Journal of Ethnopharmacology 92 (2004) 245–250

Cistus incanus and Cistus monspeliensis inhibit the contractile

response in isolated rat smooth muscle

G. Attaguile

a

,

∗

, G. Perticone

b

, G. Mania

b

, F. Savoca

c

, G. Pennisi

b

, S. Salomone

a

a

Department of Experimental and Clinical Pharmacology, University of Catania, Viale A. Doria 6, 95125 Catania, Italy

b

Department of Chemical Science, University of Catania, Viale A. Doria 6, 95125 Catania, Italy

c

Department of Botany, University of Catania, Via A. Longo 19, 95125 Catania, Italy

Received 1 August 2003; received in revised form 12 February 2004; accepted 23 February 2004

Abstract

The lyophilized aqueous extracts from Cistus incanus L. (CI) and Cistus monspeliensis L. (CM) collected in Sicily were studied in order to

evaluate their myorelaxant activity by using isolated smooth muscle of rat ileum and rat aorta. Both CI and CM extracts concentration-dependently
inhibited the contractile response to acetylcholine (ACh), phenylephrine (PE) and to 100 mM KCl. The concentration–contraction curves to
ACh in ileum and to PE in aorta, were displaced to the right by Cistus extracts in a non-competitive manner, with a depression of the maximum
contractile response. The EC

50

(

␮

g/ml) of CM and CI were: ileum/KCl, CM 457

± 99, CI 681 ± 80; ileum/ACh 100

␮

M, CM 297

± 66,

CI 335

± 41; aorta/KCl, CM 360 ± 21, CI 843 ± 36; and aorta/PE 10

␮

M, CM 287

± 33, CI 451 ± 58. The two extracts resulted almost

equi-active in ileum, whereas CM was more active than CI in aorta. These data indicate that Cistus extracts act as spasmolytic on intestinal
and vascular smooth muscle. The antagonism they exert on ACh-, PE- and KCl-evoked contractions seems to be functional, because it is not
specifically directed toward any particular receptor; furthermore, a calcium-antagonist activity seems unlikely, since the extracts are capable
of completely block the contractile response to agonists.
© 2004 Elsevier Ireland Ltd. All rights reserved.

Keywords: Cistus incanus; Cistus monspeliensis; Cistaceae; Rat ileum; Rat aorta; Spasmolytic effect

1. Introduction

Medicinal herbs have their use as medicament based sim-

ply on a folk tradition that has been perpetuated along sev-
eral generations. One example is Cistus, a genus belonging
to the family Cistaceae, which includes 16 herbaceous and
shrubs species characteristic of the degraded areas of the
Mediterranean region.

Various Cistus species are used (in Italy, Greece, Spain

and Turkey) for the treatment of diarrhoea and peptic ul-
cers, as general remedies for several skin diseases and as
anti-inflammatory and antispasmodic agents. Pharmaco-
logical studies on Cistus extracts reported them to have
antibacterial, antifungal, anti-inflammatory (

Simeray et al.,

1982; Chinou et al., 1994; Yesilada et al., 1997a; Bouamama
et al., 1999

), antiulcer (

Attaguile et al., 1995; Yesilada et al.,

1997b

), antioxidant (

Attaguile et al., 2000

), hypotensive

∗

Corresponding author. Tel.:

[phone];

fax:

[phone].

E-mail address: [e-mail] (G. Attaguile).

and spasmolytic activities (

Sanchez de Rojas et al., 1995

).

Moreover, Cistus extracts modulate leukocyte growth and
viability and cytokine release (

Lendeckel et al., 2002

).

Cistus genus shows constant genoma size and simi-

lar (AT): (GC) ratio (

Ellul et al., 2002

). Principal active

constituents are polyphenolic compounds; major phy-
tochemicals identified so far are quercetin, kaempferol,
kaempferol-3-methyl ether, aesculin, myricetin, flavan-3-ols
as (

+)-cathechin, (+)-gallocathechin, (+)-gallocathechin

3-gallate, (

+)-cathechin-3-O-␣-l-rhamnoside, and proan-

thocyanidins (

Pascual et al., 1977; Demetzos et al., 1990;

Petereit et al., 1991; Danne et al., 1993; Danne et al., 1994;
Pomponio et al., 2003

). This flavonoid pattern was quali-

tatively similar in Cistus plants collected in Sicily, as we
verified by preliminary tests.

