Cardiovascular Research 63 (2004) 593 – 602

www.elsevier.com/locate/cardiores

Review
Vascular effects of wine polyphenols
Mario Dell’Agli *, Alessandra Buscialà, Enrica Bosisio
Faculty of Pharmacy, Department of Pharmacological Sciences, Via Balzaretti, 9-20133 Milan, Italy
Received 30 January 2004; received in revised form 4 March 2004; accepted 23 March 2004
Available online 6 May 2004
Time for primary review 20 days

Abstract

Moderate consumption of red wine has been putatively associated with lowering the risk of developing coronary heart disease. This
beneficial effect is mainly attributed to the occurrence of polyphenol compounds such as anthocyanosides (ACs), catechins,
proanthocyanidins (PAs), stilbenes and other phenolics in red wine. This review focuses on the vascular effects of red wine polyphenols
(RWPs), with emphasis on anthocyanosides and proanthocyanidins. From in vitro studies, the effect of red wine polyphenols on the vascular
tone is thought to be due to short- and long-term mechanisms. NO-mediated vasorelaxation represents the short-term response to wine
polyphenols, which exert the effect by increasing the influx of extracellular Ca2 +, and the mobilization of intracellular Ca2 + in endothelial
cells. Polyphenolic compounds may also have long-term properties, as they increase endothelial NO synthase expression acting on the
promoter activity. In addition, they decrease the expression of adhesion molecules and growth factors, involved in migration and proliferation
of vascular smooth muscle cells. Moreover, they inhibit platelet aggregation. However, a paucity of data as regards the bioavailability and
metabolism of these compounds in human studies is a limiting factor to proving their efficacy in vivo.
D 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Keywords: Red wine polyphenols; Atherosclerosis; Endothelial function; Signal transduction; Vasodilation

1. Introduction
For many numbers of years, considerable attention has
been directed towards human behavioural habits that could
either be considered risk factors or even protective elements
for developing chronic pathologies. In particular, much effort
has been devoted to elucidate the role of diet in preventing
cardiovascular diseases. A so-called ‘‘Mediterranean diet’’ is
thought to prevent cardiovascular diseases [1], as a conse-
quence of its high content of antioxidants, which are crucial in
ameliorating oxidative events implicated in many diseases.
Similarly, moderate consumption of red wine has been
associated with a lowering of the risk of coronary heart
disease [2 –4]. Red wine represents a rich source of poly-
phenols such as anthocyanosides (ACs), catechins, proantho-
cyanidins (PAs), stilbenes and other phenolics. Antho-
cyanosides (ACs) are flavonoids widely distributed in fruits
and vegetables. They provide colour to red wines and to skins
of red and black grapes [5]. Proanthocyanidins are another
class of plant phenol metabolites widely occurring in fruits
including grapes [6]. ACs and PAs are among the most
important compounds in determining the quality of the red
wine, because they greatly influence colour, bitterness, as-
tringency, and chemical stability toward oxidation [7].
In addition to antioxidant/antiradical activity, red wine
polyphenols (RWPs) were shown to possess many biological
properties including the inhibition of platelet aggregation,
vasorelaxing activity, modulation of lipid metabolism, and
inhibition of low-density lipoprotein oxidation [2,3,8 –11].
Thus, the health benefits of moderate consumption of red
wine are founded on a multiplicity of actions. The biological
properties of red wine stilbenes (trans-resveratrol) have been
extensively reviewed [12 – 14]. Because ACs and PAs exert
cardioprotective effects which are not only due to antioxidant/
antiradical activity, the present review will consider the
effects of ACs and PAs at vascular level with special emphasis
on the vasorelaxing and the antiaggregating properties.
2. Proanthocyanidins and anthocyanosides in red grapes
(Vitis vinifera) and wines

* Corresponding author. Tel.: +39-02-50318345; fax: +39-02-50318391. PAs (or so-called condensed tannins) are high-molecular
E-mail address: mario.dellagli@unimi.it (M. Dell’Agli). weight polymers, made of flavan-3-ol units (Fig. 1) linked

0008-6363/$ - see front matter D 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.cardiores.2004.03.019
594 M. Dell’Agli et al. / Cardiovascular Research 63 (2004) 593–602

