Gastric mucosal damage induced by compound 48/80: Roles of serotonin and nitric oxide

Abstract

The roles of nitric oxide (NO) and serotonin (5-HT) in the development of gastric mucosal lesions induced by compound 48/80 (48/80) were investigated in rats. Repeated i.p. administration of 48/80 (1 mg/kg) produced damage in the stomach with severe oedema in the submucosa. The lesions induced by 48/80 were prevented by FPL-52694 (a mast cell stabilizer) and methysergide but not tripelennamine. The lesions were also inhibited by simultaneous administration of N(G)-monomethyl-L-arginine (L-NMMA), and this effect was mimicked by inducible NO synthase (iNOS) inhibitors, such as aminoguanidine or dexamethasone and significantly antagonized by coadministration of L-arginine. The mucosal myeloperoxidase activity, thiobarbituric acid reactants and vascular permeability in the stomach were all increased after 48/80 treatment and the changes were also attenuated by cotreatment with L-NMMA. Repeated s.c. treatment with 5-HT (20 mg/kg) provoked similar gastric lesions, which were also prevented by methysergide and iNOS inhibitors, as well as antioxidative drugs, such as allopurinol (a xanthine oxidase inhibitor) and hydroxyurea (a neutrophil-reducing agent). The Ca2 -independent NO synthase (NOS) activity was increased in the gastric mucosa after administration of 48/80 or 5-HT and this change was inhibited by dexamethasone. These results suggest that: (i) the repeated administration of 48/80 induced inflammatory gastric lesions in the rat stomach, mediated by endogenous 5-HT; (ii) NO/iNOS is involved in the pathogenic mechanism of 48/80-induced gastric lesions, in addition to oxyradical formation; and (iii) the deleterious role of NO in this lesion model can be accounted for by a cytotoxic action of peroxynitrite that is formed in the presence of superoxide radicals.

Histamine H₃ Receptors Are Involved in the Protective Effect of Ghrelin against HCl-Induced Gastric Damage in Rats

“…As opposed to this, a delay in gastric emptying and a reduction of food intake was observed after administration of the ghrelin receptor antagonist [10] . The possibility that nonspecific effects of [ D -Lys 3 ]-GHRP-6 leading to gastroprotection had masked ulcerogenic effects related to ghrelin receptor blockade cannot be excluded; in line with this, a recent study [46] ]-GHRP-6 has to be excluded, since, if present, it would have resulted in ulcerogenic rather than protective activity [47] .…”

Gastric damage induced by different doses of indomethacin in rats is variably affected by inhibiting iNOS or leukocyte infiltration

“…Many studies have demonstrated the involvement of iNOSgenerated NO in gastric damage induced by chemical substances, such as serotonin or compound 48/80 [16,17], by stress [18] or by Helicobacter pylori infection [19]. However, the role of iNOS in NSAID-induced gastric damage has not been completely elucidated.…”

Protective Effect of Ebselen, a Seleno-Organic Compound, Against the Progression of Acute Gastric Mucosal Lesions Induced by Compound 48/80, a Mast Cell Degranulator, in Rats

“…Accordingly, it seems unlikely that ebselen administered to rats treated once with compound 48 /80 at the stage of gastric mucosal lesion formation exerts a protective effect against the lesion progression by inhibiting gastric acid secretion. Yasuhiro et al (36,37) have suggested that endogenous nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) increasing in gastric mucosal tissues, in addition to enhanced gastric mucosal lipid peroxidation and released endogenous serotonin, is involved in the pathogenesis of gastric mucosal lesions induced by repeated treatment with compound 48 /80 in rats. The authors have also suggested that the deleterious role of NO during compound 48 /80 treatment may be accounted for by a cytotoxic action of peroxynitrite, which is formed in the presence of NO and superoxide radical (36, 37).…”