The flavonoids, a group of secondary plant metabolites

widely occurring in the vegetable kingdom, are currently
consumed in large amounts in the daily diet. They have been
shown to display a remarkable array of biochemical and
pharmacological actions, which can significantly affect the
functions of various mammalian cellular systems (

Di Carlo

0378-8741/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.jep.2004.02.020

246

G. Attaguile et al. / Journal of Ethnopharmacology 92 (2004) 245–250

et al., 1999; Middleton et al., 2000

). Intriguing pharmaco-

logical properties of these natural products are relaxing ef-
fects on intestinal (

Tona et al., 2000; Weiman et al., 2002;

Heinrich, 2003

) and vascular (

Huang et al., 1998; Chan et al.,

2000; Ibarra et al., 2002

) smooth muscle.

In the present work, we aimed to investigate the effects of

extracts from Cistus incanus L. (CI) and Cistus monspelien-
sis L. (CM) collected in Sicily on isolated rat aorta and lon-
gitudinal smooth muscle of rat ileum in order to evaluate
their popular use as spasmolytic and their possible mecha-
nism of action.

2. Materials and methods

2.1. Plant material and extraction procedure

Aerial parts of Cistus incanus and Cistus monspeliensis

in flower were harvested in May 2001 in Sicily: CI in the
cork-forest of Santo Pietro, CM in the Zotta Santo Pietro,
both in the Caltagirone (Catania) area. A voucher sample
of each plant material was deposited at the herbarium of
the Department of Botany, University of Catania, as authen-
ticated by Prof. C. Barbagallo. Aerial parts were dried in
a cool, dark place and powdered using a pulverizing mill
(Mikro-Feinmuhle Culatti MFC) and the weighed dust was
extracted three times with boiling water. The extracts were
filtered and lyophilised. The final yield was 14.50% for CI
and 13.43% for CM. The extracts were analysed for their
contents in (

+)-catechin and (−)-gallocatechin (

Pomponio

et al., 2003

). The lyophilised residue was stored at

−20

◦

C.

The desired concentrations (w/v) were prepared from this
powder.

2.2. Tissue preparation and recording of
contractile activity

Male Sprague-Dawley rats (Stefano Morini, S. Polo

D’Enza, Italy; 280–350 g) fasted overnight were anes-
thetized with ether and killed by decapitation. Aorta was re-
moved, immersed in a modified Krebs physiological solution
(in mM: NaCl, 118; KCl, 4.6; NaHCO

3

, 25; MgSO

4

, 1.2;

KH

2

PO

4

, 1.2; CaCl

2

, 2.5; glucose, 10; EDTA, 0.025;and pH

7.4), cleaned from the surrounding connective tissue, and
cut in rings (3–5 mm diameter). The longitudinal smooth
muscle was dissected from the ileum, by gently scraping on
the external surface with a wet cotton (using a physiologi-
cal solution identical in composition to that reported above,
except for CaCl

2

, which was 5 mM), and cut in strips of

2 cm length. The preparations were suspended in 10 ml or-
gan baths filled with physiological solution (composition as
above; for ileal strips 5 mM CaCl

2

instead of 2.5 mM was

used), bubbled with 95% O

2

, 5% CO

2

, at 37

◦

C under a rest-

ing tension of 20 mN (aortic rings) or 10 mN (ileal strips).
The preparations were isometrically connected to an isomet-
ric force transducer (Ugo Basile, Comerio Varese, Italy) and

allowed to equilibrate for 60 min in physiological solution.
A first contraction was induced with a K

+

-rich depolariz-

ing solution (in mM: NaCl, 22.6; KCl, 98.8; NaHCO

3

, 25;

MgSO

4

, 1.2; KH

2

PO

4

, 1.2; CaCl

2

, 2.5 or 5; glucose, 10;

and EDTA, 0.025). After washout and 30 min-recovery in
physiological solution, contractions were evoked by adding
cumulative concentrations of phenylephrine to aortic rings
(PE, 1 nM–10

␮M) or cumulative concentrations of acetyl-

choline to ileal strips (ACh, 10 nM–100

␮M). CI and CM

extracts, when used, were pre-incubated for 30 min with the
preparations, before challenging with 100 mM KCl, PE or
ACh.