Fig. 1. Basic structure of proanthocyanidins: R1, R2 = H, propelargonidins;

R1 = H, R2 = OH, procyanidins; R1, R2 = OH, prodelphinidins.

together by carbon –carbon bonds. Oxidative condensation

occurs between carbon C4 of the heterocycle and C6 or C8
of the adjacent units. The flavan-3-ol unit may have a 3V,4V
dihydroxy substitution on ring B (catechin and epicatechin)
and 3V,4V,5V trihydroxy substitution (gallocatechin and epi-
gallocatechin). The term procyanidins indicates the poly-
mers of catechin and epicatechin, the term prodelphinidins
indicates the polymers made by gallocatechin and epigallo- Fig. 3. Structure of procyanidins B5 – B8.
catechin. Dimers, trimers (among which procyanidin C1 is
the most abundant), tetramers and oligomers up to 8 units
are present in grape (V. vinifera L.) seeds, stems, and skins tion of complex mixture of grape seed extracts and in
[6]. The procyanidin dimers B1 –B4, characterized by the beverages [8,15 –17].
4 ! 8 linkage, are the most common in grapes (Fig. 2). The ACs are water-soluble plant pigments, localized in the
corresponding 4 ! 6 linked isomers B5 – B8, may also skin of the berries of red grape cultivars. The term ACs (or
occur (Fig. 3). Until recently, complete characterization of anthocyanins) refers to the glycosides of anthocyanidins
PAs in grapes and wines has been impaired because of the (free aglycons). ACs may be acylated on the sugar moiety
difficulty of analysing high-molecular weight compounds. with aromatic and aliphatic acids. The 3-O-h-glucosides of
However, newly developed methods based on HPLC cou- cyanidin, peonidin, delphinidin, petunidin and malvidin are
pled with mass spectrometry has allowed the characteriza- the most abundant in V. vinifera and red wines (Fig. 4).

Fig. 2. Structure of procyanidins B1 – B4.

