Methods and Findings in Experimental and Clinical Pharmacology
Vol. 24, Suppl. A, 2002, pp. 59-60
ISSN 0379-0355
Copyright 2002 Prous Science, S.A.
CCC: 0379-0355/2002
http://www.prous.com

Effects of Flavonoids on Arterial Wall

J. Duarte

Department of Pharmacology, School of Pharmacy, University of Granada, Spain

Flavonoids comprise a large group of secondary metabolites occurring widely throughout the plant kingdom. These low molecular weight polyphenolic compounds are found in most parts of the plants, including fruit, nuts, seed, flowers and bark. They are an integral part of the human diet. The term flavonoid refers to a large group of chemical compounds that share the common skeleton of diphenylpyrans (C6-C3-C6). This basic structure allows a multitude of substitution patterns and variations, leading to several flavonoid classes, including flavonols, flavones, flavanones, catechins (or flavanols), anthocyanidins, isoflavones, dihydroflavonols and chalcones. Several epidemiological studies have found an inverse correlation between dietary flavonoid intake and coronary heart disease mortality and incidence of stroke. A wide range of biological actions of flavonoids including their antiaterogenic, antiaggregant, antiproliferative and vasodilator effects could be responsible for these protective effects (1).

Flavonoids, together with other antioxidants, constitute two lines of defense in protecting cells against injury owing to oxidation of LDL. At the LDL level, they inhibit LDL oxidation due to their free radical scavenger activity; at the cellular level, they protect the cells directly, i.e., by increasing their resistance against the cytotoxic effect of oxidized LDL. Furthermore, recent studies indicate that flavonoids can prevent the expression of adhesion and chemoattractant molecules (1).

The direct effects of flavonoids on vascular smooth muscle include alteration in vascular tone and structure. The in vitro vasodilator effects of flavonoids are mainly endothelium-independent. However some flavonoids, such as chrysin, evoke endothelium- and nitric oxide-dependent vasorelaxation. This latter effect is mediated by the prevention of superoxide-induced inactivation of endothelial derived NO and also by the potentiation of cGMP-induced vasodilatation (2). The relative potency of flavonoids to relax isolated vessels is related to the structure of the compound tested, with a relative order of: flavonol > flavone = isoflavone > flavanone > cathechin. The main structural features involved in the vasodilator activity are the presence of a 4-carbonyl group and a double linkage C2-C3 that gives a coplanar conformation of the benzopyran ring system. The pattern of hydroxylation is very important for the activity. In fact, flavonoids possessing three adjacent hydroxyl groups do not relax vessels previously contracted with agonists, but potentiate contractile response. Moreover, myricetin (3¢, 4¢, 5¢-thihydroxy) produce endothelium-dependent contractile responses due to endothelial stimulation of Ca²⁺ influx and subsequent phospholipase A₂ and cyclooxygenase activation releasing TXA₂ from endothelium to contract rat aortic rings. The latter response occurs via the activation of Tp receptors on vascular smooth muscle cells (1). Several mechanisms have been proposed for the vasodilator effects of flavonoids, including inhibition of Ca²⁺ influx, cyclic nucleotide phosphodiesterases and tyrosine kinases. However, the main mechanism of flavonoid-induced vasodilation results from the inhibition of protein kinases such as myosin light chain kinase and, possibly, other kinases involved in Ca²⁺-sensitizing mechanisms including protein kinase C (3).

Flavonoids show vasodilator effects with selectivity toward the arterial resistance vessels. Moreover, they also induce venous and coronary vasodilator effects, which may contribute to the protective effects of flavonoids in ischemic heart disease, as observed in epidemiological studies (3). Furthermore, quercetin inhibits human vascular smooth muscle cell proliferation and migration, concomitant with the inhibition of mitogen-activated protein kinase phosphorylation.

Little information about the in vivo effects of flavonoids on the arterial wall is available. Recently, the chronic oral administration of quercetin, the main dietary flavonoid, has been shown to exert potent antihypertensive effects in both spontaneously hypertensive rats (SHR) and chronic nitric oxide deficient rats. After 5 weeks of treatment, quercetin improved aortic endothelium-dependent relaxation to acetylcholine and tended to reduce the media:lumen ratio in mesenteric vessels from SHR. These effects were associated with a reduced oxidant status due to the antioxidant properties of the drug (4). Quercetin prevented endothelium-dependent vasoconstriction induced by acetylcholine secondary to TXA₂ release in aortae, and also renal vascular lesion (hyaline and proliferative arteriopathy) in chronic NO-deficient rats (5).

REFERENCES

1. Duarte, J., Pérez-Vizcaino, F., Jiménez, J., Tamargo, J., Zarzuelo, A. Studies in Natural Products Chemistry, vol 25, part F. Atta-Ur-Rahman (Ed.). Elsevier: Amsterdam, 565-605.

2. Duarte, J., Jiménez R., Villar, I.C., Pérez-Vizcaino, F., Jiménez, J., Tamargo, J. Vasorelaxant effects of the bioflavonoid chrysin in isolated rat aorta. Planta Med 2001, 67(6): 567-9.

3. Pérez-Vizcaino, F., Ibarra, M., Cogolludo, A.L. et al. 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.

4. Duarte, J., Pérez-Palencia, R., Vargas, F., et al. Antihypertensive effects of the flavonoid quercetin in spontaneously hypertensive rats. Br J Pharmacol 2001, 133: 117-24.

5. Duarte, J., Jiménez, R., O'Valle, F. et al. J Hypertension 2002 (in press).

Methods and Findings in Experimental and Clinical Pharmacology Vol. 24, Suppl. A, 2002, pp. 59-60
ISSN 0379-0355 Copyright 2002 Prous Science, S.A. CCC: 0379-0355/2002 http://www.prous.com