Endothelium-independent vasodilator effects of the flavonoid quercetin and its methylated metabolites in rat conductance and resistance arteries

The flavonoid quercetin is metabolized into isorhamnetin, tamarixetin, and kaempferol, the vascular effects of which are unknown. In the present study, the effects of quercetin and its metabolites were analyzed on isometric tension in isolated rat thoracic and abdominal aorta, in isolated intact and beta-escin-permeabilized iliac arteries, and on perfusion pressure in the isolated mesenteric resistance vascular bed. In noradrenaline-precontracted vessels, the four flavonoids produced a vasodilator effect, which was inversely correlated with the diameter of the vessel studied; i.e., quercetin, isorhamnetin, tamarixetin, and kaempferol were 5-, 25-, 4-, and 6-fold, respectively, more potent in the resistance mesenteric bed (-log IC50 = 5.35 +/- 0.15, 5.89 +/- 0.11, 5.34 +/- 0.10, and 5.66 +/- 0.06, respectively) than in the thoracic aorta (-log IC50 = 4.68 +/- 0.08, 4.61 +/- 0.08, 4.73 +/- 0.11, and 4.81 +/- 0.13, respectively; n = 4- 6). The vasodilator responses of quercetin and isorhamnetin were not significantly modified after removal of the endothelium in the thoracic aorta or in the mesenteric bed. Furthermore, the guanylate cyclase inhibitor ODQ (1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one; 10(-6) M), the adenylate cyclase inhibitor SQ22536 [9-(tetrahydro-2-furanyl)-9H-purin-6-amine; 10(-6) M], KCl (40 mM), or ouabain (10(-3) M) had no effect on isorhamnetin-induced vasodilation in the mesenteric bed. In permeabilized iliac arteries stimulated with Ca2+ (pCa of 5.9), isorhamnetin was also significantly more potent (-log IC50 = 5.27 +/- 0.15) than quercetin (-log IC50 = 4.56 +/- 0.15). In conclusion, quercetin and its metabolites showed vasodilator effects with selectivity toward the resistance vessels. These effects are not due to or modulated by endothelial factors and are unrelated to changes in cytosolic Ca2+.