: Cao
authors.forename: Xue
authors.initials: X
authors.lastname: Gao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D018698:Glutamic Acid / Q000633:toxicity*; D008297:Male; D018613:Microscopy, Confocal; D009203:Myocardial Infarction / Q000139:chemically induced; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012970:Sodium Glutamate / Q000633:toxicity; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
chemical_list: D018091:Receptors, AMPA; D018698:Glutamic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D002118:Calcium; D012970:Sodium Glutamate