title: 6-Methylnitroarachidonate: a novel esterified nitroalkene that potently inhibits platelet aggregation and exerts cGMP-mediated vascular relaxation.
abstract: Nitro-fatty acids represent endogenously occurring products of oxidant-induced nitration reactions. We have previously synthesized a mixture of four isomers of nitroarachidonic acid, a novel anti-inflammatory signaling mediator. In this study, we synthesized and chemically and biologically characterized for the first time an esterified nitroalkene derived from the nitration of methylarachidonate (AAMet): 6-methylnitroarachidonate (6-AAMetNO(2)). Synthesis was performed by reacting AAMet with sodium nitrite under acidic conditions. Analysis by mass spectrometry (positive-ion ESI-MS) showed an [M+H](+) ion of m/z 364, characteristic of AAMetNO(2). Fragmentation of this ion yielded a daughter ion at m/z 317, corresponding to the neutral loss of the nitro group ([M+H-HNO(2)](+)). Furthermore, IR signal at 1378 cm(-1) and NMR data confirmed the structure of a 6-nitro-positional isomer. This novel esterified nitroalkene was capable of promoting vascular protective actions including: (a) the induction of vasorelaxation via endothelium-independent mechanisms, associated with an increase in smooth muscle cell cGMP levels, and (b) a potent dose-dependent inhibition of human platelet aggregation. We postulate that 6-AAMetNO(2) could be a potential drug for the prevention of vascular and inflammatory diseases, and the presence of the methyl group may increase its pharmacological potential.
authors.affiliation: Department of Biophysics, Faculty of Chemistry Sciences, Universidad de República, 11800 Montevideo, Uruguay.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Blanco
authors.forename: Ana M
authors.initials: AM
authors.lastname: Ferreira
authors.forename: Gloria V
authors.initials: GV
authors.lastname: López
authors.forename: Lucía
authors.initials: L
authors.lastname: Bonilla
authors.forename: Mercedes
authors.initials: M
authors.lastname: González
authors.forename: Hugo
authors.initials: H
authors.lastname: Cerecetto
authors.forename: Andrés
authors.initials: A
authors.lastname: Trostchansky
authors.forename: Homero
authors.initials: H
authors.lastname: Rubbo
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001095:Arachidonic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011921:Rats, Inbred WKY; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001095:Arachidonic Acids; D020030:Nitric Oxide Donors; D010975:Platelet Aggregation Inhibitors; D014665:Vasodilator Agents; C557785:methyl 6-nitroarachidonate; D009569:Nitric Oxide; D006152:Cyclic GMP