15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and quercetin-3--sulfate

Quercetin is anti-inflammatory in macrophages by inhibiting lipopolysaccharide (LPS)-mediated increases in cytokine and nitric oxide production but there is little information regarding the corresponding effect on the vasculature. We have examined the effect of quercetin, and its principal human metabolites, on inflammatory changes in the porcine isolated coronary artery.. Porcine coronary artery segments were incubated overnight at 37°C in modified Krebs-Henseleit solution with or without 1µg·mL(-1) LPS. Some segments were also co-incubated with quercetin-related flavonoids or Bay 11-7082, an inhibitor of NFκB. Changes in isometric tension of segments to vasoconstrictor and vasodilator agents were recorded. Nitrite content of the incubation solution was estimated using the Griess reaction, while inducible nitric oxide synthase was identified immunohistochemically.. Lipopolysaccharide reduced, by 35-50%, maximal contractions to KCl and U46619, thromboxane A(2) receptor agonist, and impaired endothelium-dependent relaxations to substance P. Nitrite content of the incubation medium increased 3- to 10-fold following exposure to LPS and inducible nitric oxide synthase was detected in the adventitia. Quercetin (0.1-10µM) opposed LPS-induced changes in vascular responses, nitrite production and expression of inducible nitric oxide synthase. Similarly, 10µM Bay 11-7082, 10µM quercetin 3'-sulphate and 10µM quercetin 3-glucuronide prevented LPS-induced changes, while myricetin (10µM) was inactive. Myricetin (10µM) prevented quercetin-induced modulation of LPS-mediated nitrite production.. Quercetin, quercetin 3'-suphate and quercetin 3-glucuronide, exerted anti-inflammatory effects on the vasculature, possibly through a mechanism involving inhibition of NFκB. Myricetin-induced antagonism of the effect of anti-inflammatory action of quercetin merits further investigation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Coronary Vessels; Cytokines; Flavonoids; In Vitro Techniques; Inflammation; Isometric Contraction; Lipopolysaccharides; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type II; Nitriles; Nitrites; Potassium Chloride; Quercetin; Sulfones; Swine

Quercetin is a major flavonoid that contributes to the reduced risk of cardiovascular disease associated with dietary ingestion of fruits and vegetables. We have pharmacologically characterized the effect of quercetin, and its sulphate and glucuronide metabolites, on vasoconstrictor and vasodilator responses in the porcine isolated coronary artery.. Segments of the porcine coronary artery were prepared for either isometric tension recording or determination of cyclic GMP content. The effect of quercetin and metabolites on submaximal responses to U46619 was examined in the presence and absence of substance P, bradykinin, forskolin, sodium nitroprusside (SNP) and glyceryl trinitrate (GTN).. Quercetin and quercetin 3'-sulphate inhibited endothelin and U46619-induced contractions with greater potency (three- to fivefold) against the former, while quercetin 3-glucoronide was inactive. Quercetin enhanced both the cyclic GMP content of the artery (threefold) and cyclic GMP-dependent relaxations to GTN and SNP (two to threefold), but forskolin-induced relaxations were unaffected. Although the effect of quercetin was qualitatively similar to that noted for UK-114,542, a selective inhibitor of phosphodiesterase 5, it was still evident against SNP-induced relaxations in the presence of 10 nM UK-114,542. Quercetin and quercetin 3'-sulphate significantly reduced the development of GTN-associated 'tolerance'.. Quercetin and quercetin 3'-sulphate inhibited receptor-mediated contractions of the porcine isolated coronary artery by an endothelium-independent action. Quercetin selectively enhanced cyclic-GMP-dependent relaxations by a mechanism not involving phosphodiesterase 5 inhibition. In addition, quercetin and quercetin 3'-sulphate opposed GTN-induced tolerance in vitro, which may be beneficial for patients treated for angina pectoris.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta, Thoracic; Arteries; Bradykinin; Coronary Vessels; Cyclic GMP; Drug Tolerance; Morpholines; Nitroglycerin; Nitroprusside; Pyrazoles; Pyrimidines; Quercetin; Sus scrofa; Swine; Vasoconstrictor Agents; Vasodilator Agents