cyclic-gmp and nitroflurbiprofen

Nitric oxide (NO) has been identified an important neurotransmitter involved in the control of the human urinary tract. It has been suggested that NO is one of the factors keeping the bladder relaxed during the filling phase. This function might be mediated by the NO-induced elevation of intracellular cyclic GMP. Prostaglandins (PG) are known to exert contractile effects on the bladder smooth musculature, especially in pathological conditions. The aim of the present study was to examine the effects of a new class of NO donor drugs, combining both anti-phlogistic and NO-donating activity (NCX 2111 and HCT 1026), on the contraction induced by PG or electrical field stimulation (EFS) of isolated human detrusor. Effects were compared to those of sodium nitroprusside (SNP), forskolin, tolterodine, and oxybutynin. Using the organ bath technique, drug effects on the contraction induced by PG ((F2 alpha)) or EFS of isolated human detrusor smooth muscle were investigated. Detrusor strips were also exposed to increasing concentrations of the compounds (0.1 microM - 10 microM) and the accumulation of cyclic GMP and cyclic AMP was determined by means of radioimmunoassays. The tension induced by PG was dose-dependently reversed by the drugs. The rank order of efficacy was: forskolin > SNP > NCX 2111 > HCT 1026. R(max) values ranged from 57% (forskolin) to 24% (HCT 1026). Compounds also dose-dependently reduced the amplitudes of contraction induced by EFS (tolterodine > oxybutynin > NNP = forskolin > HCT 1026 > 2111). The effects of forskolin, HCT 1026, NCX 2111 and SNP were paralleled by an increase in cyclic AMP or cyclic GMP. Our results provide evidence that the NO-cGMP pathway is not of utmost significance in the control of human detrusor smooth muscle. In vitro, the combination of NO-donating with anti-phlogistic activity does not seem to be of functional advantage with regard to the facilitation of detrusor relaxation.

Topics: Anti-Infective Agents; Cyclic GMP; Flurbiprofen; Humans; In Vitro Techniques; Muscle, Smooth; Nitric Oxide; Urinary Bladder, Overactive

Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat the condition of rheumatoid arthritis, where levels of prostaglandin E2 (PGE2) and granulocyte macrophage-colony stimulating factor (GM-CSF) are elevated in the synovial fluid. NO-NSAIDs are a new class of cyclooxygenase (COX)-inhibitors developed by coupling a nitric oxide (NO)-donating moiety to conventional NSAIDs. We show that, in cytokine-treated synoviocytes (from non-rheumatic patients), NO-naproxen and NO-flurbiprofen like their parent compounds concentration-dependently reduce the levels of PGE2 (an index of COX-2 activity), with a corresponding rise in the release of GM-CSF. Unlike acetylsalicylic acid (ASA), NO-ASA reduces the levels of PGE2, without increasing GM-CSF release, although cell viability is reduced at the highest concentration (1 mM). The effects of NSAIDs and NO-NSAIDs on GM-CSF release were attributable to the PGE2 mediated cyclic (c) AMP pathway because PGE2 reversed the effects of COX blockade. Second, phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine (IBMX) and Ro-201724 (both of which elevate cAMP levels) decreased GM-CSF release, in the presence of PGE2. Finally, neither sodium nitroprusside nor zaprinast (both of which elevate cGMP levels) affected GM-CSF or PGE2 release. Our findings demonstrate that GM-CSF is regulated by NSAIDs and NO-NSAIDs via inhibition of COX and appears to be mediated via the cAMP pathway. NO-ASA is the exception, because it does not increase GM-CSF release, although at millimolar concentrations cell viability is reduced.

Topics: 1-Methyl-3-isobutylxanthine; 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Blotting, Western; Cells, Cultured; Cyclic AMP; Cyclic GMP; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Dose-Response Relationship, Drug; Flurbiprofen; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Indomethacin; Membrane Proteins; Naproxen; Nitric Oxide Donors; Nitroprusside; Phosphodiesterase Inhibitors; Prostaglandin-Endoperoxide Synthases; Purinones; Synovial Membrane; Time Factors