 M. Dell’Agli et al. / Cardiovascular Research 63 (2004) 593–602
Fig. 4. Structure of the ACs of red wines.
The six-hydroxyl of the glucose may be acylated with
acetyl, coumaroyl and caffeoyl groups. During storage and
aging of red wines, ACs react with PAs to produce more
complex pigments which may partially precipitate [8]. The
AC content of red wines may be estimated using a pH
shift method adapted from Ribéreau-Gayon and Stone-
street [18] where, at pH < 1, ACs are easily detected in
their red flavylium form. ACs are then quantified spec-
trophotometrically as malvidin-3-glucoside equivalents,
using the extinction coefficient e = 28,000. Alternatively,
ACs are separated from the other polyphenols and directly
quantified by their maximal absorbance in the visible
range (536 – 542 nm) [7]. Very recently, a capillary zone
electrophoresis method for the quantitative determination
of ACs in wine has been validated as alternative to HPLC
[19].
Because of their unstability, free aglycons of ACs are
never found in grape or wine, except in trace quantities. The
levels of ACs and PAs are highly variable due to differences
in fruit source (cultivars of V. vinifera) and wine processing
[20]. According to this author, a representative content of
ACs is 400 mg/l in a red wine less than 6 months of age, not
having fermented in oak barrels, and 90 mg/l in a red wine
aged for about 2 years or fermented in oak barrels. White
wines contain only trace amounts. Red wine contains greater
amounts of PAs (750 and 1000 mg/l, young and aged
respectively) vs. white wines (20 – 25 mg/l). The content
of extractable PAs (1600 – 4300 mg/kg of grape) and ACs
(300 –1900 mg/kg of grape) in different cultivars grown in
Italy was reported by Mattivi et al. [7]. Burns et al. [21]
reported the total phenol content in 16 red wines selected to
provide a range of origins, grape varieties and vinification
methods. Total AC levels, measured using a colorimetric
assay ranged from 101 to 325 AM (expressed as malvidin 3-
glucoside equivalents).
595
3. Red wine polyphenols as protective agents against
atherogenesis
Dysfunction of the vascular endothelial cells, and prolif-
eration and migration of smooth muscle cells are among the
factors contributing to atherosclerosis. Vascular endothelium
synthesises and releases nitric oxide (NO), which in turns,
promotes vasorelaxation (endothelium-dependent), reduces
platelet aggregation, and limits the flux of atherogenic
plasma proteins into the artery wall (Fig. 5). The vaso-
relaxant effect of NO occurs through the activation of
guanyl cyclase leading to the accumulation of cGMP [22].
The interaction between wine polyphenols and cell metab-
olism in the vascular tissue has been extensively investigat-
ed. These studies aimed to support for the beneficial effects
of wine consumption in preventing cardiovascular diseases.
In several animal models, the administration of red wine,
grape juice, dealcoholized red wine and PAs extract from
grape seeds attenuated the development of atherosclerotic
lesions [23 –26]. In a pig model, the consumption of RWPs
induced a partial reduction of thickness of intimal prolifer-
ation even if not statistically significant [27]. Several
processes of vascular reactivity seem to be influenced by
wine ingredients. Red wine supplementation modulated
haemostatic function and prevented thrombosis in experi-
mental animals [10,28,29]. Wine polyphenols were shown
to modulate blood pressure, promote vasodilatation, inhibit
smooth muscle cell migration and proliferation, and inhibit
platelet aggregation.
3.1. Red wine polyphenols and vasorelaxation
Red wines and grapes exhibit endothelium-dependent
relaxation of blood vessels via enhanced generation and/or
increased biological activity of NO, leading to the elevation
of cGMP levels [30,31,35,36]. In vivo RWPs were shown to
reduce blood pressure in normo and hypertensive rats
[33,34,37]. The administration of purple grape juice im-
proved the endothelium dependent, flow-mediated vasodi-
lation in coronary artery disease patients with impaired
endothelial function [38].
The amplitude of vasorelaxation changed as a function of
the variability of wine constituents according to grape
varieties, area of cultivation, and vinification methods.
Consequently, the vasodilatatory effect does not apply to
all wines and the degree of vasorelaxation is correlated to
the content and type of phenols. Endothelium-dependent
relaxation was greatest for red wines produced ‘‘en barri-
que’’, a procedure leading to high concentration of phenolic
compounds [32]. A correlation between the phenolic content
with vasodilatatory effect was later confirmed by Burns et
al. [21]. Sixteen red wines were selected to provide a range
of origins, grape varieties, and vinification methods. The
ability of the wines to act both as vasodilators ex vivo, and
