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Vol. 299, Issue 2, 611-619, November 2001
Departments of Pharmacology and Physiology, New York Medical
College, Valhalla, New York
Nitric oxide (NO)-derived species could potentially react with
arachidonic acid to generate novel vasoactive metabolites. We studied
the reaction of arachidonic acid with nitrogen dioxide (NO2), a free radical that originates from NO oxidation.
The reaction mixture contained lipid products that relaxed
endothelium-removed bovine coronary arteries. Relaxation to the lipid
mixture was inhibited ~20% by indomethacin and ~70% by a soluble
guanylate cyclase (sGC) inhibitor (ODQ). Thus, novel lipid products,
which activate sGC presumably through a mechanism involving NO,
appeared to have contributed to the observed vasorelaxation. Lipids
that eluted at 9 to 12 min during high-performance liquid
chromatography fractionation accounted for about one-half of the
vasodilator activity in the reaction mixture, which was inhibited by
ODQ. Lipid products in fractions 9 to 12 were identified by
electrospray tandem mass spectrometry to be eight isomers having
molecular weight of 367 and a fragmentation pattern indicative
of arachidonic acid derivatives containing nitro and hydroxy groups and
consistent with the structures of vicinal nitrohydroxyeicosatrienoic
acids. These lipids spontaneously released NO (183 ± 12 nmol
NO/15 min/µmol) as detected by head space/chemiluminescence analysis.
Mild alkaline hydrolysis of total lipids extracted from bovine cardiac
muscle followed by isotopic dilution gas chromatography/mass
spectrometry analysis detected basal levels of
nitrohydroxyeicosatrienoic acids (6.8 ± 2.6 ng/g tissue;
n = 4). Thus, the oxidation product of NO,
NO2, reacts with arachidonic acid to generate biologically active vicinal nitrohydroxyeicosatrienoic acids, which may be important
endogenous mediators of vascular relaxation and sGC activation.
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