Role of prostaglandins and nitric oxide in gastric damage induced by metamizol in rats

Abstract:

Objective and design: In addition to the depletion of prostaglandins (PGs), oxygen free radicals generation and nitrogen species haven been implicated in non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastric injury. The aim of the present study was to examine changes in PGE₂ generation and its relationship with proinflammatory parameters and nitric oxide (NO) production in the comparative pathogenesis of gastric injury induced by metamizol vs. diclofenac, NSAIDs that present different gastric tolerability and cyclooxygenase (COX) inhibition profiles. Material: Studies were performed in Wistar-Han rats. Treatments: Metamizol (120, 500 and 1000 mg/kg body weight) and diclofenac (50 mg/kg body weight) were given by oral administration. Methods: Determinations were made of macroscopic and histological evaluation of gastric mucosal injury, gastric prostaglandin synthesis (PGE₂ levels), myeloperoxidase activity (MPO), tumor necrosis factor-alpha levels (TNF-α), cyclic guanosine monophosphate (cGMP), nitric oxide synthase activity (NOS) and NOS mRNA expression. Results: Metamizol, only at the highest doses assayed, provoked weak lesions in the gastric mucosa. To the contrary, diclofenac treatment presented the highest grade of lesion. All treatments decreased PGE₂ gastric generation. Treatment of the animals with metamizol neither modified the MPO activity nor TNF-α levels. In contrast, statistically significant increases in both parameters were observed after diclofenac administration. cGMP levels were not influenced with diclofenac treatment, nevertheless metamizol reduced the nucleotide levels, which was accompanied by an inhibition of constitutive NOS (cNOS) activity without modifying the mRNA expression of the enzyme. Conclusions: In addition to inhibition of PG synthesis, damage induced by metamizol was associated with an inhibition of the NO/cGMP pathway and cNOS activity. In contrast, diclofenac-induced gastric damage was associated with an increase of the inflammatory response.