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


METHODS
Studies were performed in Wistar-Han rats.


METHODS
Metamizol (120, 500 and 1,000 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-a), 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-alpha 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.
Sánchez
S
S
Departamento de Farmacologia, Facultad de Farmacia, Universidad de Sevilla, Spain.
Martín
M J
MJ
Ortiz
P
P
Motilva
V
V
Herrerías
J M
JM
Alarcón de la Lastra
C
C
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D004008:Diclofenac / Q000494:pharmacology; D004177:Dipyrone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011453:Prostaglandins; D014409:Tumor Necrosis Factor-alpha; D004008:Diclofenac; D009569:Nitric Oxide; D004177:Dipyrone; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP