cyclic-gmp and nipecotic-acid

Nitric oxide (NO) modulates the uptake and/or release of neurotransmitters through a variety of cellular mechanisms. However, the pharmacological and biochemical processes underlying these neurochemical effects of NO often remain unclear. In our study, we used immunocytochemical methods to study the effects of NO, cyclic guanosine monophosphate (cGMP), and peroxynitrite on the uptake and release of gamma-aminobutyric acid (GABA) and glycine in the turtle retina. In addition, we examined the involvement of glutamate receptors, calcium, and the GABA transporter in this GABA uptake and release. We also tested for interactions between the GABAergic and glycinergic systems. In general, we show that NO stimulated GABA release and inhibited glycine release. The NO-stimulated GABA release involved calcium-dependent or calcium-independent synaptic release or reversal of the GABA transporter. Some effects of NO on GABA release involved glutamate, cGMP, or peroxynitrite. NO promoted glycine uptake and inhibited its release, and this inhibition of glycine release was influenced by GABAergic modulation. These findings indicate that NO modulates the levels of the inhibitory transmitters GABA and glycine through several specific biochemical mechanisms in different retinal cell types and layers. Thus it appears that some of the previously described reciprocal interactions between GABA and glycine in the retina function through specific NO signaling pathways.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Bicuculline; Cadmium; Citrulline; Cyclic GMP; DEET; Dizocilpine Maleate; Drug Interactions; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Free Radical Scavengers; GABA Antagonists; gamma-Aminobutyric Acid; Glycine; Immunohistochemistry; In Vitro Techniques; Molsidomine; Neural Inhibition; Nipecotic Acids; Nitric Oxide; Potassium; Retina; Silver Staining; Thiourea; Turtles; Vigabatrin

Kainate (KA), quisqualate (QA), and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) stimulated gamma-aminobutyric acid [3H]gamma-aminobutyric acid (GABA) release from cultured cerebellar type 2 astrocytes and from their bipotential precursors. The evoked release was prevented by the antagonist 6-cyano-2,3-dihydroxy-7-nitro-quinoxaline (CNQX). AMPA and QA applied together with KA at concentrations around or above their EC50S (20-50 microM) antagonized the stimulatory effect of KA on [3H]GABA release. On the other hand, the releasing action of KA was potentiated by concentrations of QA in the low micromolar range (2-5 microM), particularly when the concentration of KA was at the borderline of effectiveness (10 microM). KA and QA did not elevate intracellular cyclic GMP levels in astrocyte cultures, although guanylate cyclase was present in both type 2 and type 1 astrocytes. The inability of KA to elevate cyclic GMP levels in astrocytes was the only major difference in the behavior of this glutamate agonist between astroglial and neuronal cultures. The GABA transport inhibitor nipecotic acid or replacement of NaCl with LiCl abolished [3H]GABA uptake and also KA- and QA-induced release of preaccumulated [3H]GABA. Therefore, [3H]GABA was released from type 2 astrocytes and their progenitors through its Na(+)-dependent transport system, operating in an outward direction when the cells were depolarized by non-NMDA receptor agonists.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Astrocytes; Carrier Proteins; Cells, Cultured; Cerebellum; Chlorides; Cyclic GMP; GABA Plasma Membrane Transport Proteins; gamma-Aminobutyric Acid; Ibotenic Acid; Ion Channel Gating; Kainic Acid; Kynurenic Acid; Lithium; Lithium Chloride; Membrane Potentials; Membrane Proteins; Membrane Transport Proteins; Nerve Tissue Proteins; Neurons; Nipecotic Acids; Nitroprusside; Organic Anion Transporters; Proline; Quinoxalines; Quisqualic Acid; Rats; Receptors, AMPA; Receptors, Kainic Acid; Receptors, Neurotransmitter; Secretory Rate; Sodium; Stimulation, Chemical