Activation of N-methyl-d-aspartate receptors reduces heart rate variability and facilitates atrial fibrillation in rats

Europace. 2017 Jul 1;19(7):1237-1243. doi: 10.1093/europace/euw086.


Aims: The goal of this study was to assess the effects of N-methyl-d-aspartate (NMDA) receptors activation on heart rate variability (HRV) and susceptibility to atrial fibrillation (AF).

Methods and results: Rats were randomized for treatment with saline, NMDA (agonist of NMDA receptors), or NMDA plus MK-801 (antagonist of NMDA receptors) for 2 weeks. Heart rate variability was evaluated by using implantable electrocardiogram telemeters. Atrial fibrillation susceptibility was assessed with programmed stimulation in isolated hearts. Compared with the controls, the NMDA-treated rats displayed a decrease in the standard deviation of normal RR intervals, the standard deviation of the average RR intervals, the mean of the 5-min standard deviations of RR intervals, the root mean square of successive differences, and high frequency (HF); and an increase in low frequency (LF) and LF/HF (all P< 0.01). Additionally, the NMDA-treated rats showed prolonged activation latency and reduced effective refractory period (all P< 0.01). Importantly, AF was induced in all NMDA-treated rats. While atrial fibrosis developed, connexin40 downgraded and metalloproteinase 9 upgraded in the NMDA-treated rats (all P< 0.01). Most of the above alterations were mitigated by co-administering with MK-801.

Conclusion: These results indicate that NMDA receptors activation reduces HRV and enhances AF inducibility, with cardiac autonomic imbalance, atrial fibrosis, and degradation of gap junction protein identified as potential mechanistic contributors.

Keywords: Atrial fibrillation; Heart rate variability; N-Methyl-d-aspartate receptors.

MeSH terms

  • Action Potentials
  • Animals
  • Atrial Fibrillation / chemically induced*
  • Atrial Fibrillation / diagnosis
  • Atrial Fibrillation / metabolism
  • Atrial Fibrillation / physiopathology
  • Connexins / metabolism
  • Disease Models, Animal
  • Excitatory Amino Acid Agonists / toxicity*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Fibrosis
  • Heart Conduction System / drug effects*
  • Heart Conduction System / metabolism
  • Heart Conduction System / pathology
  • Heart Conduction System / physiopathology
  • Heart Rate / drug effects*
  • Male
  • Matrix Metalloproteinase 9 / metabolism
  • N-Methylaspartate / toxicity*
  • Rats, Wistar
  • Receptors, N-Methyl-D-Aspartate / agonists*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Time Factors


  • Connexins
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • connexin 40
  • N-Methylaspartate
  • Matrix Metalloproteinase 9
  • Mmp9 protein, rat