The Role of Cardiac N-Methyl-D-Aspartate Receptors in Heart Conditioning—Effects on Heart Function and Oxidative Stress

Natalia Govoruskina,Aleksandra Stojanovic,Isidora Milosavljevic,Jovana Jeremic,Nevena Draginic,Katarina Radonjic,Sergey Bolevich,Dragan Djuric,Vladimir Zivkovic,Israpil Alisultanovich Omarov,Vladimir Jakovljevic,Ivan Srejovic,Jovana Bradic,Marijana Andjic

doi:10.3390/biom10071065

Abstract

As well as the most known role of N-methyl-D-aspartate receptors (NMDARs) in the nervous system, there is a plethora of evidence that NMDARs are also present in the cardiovascular system where they participate in various physiological processes, as well as pathological conditions. The aim of this study was to assess the effects of preconditioning and postconditioning of isolated rat heart with NMDAR agonists and antagonists on heart function and release of oxidative stress biomarkers. The hearts of male Wistar albino rats were subjected to global ischemia for 20 min, followed by 30 min of reperfusion, using the Langendorff technique, and cardiodynamic parameters were determined during the subsequent preconditioning with the NMDAR agonists glutamate (100 µmol/L) and (RS)-(Tetrazol-5-yl)glycine (5 μmol/L) and the NMDAR antagonists memantine (100 μmol/L) and MK-801 (30 μmol/L). In the postconditioning group, the hearts were perfused with the same dose of drugs during the first 3 min of reperfusion. The oxidative stress biomarkers were determined spectrophotometrically in samples of coronary venous effluent. The NMDAR antagonists, especially MK-801, applied in postconditioning had a marked antioxidative effect with a most pronounced protective effect. The results from this study suggest that NMDARs could be a potential therapeutic target in the prevention and treatment of ischemic and reperfusion injury of the heart.

Highlights

The N-methyl-D-aspartate receptors (NMDARs) belong to the ionotropic glutamate receptor family
The hearts of male Wistar albino rats were subjected to global ischemia for 20 min, followed by 30 min of reperfusion, using the Langendorff technique, and cardiodynamic parameters were determined during the subsequent preconditioning with the NMDAR agonists glutamate (100 μmol/L) and (RS)-(Tetrazol-5-yl)glycine (5 μmol/L) and the NMDAR antagonists memantine (100 μmol/L) and MK-801 (30 μmol/L)
NMDARs have several unique features, which makes them completely different from other glutamate receptors: (1) NMDARs require simultaneous binding of both co-agonists, glutamate and glycine, for activation, (2) the NMDAR pore is blocked by Mg2+, which is removed upon membrane depolarization, and (3) activated NMDARs are highly transient to Ca2+, unlike other glutamate receptors which are mainly Na+ channels [1,4]

Summary

Introduction

The N-methyl-D-aspartate receptors (NMDARs) belong to the ionotropic glutamate receptor family. NMDAR is a tetrameric complex composed of GluN1 and GluN3 subunits, which bind glycine (or D-serine), and glutamate-binding GluN2 subunits, which combine differently in the assembly of NMDARs [1]. Various compositions of NMDAR assembly result in different biophysical, pharmacological and functional features of NMDARs in distinct regions of the body [2,3]. The results of several studies regarding the presence of different NMDAR subunits in cardiovascular tissues have led to contradictory conclusions. The roles of NMDARs in peripheral non-neural tissues remain elusive due to differences in glutamate concentrations, the different composition of subunits where the NMDARs were built up and consequent modifications of NMDAR functionality, and variations in affinities for glutamate and glycine binding. The overactivation of NMDARs by homocysteine (Hcy) and subsequent pathological changes in the cardiovascular system have further illuminated the link between NMDAR function and the cardiovascular system [10,11]

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