Administration of selective and nonselective
cyclooxygenase (COX)-2 inhibitors to
rheumatoid arthritis patients taking low doses of
acetylsalicylic acid (ASA) for cardiovascular prevention associates with increased risk of gastrointestinal
bleeding. The present study was undertaken to investigate whether administration of
HCT-3012 [(
S)-6-methoxy-alpha-methyl-2-naphthaleneacetic
acid 4-(nitrooxy)butyl
ester], a
nitric oxide (NO)-releasing derivative of
naproxen, exacerbates gastric mucosal injury in arthritic rats administered low doses of ASA. Our results demonstrated that while treating arthritic rats with a dose of 30 mg/kg/day ASA causes detectable mucosal injury, but had no effect on
arthritis score and
interleukin-6 plasma levels, coadministration of
naproxen (10 mg/kg/day) and
celecoxib (30 mg/kg/day), in combination with ASA from day 7 to day 21, attenuates
arthritis development (P <0.01 versus
arthritis alone), but markedly enhanced gastric mucosal damage caused by ASA (P <0.01 versus ASA alone). In contrast, coadministration of
HCT-3012 (15 mg/kg/day) significantly attenuated
arthritis development, because
HCT-3012 was equally or more effective than
naproxen and
celecoxib in attenuating local and systemic
inflammation (P >0.001 versus
arthritis) without exacerbating gastric mucosal injury caused by ASA.
Arthritis development associates with gastric COX-2 induction,
mRNA and
protein, and enhanced gastric
prostaglandin E2 (
PGE2) synthesis (P <0.01 versus control rats). Although all treatments, including
celecoxib, were effective in reducing gastric
PGE2 synthesis, administering arthritic rats with ASA resulted in a significant increase in gastric content of
aspirin-triggered
lipoxin (ATL), a COX-2-derived
lipid mediator that regulates proinflammatory responses at the neutrophils/endothelial interface. Administering arthritic rats with
naproxen and
celecoxib abrogates ATL formation induced by ASA although enhanced neutrophils accumulate into the gastric mucosa (P <0.01 versus ASA alone). In contrast, whereas
HCT-3012 inhibited ATL formation, it did not increase neutrophil recruitment into the gastric microcirculation. Collectively, these data indicate that
HCT-3012 derived from NO has the potential to compensate for inhibition of
PGE2 and ATL and to protect the gastric mucosa by limiting the recruitment of neutrophils. These data suggest that
HCT-3012 might be a safer alternative to nonsteroidal anti-inflammatory drugs and
coxibs in rheumatic patients that take low doses of ASA.