Vasodilator effects of quercetin and its relationship with the oxidative status in isolated rat aortic rings F. Vargas-Macciucca, L. Moreno, A. Cogolludo, J. Tamargo & F. Perez-Vizcaino. Dept. Farmacología. Fac. Medicina. U Complutense. 28040 Madrid.

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Epidemiological studies have shown an inverse association between dietary flavonoid intake and mortality from coronary heart disease (Hertog et al., 1993). Interestingly, the most abundant flavonoid, quercetin, exerts vasodilator and antioxidant effects (Middleton et al., 2000), and reduces blood pressure, cardiac, vascular and renal structural and functional changes and oxidative status in SHR and NO-deficient rats (Duarte et al., 2001). In the present study, we have analysed the vasodilator effect of quercetin and its relationship with the vascular oxidative status in isolated rat aortic rings.

Endothelium denuded thoracic aortic rings (2-3 mm in length) from male Wistar rats were mounted in Krebs solution for isometric recording of contractile force. Rings were stimulated by 10^-6M phenylephrine, then exposed to different treatments for 20 min and, finally, a concentration-response curve was constructed by cumulative addition of quercetin (10^-6M-10^-4M). Quercetin oxidation in Krebs oxygenated buffer and its protection by drugs was analysed by its UV-VIS absorption spectra.

Quercetin-induced a concentration-dependent relaxation in aortic rings (Table 1, Ctrl) which at the maximal concentration tested (10M^-4) averaged 89 ± 3% of the phenylephrine-induced contraction (initial tension was 1591 ± 131 mg). Quercetin-induced vasodilation was endothelium-independent and unaffected by the NOS inhibitor L-NAME (10^-4M) or the guanylate cyclase inhibitor ODQ (10^-6M). Quercetin (10^-5M) significantly auto-oxidized in Krebs solution bubbled with 95% O₂within 20 min as followed by reduced absorption at 380 nm. Superoxide dismutase (SOD, 100 u/ml) , vitamin C (10^-4M) or bubbling with 95% N₂ (HYP) which prevented quercetin oxidation, potentiated quercetin-induced vasodilation (Table 1). In addition, drugs which reduced H₂O₂ concentration in the tissue, such as catalase (500 u/ml, CAT), horseradish peroxidase (50 µg ml^-1, PER), or diehtyl-dithiocarbamate (DETC, 1 mM), or which prevented H₂O₂-driven OH· production such as deferoxamine (10^-2M, DEF), potentiated quercetin-induced vasodilation. SOD-, CAT- and DETCA-induced potentiation could be inhibited by L-NAME (10^-4M) or ODQ (10^-6M). The effects of CAT were inhibited by the iNOS inhibitor 1400W (10^-5M). In contrast, Tiron (10^-2M), which increases tissue H₂O₂, significantly inhibited quercetin-induced relaxation.

Table 1. pIC50 values of the vasodilator effect of quercetin.

Means ± s.e. means (n). * P < 0.05; ,** P< 0.01, Students' t test.

In conclusion, quercetin-induced vasodilation is modulated by conditions of oxidative stress. Drugs which limit quercetin auto-oxidation or drugs reducing tissue H₂O₂ formation potentiate quercetin-induced vasodilation. The latter potentiation operated via an iNOS-dependent mechanism.

Duarte, J. et al., (2001). Br. J. Pharmacol. 133, 117-124.
Hertog, M.G. et al., (1993). Lancet 342, 1007-1011.
Middleton, E. et al., (2000). Pharmacol. Rev. 52, 673-751.