Effects of the Flavonoid Quercetin and its Methylated Metabolite Isorhamnetin in Isolated Arteries from Spontaneously Hypertensive Rats

Abstract

Chronic oral quercetin exerts antihypertensive effects in spontaneously hypertensive rats (SHR). In the present study, the vasodilator effects of the flavonoid quercetin and its main metabolite isorhamnetin were analysed in isolated thoracic aorta, iliac artery and on the isolated perfused mesenteric resistance vascular bed from SHR and normotensive Wistar Kyoto rats (WKY). In noradrenaline-precontracted vessels from SHR there was an inverse correlation between the relaxant potency (pIC₅₀) of quercetin (4.76 ± 0.02, 5.08 ± 0.12, 5.30 ± 0.18, in aorta, iliac arteries and mesentery, respectively) and isorhamnetin (4.90 ± 0.11, 5.38 ± 0.15 and 5.80 ± 0.10, respectively) and the diameter of the vessel studied. Both flavonoids were more potent in endothelium-denuded aortae and iliac arteries from SHR than from normotensive WKY rats. In addition, in aortae from SHR both flavonoids restored the endothelial-dependent vasodilation. Isorhamnetin, but not quercetin, also reduced the endothelium-dependent contractile responses induced by acetylcholine. These direct vasodilator effects, together with the improvement of endothelial function, are good candidates to explain the blood pressure reduction and vascular protective effects of quercetin in animal models of hypertension and possibly in human cardiovascular diseases.

Abbreviations

pIC₅₀:Negative logarithm of the drug concentration which inhibited 50 % of the contractile response

S.E.M.:Standard error fo the mean

SHR:Spontaneously hypertensive rats

WKY:Wistar Kyoto normotensive rats

Quercetin - flavonoid - isorhamnetin - SHR - resistance vessels

References

• 1 Rice-Evans A, Packer L. Flavonoids in health and disease. New York; Marcel Dekker Inc 1998
• 2 Sampson L, Rimm E, Hollman PC de Vries J H, Katan M B. Flavonol and flavone intakes in US health professionals.  J Am Diet Assoc. 2002;  102 1414-20
• 3 Hertog M G, Feskens E J, Hollman P C, Katan M B, Kromhout D. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study.  Lancet. 1993;  342 1007-11
• 4 Hirvonen T, Pietinen P, Virtanen M, Ovaskainen M L, Hakkinen S, Albanes D, Virtamo J. Intake of flavonols and flavones and risk of coronary heart disease in male smokers.  Epidemiology. 2001;  12 62-7
• 5 Yochum L, Kushi L H, Meyer K, Folsom A R. Dietary flavonoid intake and risk of cardiovascular disease in postmenopausal women.  Am J Epidemiol. 1999;  49 943-9
• 6 Middleton E J r, Kandaswami C, Theoharides C T. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer.  Pharmacol Rev. 2000;  52 673-751
• 7 Hollman P C, Katan M B. Health effects and bioavailability of dietary flavonols.  Free Radic Res. 1999;  31 (Suppl) S75-80
• 8 Feng Q, Kumagai T, Torii Y, Nakamura Y, Osawa T, Uchida K. Anticarcinogenic antioxidants as inhibitors against intracellular oxidative stress.  Free Radic Res. 2001;  35 779-88
• 9 Duarte J, Perez-Vizcaino F, Jimenez J, Zarzuelo A, Tamargo J. Flavonoids and cardiovascular diseases. In: Atta-Ur-Rahman A, editors Studies in Natural Products Chemistry. Vol 25 Amsterdam; Elsevier 2001: pp. 565-603
• 10 Duarte J, Perez-Palencia R, Vargas F, Ocete M A, Perez-Vizcaino F, Zarzuelo A, Tamargo J. Antihypertensive effects of the flavonoid quercetin in spontaneously hypertensive rats.  Br J Pharmacol. 2001;  133 117-24
• 11 Duarte J, Perez-Vizcaino F, Zarzuelo A, Jimenez J, Tamargo J. Vasodilator effects of quercetin on isolated rat vascular smooth muscle.  Eur J Pharmacol. 1993;  239 1-7
• 12 Duarte J, Perez-Vizcaino F, Zarzuelo A, Jimenez J, Tamargo J. Vasodilator effects of flavonoids in rat aortic smooth muscle. Structure-activity relationships.  Gen Pharmacol. 1993;  24 857-62
• 13 Ibarra M, Perez-Vizcaino F, Cogolludo A, Duarte J, Zaragoza-Arnaez F, Lopez-Lopez J G, Tamargo J. Cardiovascular effects of isorhamnetin and quercetin in isolated rat and porcine vascular smooth muscle and isolated rat atria.  Planta Med. 2002;  68 307-10
• 14 Chan E C, Pannangpetch P, Woodman O L. Relaxation to flavones and flavonols in rat isolated thoracic aorta: mechanism of action and structure-activity relationships.  J Cardiovasc Pharmacol. 2000;  35 326-33
• 15 Chen C K, Pace-Asciak C R. Vasorelaxing activity of resveratrol and quercetin in isolated rat aorta.  Gen Pharmacol. 1996;  27 263-6
• 16 Rendig S V, Symons J D, Longhurst J C, Amsterdam E A. Effects of red wine, alcohol, and quercetin on coronary resistance and conductance arteries.  J Cardiovasc Pharmacol. 2001;  38 219-27
• 17 Perez-Vizcaino F, Ibarra M, Cogolludo A L, Duarte J, Zaragoza-Arnaez F, Moreno L, Lopez-Lopez G, Tamargo J. Endothelium-independent vasodilator effects of the flavonoid quercetin and its methylated metabolites in rat conductance and resistance arteries.  J Pharmacol Exp Ther. 2002;  302 66-72
• 18 Yin K, Chu Z M, Beilin L J. Blood pressure and vascular reactivity changes in spontaneously hypertensive rats fed fish oil.  Br J Pharmacol. 1991;  102 991-7
• 19 Scalbert A, Williamson G. Dietary intake and bioavailability of polyphenols.  J Nutrition. 2000;  130 2073S-85S
• 20 Vanhoutte P M. Endothelial dysfunction in hypertension.  J Hypertension. 1996;  14 S83-S93
• 21 Grunfeld S, Hamilton C A, Mesaros S, McClain S W, Dominiczak A F, Bohr D F, Malinski T. Role of superoxide in the depressed nitric oxide production by the endothelium of genetically hypertensive rats.  Hypertension. 1995;  26 854-7
• 22 Yang D, Feletou M, Levens N, Zhang J N, Vanhoutte P M. A diffusible substance(s) mediates endothelium-dependent contractions in the aorta of SHR.  Hypertension. 2003;  41 143-8