8-bromocyclic-gmp and alpha-methyl-4-carboxyphenylglycine

1. This study examines the role of a central pathway involving glutamate receptors, nitric oxide (NO) and cyclic GMP in the acute inhibitory effects of low doses of peripheral endotoxin on pentagastrin-stimulated acid production. 2. Vagotomy or intracisternal (i.c.) microinjections of the NO-inhibitor, N(G)-nitro-L-arginine methyl esther (L-NAME; 200 microg rat(-1)) restored acid secretory responses in endotoxin (10 microg kg(-1), i.v.)-treated rats. 3. The acid-inhibitory effect of i.v. endotoxin (10 microg kg(-1), i.v.) was prevented by prior i.c. administration of the NMDA receptor antagonists, dizocilpine maleate (MK-801; 10 nmol rat(-1)) and D-2-amino-5-phosphono-valeric acid (AP-5; 20 nmol rat(-1)), or the AMPA/kainate antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX; 10 nmol rat(-1)). However, the competitive metabotropic glutamate receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine (MCPG; 20 - 1000 nmol rat(-1)) did not antagonize the effects of endotoxin. 4. I.c. administration of L-glutamate (0.1 nmol rat(-1)) inhibited pentagastrin-stimulated gastric acid secretion. Coadministration with L-NAME (200 microg rat(-1)) prevented the inhibition of gastric acid secretion by the aminoacid. 5. I.c. administration of 1H-[1,2, 4]Oxazodiolo[4,3-a]quinoxalin-1-one (ODQ; 100 nmol rat(-1)), a soluble guanylyl cyclase (sGC) blocker, reversed the hyposecretory effect of endotoxin. 6. I.c. administration of the cyclic GMP analogue 8-Bromoguanosine-3,5-cyclic monophosphate (8-Br-cGMP; 100 - 300 nmol rat(-1)) reduced gastric acid production in a dose-dependent manner. 7. We conclude that central NMDA and AMPA/kainate receptors are involved in the acid inhibitory effect of peripherally administered endotoxin. This central pathway involves synthesis of NO, which acts on the enzyme sGC.

Topics: Animals; Benzoates; Cyclic GMP; Dizocilpine Maleate; Dose-Response Relationship, Drug; Endotoxins; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Gastric Acid; Gastric Mucosa; Glycine; Guanylate Cyclase; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxadiazoles; Pentagastrin; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Solubility; Stomach; Vagotomy

Glutamate, the neurotransmitter released by photoreceptors, excites horizontal cells and OFF-type bipolar cells by activating ionotropic receptors. This study investigated an additional action of glutamate in which it modulates a voltage-gated ion channel in horizontal cells. We find that glutamate and APB (2-amino-4-phosphonobutyrate) produce a delayed and moderately prolonged suppression of an inward rectifier current (IRK+). This effect is proposed to occur via an APB-sensitive metabotropic glutamate receptor (mGluR) because common agonists for the ionotropic or APB-insensitive mGluRs are ineffective and the APB-insensitive receptor antagonist alpha-methyl-4-carboxyphenylglycine (MCPG) does not block the actions of glutamate or APB. 8-Br-cGMP, 1-methyl-3-isobutylxanthine (IBMX), and atrial natriuretic peptide (ANP) but not 8-Br-cAMP mimic the suppression of IRK+. The effects of glutamate and APB are blocked by protein kinase inhibitors including Rp-8-pCPT-cGMPS, H-8, and H-7 as well as by ATPgammaS. We hypothesize that the APB receptor suppresses IRK+ via upregulation of cGMP and subsequent activation of a cGMP-dependent protein kinase. This pathway is likely regulated by an ATP-dependent phosphorylation. This is a novel signaling pathway for mGluRs and indicates that at least two distinct APB-activated pathways exist in the retina. Functionally, this APB receptor-mediated action found in horizontal cells would provide a means by which spatially restricted changes of glutamate, produced by local illumination of photoreceptors, could regulate IRK+ and consequently the response properties of these neurons. This would serve to adapt selectively retinal regions stimulated by small regions of the visual world.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; 1-Methyl-3-isobutylxanthine; 8-Bromo Cyclic Adenosine Monophosphate; Adenosine Triphosphate; Aminobutyrates; Animals; Atrial Natriuretic Factor; Benzoates; Cyclic GMP; Enzyme Inhibitors; Glutamic Acid; Glycine; Ictaluridae; Ion Channel Gating; Isoquinolines; Models, Neurological; Patch-Clamp Techniques; Photoreceptor Cells; Potassium Channels; Receptors, Metabotropic Glutamate; Second Messenger Systems; Thionucleotides

In rat cerebellar slices, 500 microM (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) reversibly inhibited both dendritic and somatic increases in FLUO-3 fluorescence intensity induced by bath applications of 50-100 microM (+-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD). No effect of MCPG was observed on dendritically recorded excitatory postsynaptic potentials evoked by synaptic activation of either parallel or climbing fibres. Long-term depression of parallel fibre-Purkinje cell transmission, induced either by conjunctive activation of parallel and climbing fibres or by pairing parallel fibre stimulation with intradendritic injections of 8-BrcGMP, was not only prevented in the presence of MCPG but a robust long-term potentiation of responses consistently occurred. These data show that metabotropic glutamate receptor activation is necessary for the induction of LTD.

Topics: Aniline Compounds; Animals; Benzoates; Biotransformation; Cerebellum; Cyclic GMP; Cycloleucine; Cyclopropanes; Evoked Potentials; Fluorescent Dyes; Glycine; In Vitro Techniques; Nerve Fibers; Neuronal Plasticity; Neurotoxins; Purkinje Cells; Rats; Receptors, Metabotropic Glutamate; Synaptic Transmission; Xanthenes