Chronic N-methyl-D-aspartate receptor activation induces cardiac electrical remodeling and increases susceptibility to ventricular arrhythmias.

BACKGROUND: N-Methyl-d-aspartate receptors, also known as NMDA Receptors or NMDAR, are glutamate receptors that control calcium ion channels and regulate synaptic plasticity. Acute NMDAR activation can induce ventricular arrhythmias (VAs). However, the influence of chronic NMDAR activation on cardiac electrophysiology remains unknown. METHODS AND
RESULTS: Wistar rats were randomly administered 0.9% saline (CTL group), NMDA (N group), or NMDA plus MK801 (N+M group) for 14 days. Compared with the CTL group, the N group displayed elevated heart rate and prolonged QT, QTc, and TpTe intervals in the electrocardiogram (P < 0.05 for all). Then, the S1 S2 , S1 S1 , and Burst pacing were performed to assess the characteristics of repolarization; threshold of action potential duration (APD) alternans; beat-to-beat variability of repolarization (BVR); and VAs susceptibility in the left ventricular. The prolonged APD at 90% repolarization (APD90 ); decreased ERP/APD90 ; increased dispersion of APD90 , ERP, and ERP/APD90 ; decreased threshold of APD alternans; increased BVR; and incidence of VAs were showed in the N group compared with those of the CTL group (P < 0.01 for all). Moreover, chronic NMDA administration reduced the expression of Kv4.2, Kv4.3, KChIP2, and Kv11.1 proteins, and induced mild myocardial interstitial fibrosis (P < 0.01 for all). Importantly, these alterations induced by NMDA were normalized by co-treatment with MK801.
CONCLUSION: Chronic NMDAR activation prolonged repolarization, induced electrical instability, and facilitated VAs, which may be associated with reduced Ito and IKr and myocardial fibrosis. ©2014 Wiley Periodicals, Inc.