P341N-methyl D-aspartate receptors in rat heart

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N-methyl-D-aspartate (NMDA) receptor is a subtype of glutamate receptors highly expressed in mammalian brain. NMDA-receptor is a ligand-gated non-selective cation channel with 10-fold preference for Ca2+ over Na+ and K+. Activation of NMDA-receptor in neuron results in Ca2+ influx and activation of Ca-sensitive signalling cascades and processes. Recently expression of NMDA receptors was reported in numerous non-neuronal cells and tissues including the heart. Physiological role of these receptors in the myocardium, subunit speciation and localisation of the receptors in the heart remained unknown. Using isolated blood-perfused rat heart model and adult as well as neonatal cardiomyocytes we have explored the NMDA receptor subunit speciation, its expression pattern as a function of age, localisation and role in control of contractile function of the heart. In myocardium of rats aging from P3 to two years old all essential subunits of the receptor (NR1, NR2A, NR2B, NR2C and NR2D) were detected at the mRNA and protein levels. Treatment of isolated cardiomyocytes with NMDA-receptor agonists resulted in an increase in basal intracellular Ca2+ levels thus suggesting that the expressed receptors are functional. Isolated rat hearts treated with a broad array of NMDA receptor agonists developed tachycardia. Transient positive inotropic effect was observed during first minutes of agonists' administration. Hyperactivation of the NMDA receptors resulted in development of arrhythmia and reduction in ventricular capillary perfusion. NMDA receptor antagonists on the contrary reduced pre-existing arrhythmia as well as abolished the loss of rhythmicity triggered by hyperactivation of the receptors. Transient bradykardia was observed in response to administration of antagonists to blood used for coronary perfusion. Capillary perfusion in hearts treated with antagonists was significantly improved compared to that in control. Improved capillary perufsion in antagonists-treated ventricular associated with K+ loss from cardiomyocytes was beneficial and resulted in stabilisation in myocardial function under hypoxic conditions. The obtained findings indicate that NMDA receptors are essential for myocardial performance and represent an attractive pharmacological target for therapeutic interventions.

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