as antioxidants in vitro was strongly correlated with the
phenolic content of wines. In addition, while the antioxidant
596 M. Dell’Agli et al. / Cardiovascular Research 63 (2004) 593–602
Fig. 5. Protective effects of red wine polyphenols on the arterial wall.
activity was associated with different classes of phenols
(gallic acid, resveratrol and catechins), vasodilatation activ-
ity was correlated only with the total content of ACs [21].
Investigations devoted to characterize the RWPs responsible
for the endothelium-dependent relaxation activity [35,39 –
42] agree that monomeric catechins and simple phenols
(benzoic acid, gallic acid and hydroxycinnamic acids) are
devoid of effect. On the contrary, AC enriched fractions and
oligomeric PAs (dimers, trimers and tetramers) were the
active compounds. Threshold for relaxation by PAs
oligomers was between 0.5 and 4 Ag/ml [35,42]. Much
higher concentration (>0.1 mg/l) were required for ACs
[41]. The endothelium-dependent relaxation activity was
lost when higher molecular weight polymers were assayed
[41]. RWPs enhanced NO synthesis and cGMP accumula-
tion only in the presence of functional endothelium. In
denuded aortic rings, RWPs concentration 103-fold higher
was necessary to induce relaxation [43,45].
Besides NO, red wine affected the formation of other
mediators of vascular tone, such as endothelium-derived
hyperpolarizing factor [43] and prostacyclin [44]. In addi-
tion, the synthesis of a potent vasoconstrictor such as
endothelin-1 is reduced by red wine in bovine aortic
endothelial cells. The suppression occurred at transcriptional
level. The decreased synthesis of endothelin-1 was associ-
ated with the inhibition of tyrosine kinase family of phos-
phorylating enzymes. The effect was correlated with the
polyphenol content of red wine [45].
The mechanisms underlining NO-dependent vasorelax-
ation caused by RWPs were investigated [36,46,47]. All
studies support for an increase in intracellular Ca2 + as the
critical step for the activation of NO-synthase. RWPs
increased cytosolic free Ca2 + by enhancing extracellular
Ca2 + entry and by increasing Ca2 + mobilization from
intracellular stores. The authors suggested that Ca2 + signal-
ling pathways leading to NO production could involve the
activation of multiple cellular targets (G-proteins, phospho-
lipase C, tyrosine kinase), depending on the composition of
the polyphenol mixture. In addition to increased NO syn-
thase activity, RWPs may prolong the half-life and increase
the bioavailability of NO, by reducing its degradation
mediated by reactive oxygen species [27].
3.2. Modulation of gene expression by red wine polyphenols
All events previously described are responsible for a
short-term response mediated by RWPs. Recent studies
pointed out that polyphenolic compounds from several
sources may also have long-term properties, as they are
able to modulate gene expression in different cancer cell
lines and in macrophages [48 – 50].
RWPs significantly increased NO synthase expression,
acting on the promoter activity [51]. Thus, polyphenols not
only activate the enzyme, but also increase its levels, which
might lead to a long-lasting effect. Adhesion of leukocytes,
monocytes and T-lymphocytes to the vascular endothelium
is among the earliest events in inflammatory response and
atherogenesis. Successively, accumulation of leukocytes in
the arterial intima can make atherosclerotic plaque worsen-
ing. Adhesion process is facilitated by the action of endo-
thelial-leucocyte adhesion molecules, which include
intercellular adhesion molecule 1 (ICAM-1), E-selectin
and vascular cell adhesion molecule 1 (VCAM-1). The
expression of these molecules can be transcriptionally
regulated by inflammatory cytokines such as interleukin-1
alpha and tumor necrosis factor alpha (TNF-a). It was
reported that at 5 Ag/ml, PAs extracted from grape seeds
downregulated the TNF-a induced expression of VCAM-1
 M. Dell’Agli et al. / Cardiovascular Research 63 (2004) 593–602
in primary human umbilical endothelial cells, leading to a
reduced adherence with leukocytes and T-cells [52,53].
Similar results were reported in one human study [54]. In
systemic sclerosis patients, plasma levels of VCAM-1,
ICAM-1 and P-selectin were found to be higher than in
normal volunteers. The administration of 100 mg/day of
PAs derived from grape seeds for 1 month attenuated the
increased expression of these adhesion molecules.
Another study used ACs from blackberry administered
to carrageenan-treated rats, a model of acute lung inflam-
mation. ACs reduced the upregulation of ICAM-1 in lung
tissue [55]. The AC mixture used in this study differs
from that found in wine, since cyanidin-3-O-glucoside
was predominant (80% of the total ACs); nevertheless, it
might be expected that a similar behaviour by ACs occurs
in red wines.