All the experiments were conducted in accordance to GLP

guidelines.

2.3. Drugs

Lyophilised aqueous extracts of CI and CM were dis-

solved in water at the concentration of 10 mg/ml, and further
added to the organ baths as required. PE and ACh (Sigma,
St. Louis, MO, USA) were dissolved in water as 10 mM
stock solutions and further diluted as required.

2.4. Data analysis

The results are presented as the mean

± S.E.M. of n ob-

servations. Values were analysed using a Student’s t-test or
one-way ANOVA followed by Fisher’s test, as appropri-
ate, and were considered to differ significantly when

P <

0

.05. IC

50

values were calculated by interpolation from

semi-logarithmic plots.

3. Results

3.1. Relaxant effects of CI and CM on KCl-evoked
contractions

KCl (100 mM) induced reproducible contractions in both

longitudinal smooth muscle of ileum and aorta. In longitu-
dinal smooth muscle of ileum, the KCl-evoked contraction
clearly showed to distinct components: a transient phasic
component (peak), followed by a tonic component (con-
tractile tone much lower than the phase, but long lasting).
CM and CI aqueous extracts inhibited both the phasic and
the tonic component in a concentration-dependent manner,
but resulted more active on the latter than on the for-
mer (

Fig. 1

). The two extracts resulted almost equi-active

in inhibiting KCl-evoked contraction of ileum (see also

Table 1

).

In aorta KCl-evoked contraction was characterised by a

sustained tonic component.

Fig. 2

shows the effects of CM

and CI on KCl-evoked contraction of aorta. At variance with
ileum, in aorta CM resulted significantly more active than
CI in inhibiting KCl-evoked contraction.

Table 1

illustrates

the IC

50

of CM and CI on ileum and aorta.

G. Attaguile et al. / Journal of Ethnopharmacology 92 (2004) 245–250

247

Fig. 1. Effects of CM and CI on 100 mM KCl-evoked contraction in longi-
tudinal smooth muscle of rat ileum. Each bar represents the mean

±S.E.M.

from eight different preparations (from four rats). Contractions are ex-
pressed in percentage of the peak of a previous contraction (control)
evoked by KCl in the same preparation in the absence of aqueous ex-
tract. Given the particular shape of the KCl-evoked contraction in ileum
(see also text), the effects of CM and CI have been estimated at three
different time points: peak, 2 and 5 min. (*)

P < 0.05, (**) P < 0.01 vs.

untreated control; one-way ANOVA and Fisher’s test.

3.2. Relaxant effects of CI and CM on agonist-evoked
contractions

Acetylcholine was used as agonist for stimulating longi-

tudinal smooth muscle of ileum. As shown in

Fig. 3

, both

CM and CI were effective in displacing to the right the

Table 1
Concentrations of CM and CI inhibiting by 50% (IC

50

) the contractile

effect of 100 mM KCl in longitudinal smooth muscle of ileum and in
aorta of rat

Preparation–treatment

IC

50

(

␮g/ml)

Ileum–CM

457

± 99 (n = 8)

Ileum–CI

681

± 80 (n = 8)

Aorta–CM

360

± 21

a

(n

= 6)

Aorta–CI

843

± 36 (n = 6)

The IC

50

on ileum concern the phasic component of the contraction.

a

P < 0.05 vs. Aorta–CI; unpaired Student’s t-test.

