This study evaluated the properties of endogenous
nitric oxide synthases (NOS) and annexin-A1 (ANXA1) and determined how they can be exploited in the
N-methyl-N-nitro-N-nitrosoguanidine (
MNNG)-induced gastric
carcinogenesis and myenteric
denervation model. Male Wistar rats were treated with
MNNG and/or
aminoguanidine (AG) for 20 weeks. In another set of experiments, rats with nondenervated and denervated stomachs were treated with
MNNG or water for 28 weeks. Fragments of the pyloric region were processed for histopathology, NOS activity, and immunohistochemistry to explore the activity and expression of constitutive (cNOS) and inducible (iNOS)
NO synthase and their relationship with annexin-A1 (ANXA1) expression. NO inhibition by AG increased the percentage of animals with
adenocarcinomas (~29%) compared with the untreated
MNNG group (~4%). Myenteric
denervation did not alter NOS activity. cNOS activity was significantly greater in nondernervated and denervated stomachs with or without lesions (P<0.001) than iNOS activity (P<0.01), as confirmed by immunohistochemistry. Further, cNOS activity in normal stomachs and outside the lesion area was considerably higher than inside it (P<0.01). By densitometric analysis of nondenervated and denervated stomachs, ANXA1 expression was modulated in epithelial and inflammatory cells (mast cells and neutrophils), wherein significant alterations were induced by lesion development and myenteric
denervation. In conclusion, NO protects against the development of gastric
adenocarcinomas. The pattern of ANXA1 expression was not associated with NOS activity or expression, suggesting that NO and ANXA1 act in gastric
tumors in disparate pathways.