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

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. Vagotomy or intracisternal (i.c.) microinjections of the NO-inhibitor, NG-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. 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. 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. 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. 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. 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. British Journal of Pharmacology (2000) 130, 1283–1288; doi:10.1038/sj.bjp.0703436