Fig. 2. Effects of CM and CI on 100 mM KCl-evoked contraction in
rat aorta. Each bar represents the mean

± S.E.M. from six different

preparations (from three rats). Contractions are expressed in percentage
of a previous contraction (control), at the steady-state, evoked by KCl in
the same preparation in the absence of aqueous extract. (*)

P < 0.05,

(**)

P < 0.01 vs. untreated control; one-way ANOVA and Fisher’s test.

concentration–contraction curve to ACh; the displacement
was not parallel and the curves in the presence of CM or CI
showed a significant depression of the maximum effect. CM
and CI resulted almost equi-active in inhibiting ACh-evoked
contraction of ileum.

Phenylephrine was used as agonist for stimulating aorta.

As shown in

Fig. 4

, both CM and CI were effective in dis-

placing to the right the concentration–contraction curve to
PE; the displacement, again, was not parallel and the curves
in the presence of CM or CI showed a significant depres-
sion of the maximum effect. At variance with ileum, in aorta
CM resulted significantly more active than CI in inhibiting
PE-evoked contraction.

Table 2

illustrates the IC

50

of CM

and CI on ileum and aorta.

3.3. Reversibility of the myorelaxant effect of Cistus
extracts

In order to elucidate whether or not the myorelaxant

effects of Cistus extracts were reversible, some aortic
preparations were first incubated with CM or CI extracts,
then challenged with 100 mM KCl solution and after that,

248

G. Attaguile et al. / Journal of Ethnopharmacology 92 (2004) 245–250

0

20

40

60

80

100

Contraction (% KCl 100mM-Peak)

ACh (M)

10

-8

10

-7

10

-6

10

-5

Control

CM 100

µ

g/ml

CM 200

µ

g/ml

CM 400

µ

g/ml

0

20

40

60

80

100

Contraction (% KCl 100mM-Peak)

ACh (M)

10

-8

10

-7

10

-6

10

-5

Control

CI 200

µ

g/ml

CI 400

µ

g/ml

CI 800

µ

g/ml

Fig. 3. Concentration–contraction curves to ACh in longitudinal smooth
muscle of rat ileum. Each curve represents the mean

± S.E.M. (when it

exceeds the size of the symbol) from eight different preparations (from four
rats). Contractions are expressed in percentage of the peak of a previous
contraction (control) evoked by 100 mM KCl in the same preparation in
the absence of aqueous extract. All the concentration contraction curves
in the presence of CM or CI illustrated in the figure were significantly
depressed in comparison of the curves obtained in untreated controls
(

P < 0.01, one-way ANOVA and Fisher’s test). Lower concentrations of

CM (10 and 40

␮g/ml) and CI (40 and 100 ␮g/ml) were tested, but they

did not reach a statistically significant effect (not shown).

Fig. 5. Reversibility of the inhibitory effect of CM (800

␮g/ml) in rat aorta challenged with 100 mM KCl. Four consecutive stimulations with KCl were

carried out at 1 h intervals. Upper traces: control (untreated) preparation; lower traces: preparation incubated with 800

␮g/ml CM after run 1 and before

run 2; after run 2, the preparation in the lower trace was incubated in the absence of CM (wash). Notice that in the presence of CM, the KCl-evoked
contraction reached about 20% of the tone evoked in its absence in the same preparation; after 1 and 2 h wash out the preparation recovered about
50–70% of the initial tone. Similar results were obtained with CI (not shown).

0

20

40

60

80

100

Contraction (% KCl 100 mM)

CTR
CM 200

µ

g/ml

CM 400

µ

g/ml

CM 800

µ

g/ml

PE (M)

10

-9

10

-8

10

-7

10

-6

10

-5

PE (M)

10

-9

10

-8

10

-7

10

-6

10

-5

0

20

40

60

80

100

Contraction (% KCl 100 mM)

CTR
CI 200

µ

g/ml

CI 400

µ

g/ml

CI 800

µ

g/ml

a

b

b

b

Fig. 4. Concentration–contraction curves to PE in rat aorta. Each curve
represents the mean

±S.E.M. (when it exceeds the size of the symbol) from

6 different preparations (from three rats). Contractions are expressed in
percentage of a previous contraction (control), at the steady-state, evoked
by 100 mM KCl in the same preparation in the absence of aqueous extract.
(a)

P < 0.05 and (b)P < 0.01 vs. untreated control; one-way ANOVA and

Fisher test. Lower concentrations 100

␮g/ml CM or CI were also tested,

but their effects did not reach a statistical significance (not shown).

