Chemical evaluation of compounds as nitric oxide or peroxynitrite donors using the reactions with serotonin.
The aim of this work was to assess the capacities of some .NO-donors to release .NO, and consequently NOx in aerobic medium, or to give peroxynitrite. The method was based on the differential reactivity of serotonin (5-HT) with either NO(x) or peroxynitrite, leading in phosphate-buffered solutions to 4-nitroso- and 4-nitro-5-HT formation, respectively. Yields and formation rates of 5-HT derivatives with .NO-donor were compared to those obtained with authentic .NO or peroxynitrite in similar conditions. Aside from the capacity of diazenium diolates (SPER/NO and DEA/NO) to release .NO spontaneously, converting 5-HT exclusively to 4-nitroso-5-HT, all other .NO donors must undergo redox reactions to produce .NO. S-nitrosoglutathione (GSNO) and sodium nitroprusside (SNP) modified 5-HT only in the presence of Cu2+, GSNO yielding 6 times more 4-nitroso-5-HT than SNP. Furthermore, in the presence of Cu+, the yield of .NO-release from GSNO was 45%. The molsidomine metabolite (SIN-1), which was presumed to release both .NO and O2(7-) at pH 7.4, reacted with 5-HT differently, depending on the presence of reductant or oxidant. Under aerobic conditions, SIN-1 acted predominantly as a 5-HT oxidant and also as a poor .NO and peroxynitrite donor (15% yield of .NO-release and 14 % yield of peroxynitrite formation). The strong oxidant Cu2+, even in the presence of air oxygen, accelerated oxidation and increased .NO release from SIN-1 up to 86%. Only a small part of SIN-1 gave simultaneously .NO and O2(7-) able to link together to give peroxynitrite, but other oxidants could enhance .NO release from SIN-1.
Institut de Chimie des Substances Naturelles, C.N.R.S., Avenue de la Terrasse, F-91198 Gif sur Yvette (France).
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D000332:Aerobiosis; D002851:Chromatography, High Pressure Liquid; D003300:Copper / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009566:Nitrates / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009574:Nitro Compounds / Q000032:analysis; D009599:Nitroprusside / Q000494:pharmacology; D009603:Nitroso Compounds / Q000032:analysis / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D026422:S-Nitrosoglutathione; D012701:Serotonin / Q000032:analysis / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
C115053:4-nitro-5-HT; C115054:4-nitroso-5-HT; D009566:Nitrates; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D009603:Nitroso Compounds; D016877:Oxidants; D009599:Nitroprusside; C039642:peroxynitric acid; D009569:Nitric Oxide; D012701:Serotonin; D014443:Tyrosine; D026422:S-Nitrosoglutathione; C002385:linsidomine; D003300:Copper; D008981:Molsidomine; D005978:Glutathione