3.3. Red wine polyphenols and vascular smooth muscle
cells
Vascular smooth muscle cells contribute to the patho-
genesis of atherosclerotic lesions, in as much as their
proliferation and migration are critical events for progres-
sive intimal thickening and development of arterial wall
sclerosis. At the site of the lesion formation, the most potent
mitogenic and chemotactic agent for vascular smooth mus-
cle cells is platelet-derived growth factor (PDGF) released
by platelets, endothelial cells and vascular smooth muscle
cells themselves. PDGF exerts its biological effects via
activation of two subtypes of transmembrane receptor
tyrosine kinases, termed a and h PDGF receptor. Ligand
binding to the h receptor promotes the activation of signal-
ling enzymes which are important for cell migration and
proliferation. Activation of phosphatidylinositol 3V-kinase
(PI3K) and mitogen-activated protein kinase (MAPK) path-
ways as response to PDGF is implicated in vascular smooth
muscle cells motility [56 – 58].
Then, the effect of RWPs on the proliferation and the
migration of cultured vascular smooth muscle cells has also
been investigated [59,60]. RWPs (1– 100 Ag/ml) inhibited
rat aortic smooth muscle cells proliferation and DNA
synthesis. Polyphenol fractions of different molecular
weights, c 200 – 400 for monomeric components (ACs,
catechins and flavonoids) and 1600 – 2000 for oligomeric
PAs, showed similar antiproliferative effects. Two distinct
mechanisms have been postulated. One involves the down-
regulation of cyclin A gene expression, through the de-
creased expression of transcription factors ATF-1 and CREB
(cAMP-responsive element). The second is associated with
the downregulation of PI3K activity, which is known to
interfere with cell-cycle regulation via the upregulation of
p27kip1 acting as inhibitor of cyclin-dependent kinase
[61,62]. In addition to proliferation, RWPs (1 –100 Ag/ml)
inhibited vascular smooth muscle cell migration through the
specific inhibition of PI3K and p38MAPK, but not through
other MAPKs and ERK 1/2 (extracellular signal-regulated
597
protein kinase 1 and 2). The attenuation of the signals
leading to vascular smooth muscle cell proliferation and
migration could also be the consequence of the inhibition of
PDGF h receptor by RWPs [63].
Vascular endothelial growth factor (VEGF) released from
vascular smooth muscle cells is a powerful endothelial
mitogen and stimulates the expression of adhesion mole-
cules and monocyte chemotactic protein-1 [64]. Red wine
administered to cholesterol-fed rabbits inhibited the expres-
sion of monocyte chemotactic protein-1, but this effect was
found also in animals receiving white wine [65]. The
exposure of vascular smooth muscle cells to RWPs ( z 3
Ag/ml) markedly reduced the overexpression of VEGF
induced by PDGF and other growth factors such as a-
thrombin and transforming growth factor-h1 [66]. This
effect was due to a reduced phosphorylation of p38MAPK,
in agreement with previous findings [60]. Because the
phosphorylation of p38MAPK and VEGF expression in
vascular smooth muscle cells were stimulated in the pres-
ence of reactive oxygen species, the authors concluded that
the inhibition of VEGF expression by RWPs involves their
antioxidant properties.
3.4. Red wine polyphenols and platelet aggregation
Platelets contribute to the rate of development of athero-
sclerosis and coronary artery diseases through several
mechanisms [67]. While it is widely demonstrated the
antiaggregating effect of alcohol [68], flavonoids [69 – 72]
and resveratrol [12], the literature survey provided only
fragmentary and contradictory information about the con-
tribution of ACs and PAs to the inhibition of platelet
aggregation.
Demrow et al. [10] compared the effect of red and white
wines (ml/kg), and grape juice (ml/kg) on platelet activity
and thrombus formation in an in vivo dog model. Red wine
and grape juice were effective as antiplatelet and antithrom-
botic compounds when administered intragastrically. Ad-
ministration of white wine did not produce significant
effects. Because the amount of ethanol necessary to produce
the antiplatelet and antithrombotic activity is greatly re-
duced when red wine rather than pure ethanol was given, it
was concluded that red wine contained platelet inhibitors in
addition to ethanol. Rein et al. [73] reported the effects of
dealcoholized red wine on platelet function in vitro and in
vivo in healthy humans. In nonstimulated platelets, deal-
coholized red wine added to whole blood induced platelet
activation while suppressed the activation in response to
epinephrine. A partial confirmation of these findings derives
from the study by Russo et al. [74], who found in vitro a
significant antiaggregating activity associated with a frac-
tion of dealcoholized red wine containing procyanidins,
ACs and catechins. No activity was associated to the other
