Vicinal nitrohydroxyeicosatrienoic acids: vasodilator lipids formed by reaction of nitrogen dioxide with arachidonic acid.
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 approximately 20% by indomethacin and approximately 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/micromol) 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.
Balazy
M
M
Department of Pharmacology, New York Medical College, Valhalla, New York 10595, USA. Michael_Balazy@nymc.edu
Iesaki
T
T
Park
J L
JL
Jiang
H
H
Kaminski
P M
PM
Wolin
M S
MS
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D016718:Arachidonic Acid / Q000737:chemistry*; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D050356:Lipid Metabolism; D008055:Lipids / Q000138:chemical synthesis* / Q000494:pharmacology*; D008163:Luminescent Measurements; D008297:Male; D013058:Mass Spectrometry; D009119:Muscle Contraction / Q000187:drug effects; D020030:Nitric Oxide Donors / Q000138:chemical synthesis* / Q000494:pharmacology*; D009585:Nitrogen Dioxide / Q000737:chemistry*; D009595:Nitroparaffins / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000494:pharmacology*
D008055:Lipids; D020030:Nitric Oxide Donors; D009595:Nitroparaffins; D014665:Vasodilator Agents; D016718:Arachidonic Acid; D015126:8,11,14-Eicosatrienoic Acid; D009585:Nitrogen Dioxide