Nitric oxide‐releasing flurbiprofen reduces formation of proinflammatory hydrogen sulfide in lipopolysaccharide‐treated rat

The biosynthesis of both nitric oxide (NO) and hydrogen sulfide (H 2 S) 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 H 2 S metabolism in tissues from LPS‐pretreated rats. Administration of LPS (10 mg kg −1 , i.p.; 6 h) resulted in an increase ( P <0.05) in plasma TNF‐ α , IL‐1 β and nitrate/nitrite (NO x ) concentrations, liver H 2 S synthesis (from added cysteine), CSE mRNA, inducible nitric oxide synthase (iNOS), myeloperoxidase (MPO) activity (marker for neutrophil infiltration) and nuclear factor‐kappa B (NF‐ κ B) activation. Nitroflurbiprofen (3–30 mg kg −1 , i.p.) administration resulted in a dose‐dependent inhibition of the LPS‐mediated increase in plasma TNF‐ α , IL‐1 β and NO x concentration, liver H 2 S 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‐ κ B activation. Flurbiprofen (21 mg kg −1 , i.p.) was without effect. These results show for the first time that nitroflurbiprofen downregulates the biosynthesis of proinflammatory H 2 S and suggest that such an effect may contribute to the augmented anti‐inflammatory activity of this compound. These data also highlight the existence of ‘crosstalk’ between NO and H 2 S in this model of endotoxic shock.British Journal of Pharmacology (2006) 147 , 966–974. doi: 10.1038/sj.bjp.0706696