Contribution of interaction between nitric oxide and cyclooxygenases to the production of prostaglandins in carrageenan-induced inflammation.
BACKGROUND: Nitric oxide (NO) and prostaglandins (PGs) are crucial mediators contributing to generation of inflammatory responses and pain. This study was designed to investigate the effects of peripherally released NO on cyclooxygenase (COX) expression/activation and production of PGs in carrageenan-induced inflammation. METHODS: A microdialysis probe was implanted subcutaneously into the skin of hind paws of rats. The concentrations of NO metabolites, PGE2, and 6-keto-PGF1alpha (metabolite of PGI2) in the dialysate were measured. Carrageenan was injected into the plantar surface of the hind paw during perfusion of the dialysis catheter with modified Ringer's solution or N-monomethyl-L-arginine acetate. In addition, the effects of the selective COX-1 inhibitor SC-560 and the selective COX-2 inhibitor NS-398 on the production of NO, PGE2, and 6-keto-PGF1alpha were examined. Western blotting was performed to evaluate the expression of COX-1 and COX-2 in the skin at the site of the inflammation. RESULTS: Carrageenan injection resulted in increases in the concentrations of NO, PGE2, and PGI2, and these increases were completely suppressed by N-monomethyl-L-arginine acetate. SC-560 effectively inhibited the increase in PGE2 and PGI2 concentrations for the first 2 h, and NS-398 inhibited 3-6 h after carrageenan. Western blot analysis showed that the concentrations of both COX-1 and COX-2 in the skin increased after carrageenan. The up-regulation of COX-1 in the skin was observed 3 and 6 h after carrageenan and was not suppressed in the rats treated with N-monomethyl-L-arginine acetate. The up-regulation of COX-2 in the skin was also observed 3 and 6 h after carrageenan and was completely suppressed in the rats treated with N-monomethyl-L-arginine acetate. CONCLUSION: The results of the current study suggest that NO activates COX-1 in the early phase of carrageenan and up-regulates COX-2 expression in the late phase in the skin, resulting in production of PGE2 and PGI2 at the site of inflammation, which would contribute to exacerbation of the inflammatory process.[1]References
- Contribution of interaction between nitric oxide and cyclooxygenases to the production of prostaglandins in carrageenan-induced inflammation. Toriyabe, M., Omote, K., Kawamata, T., Namiki, A. Anesthesiology (2004) [Pubmed]
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