title: Inhibition of neutrophil activation by lafutidine, an H2-receptor antagonist, through enhancement of sensory neuron activation contributes to the reduction of stress-induced gastric mucosal injury in rats.
abstract: Sensory neuron activation reduces water-immersion restraint stress (WIR)-induced gastric mucosal injury by inhibiting neutrophil activation through increase in endothelial production of prostacyclin. This study was designed to examine whether lafutidine, which is an H(2)-receptor antagonist and activates sensory neurons, inhibits neutrophil activation, thereby reducing WIR-induced gastric mucosal injury. Lafutidine enhanced WIR-induced increases in gastric tissue levels of calcitonin gene-related peptide (CGRP) and 6-keto-PGF(1alpha), a stable metabolite of prostacyclin, whereas famotidine, another H(2)-receptor antagonist, did not. Such lafutidine-induced increases in gastric tissue levels of 6-keto-PGF(1alpha) were reversed by pretreatment with capsazepine, an inhibitor of sensory neuron activation, CGRP(8-37), a CGRP antagonist, and indomethacin. Lafutidine inhibited acid-induced exacerbation of gastric mucosal injury in animals subjected to WIR by inhibiting neutrophil activation, whereas famotidine did not. Lafutidine synergistically increased CGRP release from isolated rat dorsal root ganglion neurons in the presence of anandamide, but famotidine did not. These observations suggest that lafutidine might reduce WIR-induced gastric mucosal injury not only by inhibiting acid secretion but also by inhibiting neutrophil activation through enhancement of sensory neuron activation.
authors.affiliation: Department of Biodefense Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Naoaki
authors.initials: N
authors.lastname: Harada
authors.forename: Kenji
authors.initials: K
authors.lastname: Okajima
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000081:Acetamides / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D001095:Arachidonic Acids / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D063388:Endocannabinoids; D015738:Famotidine / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D006635:Histamine H2 Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects*; D018375:Neutrophil Activation / Q000187:drug effects*; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012149:Restraint, Physical / Q000009:adverse effects; D013276:Stomach Ulcer / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D013315:Stress, Psychological / Q000209:etiology*
chemical_list: D000081:Acetamides; D000897:Anti-Ulcer Agents; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D063388:Endocannabinoids; D006635:Histamine H2 Antagonists; D010446:Peptide Fragments; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011725:Pyridines; C058636:calcitonin gene-related peptide (8-37); C076948:lafutidine; D015121:6-Ketoprostaglandin F1 alpha; D015738:Famotidine; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; C078814:anandamide; D007213:Indomethacin