NITRIC-OXIDE IN RETINA - RELATION TO EXCITATORY AMINO-ACIDS AND EXCITOTOXICITY

This study was undertaken to determine whether nitric oxide pathways exist in the retina and are linked to excitatory amino acid (EAA)-induced increases in cyclic guanosine monophosphate (cGMP). Exposure of embryonic day 15 chick retina for 5 min to either 1 mM glutamate, 100 μM NMDA or 100 μM kainate (KA) increased cGMP content 2-3-fold. The putative environmental neurotoxins, domoic acid (DO, 20 μM), and β-oxalyl-amino-l-alanine (BOAA, 200 μM), but not β-methyl-amino-l-alanine (BMAA, 3 mM), also increased cGMP. The nitric oxide synthase inhibitor N-nitro-l-arginine (NNA) and nitric oxide scavenger, hemoglobin, completely blocked the increases in cGMP induced by the above glutamate-agonists. These glutamate agonist induced increases in cGMP were receptor mediated. MK-801, a NMDA receptor antagonist, blocked NMDA, and partially blocked glutamate-stimulated, cGMP formation. CNQX, a KA/AMPA receptor antagonist blocked cGMP increases produced by KA, BOAA and partially blocked those evoked by DO and glutamate. In order to examine the involvement of nitric oxide pathways in NMDA-mediated toxicity, the ability of NNA to protect against delayed excitotoxic damage caused by a 60 min exposure to NMDA was assessed. Delayed cell death, determined by LDH release and histology, following a 24 hr recovery period after NMDA treatment, was unchanged by the presence of NNA. NNA did not interfere with acute NMDA-stimulated GABA release indicating that NNA did not effect NMDA receptor interactions. These studies demonstrate that nitric oxide pathways exist in embryonic retina and link EAA receptor activation to cGMP formation; however, this pathway may not play a role in NMDA-mediated excitotoxicity. © 1994 Academic Press. All rights reserved.