1. 6-Methylnitroarachidonate: a novel esterified nitroalkene that potently inhibits platelet aggregation and exerts cGMP-mediated vascular relaxation.
- Author
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Blanco F, Ferreira AM, López GV, Bonilla L, González M, Cerecetto H, Trostchansky A, and Rubbo H
- Subjects
- Animals, Aorta, Thoracic drug effects, Aorta, Thoracic physiology, Arachidonic Acids chemistry, Endothelium, Vascular drug effects, Endothelium, Vascular physiology, Humans, In Vitro Techniques, Male, Muscle, Smooth, Vascular drug effects, Muscle, Smooth, Vascular physiology, Nitric Oxide metabolism, Nitric Oxide Donors chemical synthesis, Nitric Oxide Donors chemistry, Nitric Oxide Donors pharmacology, Platelet Aggregation Inhibitors chemistry, Platelet Aggregation Inhibitors pharmacology, Rats, Rats, Inbred WKY, Vasodilation drug effects, Vasodilator Agents chemistry, Vasodilator Agents pharmacology, Arachidonic Acids chemical synthesis, Arachidonic Acids pharmacology, Cyclic GMP metabolism, Platelet Aggregation Inhibitors chemical synthesis, Vasodilator Agents chemical synthesis
- 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., (Copyright © 2010 Elsevier Inc. All rights reserved.)
- Published
- 2011
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