G. Attaguile et al. / Journal of Ethnopharmacology 92 (2004) 245–250

249

Table 2
Concentrations of CM and CI inhibiting by 50% (IC

50

) the contractile

effect of 30

␮M ACh in longitudinal smooth muscle of ileum and of

10

␮M PE in aorta of rat

Preparation–treatment

IC

50

(

␮g/ml)

Ileum–CM

297

± 66 (n = 8)

Ileum–CI

335

± 41 (n = 8)

Aorta–CM

287

± 33

a

(n

= 6)

Aorta–CI

451

± 58 (n = 6)

a

P < 0.05 vs. Aorta–CI; unpaired Student’s t-test.

extensively rinsed in physiological solution in the absence
of Cistus extract. As shown in

Fig. 5

, in the presence of CM,

the KCl-evoked contraction reached about 20% of the tone
evoked in its absence in the same preparation; after 1 and
2 h wash out the preparation recovered about 50–70% of the
initial tone. Similar results were obtained with CI (data not
shown).

4. Discussion and conclusions

The present data show that the aqueous extracts of Cis-

tus monspeliensis and Cistus incanus exert concentration-
dependent and reversible inhibitory effects on contractile
responses in both ileal longitudinal smooth muscle and
aorta of rat. The underlying mechanisms remain to be
elucidated fully. It is tempting to speculate that the antag-
onism the extracts exerted on ACh-, PE- and KCl-evoked
contractions is functional, because it is not specifically
directed toward any particular receptor. Furthermore, a
calcium–antagonist activity of Cistus extracts seems un-
likely, since they are capable of completely block the
contractile response to agonists (at least the contraction
to 10

␮M PE in aorta), which is not the case for classical

calcium entry blockers (

Godfraind et al., 1986

). It seems

likely that the myorelaxant activity is related to a direct
effect on the smooth muscle rather than an indirect action
on neurotransmitter release, because rat aorta is poorly
innervated by autonomous nervous system; however, such
an effect on neurotransmitter release cannot be excluded in
ileum.

It is quite plausible that the myorelaxant effects of Cistus

incanus and Cistus monspeliensis extracts may be attributed
to the presence of polyphenolic compounds, since it is well
established that flavonoids from a great variety of plants
inhibit intestinal motility in vitro (

Tona et al., 2000; Weiman

et al., 2002; Heinrich, 2003

) and are provided with vascular

effects in vessels of different territories and/or of different
mammals (

Huang et al., 1998; Chan et al., 2000; Ibarra et al.,

2002; Rodriguez-Cruz et al., 2003

).

For example, quercetin was shown to produce relaxation

in guinea pig ileum contracted by an anaphylactic response
(

Fanning et al., 1983

) or by KCl (

Lozoya et al., 1994

). as

well as in rat aorta contracted by various vasoconstrictors
(

Morales and Lozoya, 1994; Chen and Pace-Asciak, 1996

).

In isolated rat aortic smooth muscle, the KCl-, Ca

2

+

-, phor-

bol ester- (

Duarte et al., 1993

) and the noradrenaline-evoked

(

Perez-Vizcaino et al., 2002

) contractions were inhibited by

quercetin and kaempferol. Rat mesenteric arteries were re-
laxed by four epicatechin derivatives (

Huang et al., 1998;

Huang et al., 1999

).

The observed final pharmacological activity of aque-

ous Cistus extracts may be due to an unspecific “reactive
compound” and/or to the combined effects of the sev-
eral chemical constituents of the plant, such as quercetin,
kaempferol, kaempferol-3-methyl ether, aesculin, myricetin,
flavan-3-ols and proanthocyanidins.

In conclusion, Cistus monspeliensis and Cistus incanus

have been shown to exert relaxant effects in vitro on the
isolated intestinal and vascular smooth muscle. Our results
provide a rational basis to understand the beneficial effects of
Cistus extracts as spasmolytic agents in local folk medicine
in diarrhoea and digestive disorders. