ROLE OF NITRIC-OXIDE IN PATHOGENESIS OF SEROTONIN-INDUCED GASTRIC-LESIONS IN RATS

We investigated the role of nitric oxide (NO) in the development of ga stric mucosal lesions induced by serotonine (5-HT) in rats. Repeated s ubcutaneous administration of 5-HT (20 mg kg(-1)) produced damage in t he stomach with severe edema in the submucosa. Gastric lesions induced by 5-HT were prevented by simultaneous administration of aminoguanidi ne, a selective inducible NO synthase (iNOS) inhibitor, as well as by methysergide, a 5-HT antagonist. In addition, the lesions were inhibit ed by pretreatment with the antioxidative drugs, such as allopurinol. (a xanthine oxidase inhibitor) and hydroxyurea (a neutrophil reducing agent). Following 5-HT treatment, the Ca2+-independent NOS activity in the gastric mucosa was significantly increased within 6 h and remaine d elevated for 2 days thereafter. The serum NOx levels increased 12 h after the administration of 5-HT, reaching a peak 24 h later. Gastric mucosal thiobarbituric acid (TEA) reactants and myeloperoxidase (MPO) activity were also significantly increased after 2 days treatment with 5-HT. Our results suggest that: (1) the repeated administration of 5- HT induced inflammatory gastric lesions in the rat stomach; (2) iNOS i s upreguated during 5-HT treatment, and NO produced by iNOS contribute s to development of gastric lesions in response to 5-HT, in addition t o the oxyradical formation; and (3) the deleterious role of NO in this model may be accounted for by a cytotoxic action of peroxynitrite tha t is formed in the presence of NO and superoxide radicals. (C) 1997 Th e Italian Pharmacological Society.