constituents: phenolic acids, flavonols, and polymeric PAs.
However, dealcoholized red wine showed no effects when
given orally to healthy subjects [73,75]. Other studies on
598 M. Dell’Agli et al. / Cardiovascular Research 63 (2004) 593–602
humans failed to show differences in platelet aggregation
after red and white wine intake [76,77]. Further studies are
needed to sort out these discrepancies.
4. Bioavailability of red wine polyphenols
Two-thirds of the total intake of polyphenols in the
human diet has been estimated to be accounted by flavo-
noids, the most abundant being flavan-3-ols (catechins and
PAs), ACs and their oxidation products [78]. Information
about the absorption, distribution, metabolism and excretion
of individual flavonoids in humans is scarce. Furthermore,
most studies have been designed using flavonoids in the
aglycon form rather than their glycosides, which predomi-
nate in plants. Because the term flavonoid is applied in
general to a multitude of compounds, in this section we will
focus on absorption and metabolism of ACs and PAs
(dimers, trimers, oligomers and long chain polymers).
The question whether ACs are absorbed as free aglycon
or in their glycoside form was approached for the first time
by Paganga and Rice-Evans [79] who demonstrated the
presence of ACs in human plasma, but without quantifica-
tion. Later, several other studies confirmed that ACs are
absorbed in the glycosilated form after oral consumption
[80 –85].
All studies performed in animals and humans agree that
the bioavailability of ACs is limited [86 – 90]. In humans,
plasma levels of total ACs are low, the order of magnitude
being around 0.1 AM or less [82,83,91 – 93] and most of
the ACs are excreted in urines during the first 4 h [83].
Between 1.5% and 5.1% of the ingested ACs were
recovered in the urine of healthy subjects, within 12 h after
consumption of 300 ml of wine containing around 218 mg
of anthocyanosides. The AC levels in the urine reached a
peak within 6 h from consumption [87]. More recent
studies indicated that the amount of ACs excreted in urine
was in much lower range, 0.04– 0.1% of the dose [84,85].
After the ingestion of 400 ml of Lemberger wine (con-
taining 270 mg of ACs) by healthy volunteers, red wine
ACs were found in human plasma (Cmax: 42 F 8 Ag/l) and
urine (cumulative excretion: 0.20 – 0.23% of the oral dose)
as unchanged glucosides [93,94]. Other peaks detected in
the urine samples showed similar absorption spectra as the
ACs. These additional AC-like compounds may be metab-
olites of ACs, but the nature of the compounds was not
elucidated [85,93]. Neither the aglycon nor glucoronide
and/or sulphate derivatives were found in plasma and
urines from subjects taking wine or other sources of ACs
[80,83,88,91], but in some studies plasma and urines were
not enzymatically treated. Recently, Wu et al. [95] reported
methylated and glucoronidated AC metabolites in elderly
women after ingestion of eldberry extract. Then the issue
whether ACs undergo metabolism pre/post absorption
requires further investigations. As ACs are bulky and polar
molecules, it is expected that they are absorbed at gastro-
intestinal level through a carrier-mediated system. Indeed,
Passamonti et al. [90,96] reported that ACs are competitive
inhibitors of bilitranslocase (Ki ranging from 1.4 to 22
AM), a carrier protein expressed on gastric mucosa [97]
and in vivo experiments proved the involvement of the
stomach in the absorption of grape anthocyanosides in rats.
The structure – activity relationship revealed that monoglu-
cosyl and diglucosyl ACs were better substrates than the
corresponding aglycon [96]. The latter observation repre-
sents a further confirmation that glycosides are the pre-
ferred form for absorption. Furthermore, the ability of ACs
to penetrate the gastric mucosa could be the explanation
for the rapid appearance ( c 5– 20 min) of ACs in sys-
temic plasma [83,88,89,91]. At the same time, the contri-
bution of the upper part of the intestine in the process of
absorption cannot be excluded.
Other questions that remain open concern the influence
of alcohol, tartaric acid, a major organic acid in wine, and
PAs to the efficiency of absorption. Results from the study
by Bub et al. [88] tend to exclude the effect of alcohol on
AC bioavailability, but the low number of subjects (6) is a
limit to draw clearcut conclusions. On the other hand,
tartaric acid increased the AUC of (+)-catechin metabolites
in plasma of rats treated orally with a dose of 100 mg/kg of
RWPs, suggesting that it can enhance the absorption and the
bioavailability of polyphenols in red wine [98]. This obser-
vation needs to be confirmed in human studies.
In comparison with ACs, the bioavailability of PAs has
received much less attention, maybe partially due to the
