Role of central glutamate receptors, nitric oxide and soluble guanylyl cyclase in the inhibition by endotoxin of rat gastric acid secretion.
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.
García-Zaragozá
E
E
Department of Pharmacology, Faculty of Medicine, University of Valencia, Spain.
Barrachina
M D
MD
Moreno
L
L
Esplugues
J V
JV
D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004731:Endotoxins / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010069:Oxadiazoles / Q000494:pharmacology; D010418:Pentagastrin / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects / Q000502:physiology*; D012995:Solubility; D013270:Stomach / Q000187:drug effects; D014628:Vagotomy
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D001565:Benzoates; D004731:Endotoxins; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D010069:Oxadiazoles; D011810:Quinoxalines; D017470:Receptors, Glutamate; C079694:alpha-methyl-4-carboxyphenylglycine; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; C056723:FG 9041; D016291:Dizocilpine Maleate; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D010418:Pentagastrin; D006152:Cyclic GMP; D005998:Glycine; D019331:NG-Nitroarginine Methyl Ester