Effect of nitric oxide releasing paracetamol and flurbiprofen on cytokine production in human blood.

Exposure of anti-coagulated human blood to Escherichia coli lipopolysaccharide (50 ng/ml) resulted in the time-dependent (maximum at 5 h) biosynthesis of interleukin-1beta and tumour necrosis factor-alpha (TNF-alpha). Preincubation with nitroparacetamol or nitroflurbiprofen (but not paracetamol or flurbiprofen) caused dose-related inhibition of the formation of interleukin 1 beta (IC(50)s, 44.5 and 362 microM, n=12) and tumour necrosis factor-alpha (IC(50)s, 9.0 and 0.0009 microM, n=12). The inhibitory effect of nitroparacetamol was completely reversed by (2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H-imidazol-1-yloxy-3-oxide potassium (carboxy-PTIO, 100 microM; NO scavenging agent). Neither the nuclear factor-kappaB transduction inhibitor, pyrrolidinedithiocarbamate (10-1000 microM) nor the nitric oxide donor, 1-hydroxy-2-oxo-3-(3-aminopropyl)-3-isopropyl-1-triazene (NOC-5, 10-1000 microM), affected cytokine formation in these experiments.