CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 3, May/June 2010
AFRICA
135
the venous tissues. However, the quercetin-provoked initial brief
contractions of the muscle preparations were not modified by
pre-incubation with prazosin (10
-6
M). This observation suggests
that the initial brief contractile effects of quercetin on the basal
tones and increases in contractile frequencies of the preparations
were unlikely to have been mediated via alpha
1
-adrenoceptor
stimulation.
The possible role of Ca
2+
influx in the quercetin-induced initial
rise in the basal tone and increases in contractile frequencies of
the preparations was examined by pre-incubating the venous
tissues with nifedipine (10
-7
M) before challenging them with
quercetin. Nifedipine inhibits contractions of smooth muscles
by reducing extracellular Ca
2+
influx through a direct action on
structural proteins of the L-type calcium channels.
29
The partial
blockade of the quercetin-induced initial brief contraction of
the portal vein by nifedipine (10
-7
M) probably suggests partial
blockade of the influx of extracellular Ca
2+
through L-type volt-
age-dependent calcium channels.
29
This observation confirms
and extends the earlier proposal that quercetin is a novel activator
of L-type voltage-dependent calcium channels.
1
The effect of quercetin is rather specific to L-type calcium
channels, since T-type calcium channels were not affected
by quercetin in an earlier study by Saponara
et al
.
1
However,
quercetin’s activation of L-type calcium channels would seem
to contradict its well-known vasodilatory effect,
23,24
as it would
be expected to cause contraction of the vascular musculature.
Therefore, the myorelaxant effect of quercetin on vascular tissue
preparations originates from its reaction with a second target
beyond the Ca
2+
channel, which hierarchically prevails over the
increase in Ca
2+
influx expected from L-type calcium channel
stimulation.
1
It is, therefore, not unreasonable to speculate that
the quercetin-induced initial contractile effects are likely to be as
a result of a sudden influx of calcium into cells due to activation
of L-type calcium channels by the flavonoid.
The possible involvement of endothelium mediators such as
EDRF and PGI
2
in quercetin-induced vasodilation was investi-
gated by pre-treating the venous tissues with N
G
-nitro-L-arginine
methyl ester (L-NAME, 100
µ
M), a nitric oxide synthase inhibi-
tor, and indomethacin (10
µ
M) (to block prostanoid production),
respectively, 20 minutes prior to addition of quercetin to the
bath fluid. Pre-treatment of the portal vein tissues with either
L-NAME or indomethacin did not significantly (
p
>
0.05)
modify the vasorelaxant effects of quercetin, suggesting that
quercetin-induced vasodilation is not mediated via EDRF, or
through the PGI
2
pathways.
The findings of this study are in agreement with, and extend
the observations of, Duarte
et al
.
24
and Pérez-Vizcaíno
et al
.,
19
who noted that quercetin exhibited endothelium-independent
vasodilation effects
in vitro
. However, in a chronic study by
Duarte
et al
.
9
quercetin restored endothelium-dependent relaxa-
tion, indicating that quercetin exerted marked acute vasodilator
effects
in vivo
when administered intravenously. Chronic studies
have also revealed that quercetin restored impaired endothelial
function
in vivo
.
9,10
Recent available data suggest that the vascular
beneficial effects of flavonoids are closely related to their free-
radical scavenging and anti-oxidant properties, which might thus
protect NO from superoxide-induced inactivation.
30,31
Quercetin
is a potent anti-oxidant and has been shown to protect NO from
scavenging actions of superoxide anions.
30
The possible involvement of cAMP-dependent protein kinas-
es on the relaxant effect of quercetin was examined by pre-incu-
bating the venous tissues with TPCK (3
µ
M) 20 minutes prior to
addition of quercetin. TPCK significantly (
p
<
0.01) antagonised
but did not completely abolish quercetin-elicited vasorelaxation,
suggesting that an intracellular upsurge in cAMP, due to cAMP-
dependent protein kinase inhibition, might contribute, at least in
part, towards the relaxant effects of quercetin on the spontane-
ously contracting portal veins. The mechanisms of the cAMP
increase by quercetin could have been mediated via inhibition of
cAMP phosphodiesterase.
11-13,26,28
The results of the present study
are also in agreement with those reported by Revuelta
et al
.
28
Overall, the findings of the present study indicate that: (1)
quercetin inhibited spontaneous contraction of, and relaxed
rat isolated portal veins in a concentration-related manner;
(2) quercetin is a novel activator of L-type voltage-dependent
calcium channels; and (3) quercetin elicited an upsurge in
intracellular cAMP, resulting in vascular smooth muscle relaxa-
tion. The myorelaxing properties of quercetin observed in this
study lend pharmacological support to epidemiological studies,
which postulate an inverse association between dietary flavonoid
consumption and mortality from coronary heart diseases.
The authors are grateful to Miss Kogi Moodley for her technical assistance.
References
Saponara S, Sgaragli G., Fusi F. Quercetin as a novel activator of L-type
1.
Ca
2+
channels in rat tail artery smooth muscle cells.
Br J Pharmacol
2002;
135
: 1819–1827.
Orgogozo JM, Dartigues JF, Lafont S, Letenneur L, Commenges D,
2.
Salamon R,
et al
. Wine consumption and dementia in the elderly: a
prospective community study in the Bordeaux area.
Revista Neurol
Log [Quercetin] (M)
0
20
40
60
80
100
–4
% Relaxation
–5
–6
*
*
*
***
***
δδδ
δδδ
δδδ
Control
Quercetin alone
Quercetin + TPCK (3
µ
M)
Fig. 5. Concentration–effect curves of quercetin (10
-7
–10
-4
M) on contractile amplitudes of spontaneously contract-
ing rat isolated portal veins in the absence and presence
of TPCK (3
µ
M). Each point represents the mean (
±
SEM)
of six to eight observations, while vertical bars denote
standard errors of the means (SEM). *
p
<
0.05; **
p
<
0.01;
***
p
<
0.001 for quercetin alone versus control;
δδδ
p
<
0.001
for quercetin alone versus quercetin
+
TPCK (3
µ
M).
