Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 147, Issue 8, Pages 966-974Publisher
WILEY
DOI: 10.1038/sj.bjp.0706696
Keywords
nitric oxide; nitroflurbiprofen; flurbiprofen; hydrogen sulphide; lipopolysaccharide-induced endotoxic shock; interleukin-1 beta; tumour necrosis factor-alpha cystathionine gamma lyase
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1 The biosynthesis of both nitric oxide (NO) and hydrogen sulfide (H2S) is increased in lipopolysaccharide (LPS)-injected mice and rats but their interaction in these models is not known. In this study we examined the effect of the NO donor, nitroflurbiprofen (and the parent molecule flurbiprofen) on NO and H2S metabolism in tissues from LPS-pretreated rats. 2 Administration of LPS (10 mg kg-(1), i.p.; 6 h) resulted in an increase (P < 0.05) in plasma TNF-alpha, IL-1 beta and nitrate/nitrite (NOx) concentrations, liver H2S synthesis (from added cysteine), CSE mRNA, inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO) activity (marker for neutrophil infiltration) and nuclear factor-kappa B (NF-kappa B) activation. 3 Nitroflurbiprofen (3-30 mg kg(-1), i.p.) administration resulted in a dose-dependent inhibition of the LPS-mediated increase in plasma TNF-alpha, IL-1 beta and NOx concentration, liver H2S synthesis (55.00 +/- 0.95 nmole mg protein(-1), c.f. 62.38 +/- 0.47 nmole mg protein(-1), n = 5, P < 0.05), CSE mRNA, iNOS, MPO activity and NF-kappa B activation. 4 Flurbiprofen (21 mg kg(-1), i.p.) was without effect. 5 These results show for the first time that nitroflurbiprofen downregulates the biosynthesis of proinflammatory H2S and suggest that such an effect may contribute to the augmented anti-inflammatory activity of this compound. 6 These data also highlight the existence of 'crosstalk' between NO and H2S in this model of endotoxic shock.
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