complexity of structures, which makes their analysis diffi-
cult, and for the lack of commercially available pure stand-
ards. Few data are available in animals and in humans. Early
studies were performed with radiolabelled PA extracts
which did not allow discrimination between monomers,
oligomers and/or metabolites. Feeding rats and mice with
a radiolabelled mixture of grape PAs [largely dimers, plus
(+)-catechin and (  )-epicatechin] permitted the identifica-
tion in urines and faeces of some ill-defined PAs and of
hippuric acid, ethylcatechol and various phenolic acids. The
radioactivity was found in all the tissues of the animals
within few hours after the ingestion [99,100]. Other data
obtained from studies in chickens and sheep indicated that
the radioactivity associated with PA polymers was com-
pletely recovered in the bowel and the faeces of the treated
animals, thus showing a lack of absorption of these large
molecules [101,102].
Procyanidin polymers were also shown to be degraded in
vitro into low-molecular weight phenolic acids by a human
colonic microflora grown anaerobically [103,104]. Dimers
and trimers were uptaken at similar extent into Caco-2 cell
layer, a well-established model for human absorption, while
polymers adhered partially to the cell surface [105]. The fate
of procyanidin dimers has been studied recently: procyani-
din B2 was found in plasma of subjects receiving 0.375 g
cocoa/kg body weight, as beverage. The compound
appeared in plasma as early as 0.5 h (16 nM). The maximal
 M. Dell’Agli et al. / Cardiovascular Research 63 (2004) 593–602
concentration was reached by 2 h (41 nM). The single
monomers and their metabolites were also detected indicat-
ing cleavage of the dimer in the digestive tract and bio-
transformation [106]. The cleavage of procyanidin dimers
B2 and B5 to the corresponding monomers at gastrointes-
tinal level has been confirmed by other studies [107 – 109].
Monomers are then O-methylated and conjugated as glucor-
onides as described for other flavonoids [110]. In contrast,
Donovan et al. [111] found that procyanidin B3, which is
also present in wine, was not bioavailable: no trace of the
compound was detected in plasma and urine after treating
rats with a grape seed extract or procyanidin B3 alone. Nor
procyanidins were cleaved to the bioavailable monomers.
The reason for these discrepancies might reside in the
experimental protocols and in the use of animal models.
Rats were fasted before receiving procyanidin B2 [109]; in
the study by Holt et al. [106], subjects consumed a flavanol-
rich cocoa; in the study by Donovan et al. [111], rats were
fed a standard semipurified diet supplemented with procya-
nidin B3 or the grape seed extract.
No studies thus far have addressed the issue of evaluating
absorption and metabolism of PAs after wine drinking. It is
then of utmost priority to eliminate this deficiency.
5. Conclusions
The interest in compounds present in red wine was
stimulated by the claim that the regular consumption of
this beverage could help in preventing cardiovascular
diseases. In comparison with white wine, which does not
share the same putative beneficial effects as red wine, the
latter contains ACs and PAs in greater amounts. Then most
of the studies reported in this review aimed to ascertain the
contribution of these two classes of polyphenolic com-
pounds to the overall effect of red wine. As shown by the
large number of publications, ACs and PAs possess in
vitro relevant biological activities and interact with many
targets of the cell signalling pathways. However, the
physiological significance of these findings depends on
the assumption that ACs and PAs are bioavailable in the
same chemical form as that used for the in vitro studies
and can attain plasma levels as high as those used for in
vitro studies. As reported in the previous paragraph, both
assumptions are questionable. Even if most of the data
were not obtained after wine drinking, few studies avail-
able about the plasma levels of ACs and PAs report values
as 100 nM or lower, while concentrations used in vitro
exceeded these values. In addition, no data are available to
assess the distribution of ACs and PAs at the site of action
in the unmetabolized form, as it would be required to
mimic the situation of in vitro experiments. Among PAs, it
is apparent that only dimers appear in plasma as the native
compounds, but this observation needs to be confirmed in
humans drinking wine. It is then imperative to acquire
knowledge on the fate of red wine polyphenols after single
599
dosing and in conditions simulating the regular consump-
tion of this beverage.
Acknowledgements
This review is dedicated to the memory of Professor
Giovanni Galli. We gratefully acknowledge Dr. Germana
Galli for her help during the preparation of this manuscript.
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