Activation of A 3 receptors by endogenous adenosine inhibits synaptic transmission during hypoxia in rat cortical neurons

Purpose: The aim of our study was to characterize the influence of A 3 receptors on synaptic potentials (PSPs) in pyramidal cells from the rat cingulate cortex during hypoxia. METHODS: Intracellular recordings (n = 49) were taken from slice preparations. PSPs were evoked by electrical stimulation. Results: Hypoxia (95%N 2 -5%CO 2 , 5 min) reduced the amplitude of the PSPs significantly. The effect was more pronounced in the presence of adenosine re-uptake inhibitor S-(p-nitrobenzyl)-6-thioguanosine (NBTG) and deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA); the effect was completely reversed by bovine adenosine deaminase. Hypoxic inhibition induced after A 1 receptor blockade with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) in the presence of NBTG was completely reversed by the A 3 antagonist 9-chloro-2-(2-furanyl)-5-[(phenylacetyl)amino]-1,2,4-triazolo[1,5-c]quinazoline (MRS 1220), indicating the involvement of A 3 receptors in hypoxic PSP inhibition. This was confirmed by A 3 agonist N 6 -(3-iodobenzyl)-adenosine-5'-N-methylcarboxamide (IB-MECA) inhibiting PSPs. The effect of IB-MECA was blocked by the rat A 3 receptor-selective antagonist 3-propyl-6-ethyl-5-[(ethylthio)carbonyl]-2-phenyl-4-propyl-3-pyridinecarboxylate (MRS 1523) and was not observed in the presence of G-protein inhibitor guanosine-5'-O-2-thiodiphosphate (GDP-β-S). Conclusion: We conclude that a high level of endogenous adenosine, which occurs during hypoxia, activates A3 receptors. Their activation contributes to PSP inhibition by adenosine during hypoxia.