Role of central glutamate receptors, nitric oxide and soluble guanylyl cyclase in the inhibition by endotoxin of rat gastric acid secretion

Abstract

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 μg rat-1) restored acid secretory responses in endotoxin (10 μg kg-1, i.v.)-treated rats. 3. The acid-inhibitory effect of i.v. endotoxin (10 μg 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 (+)-α-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 μg 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.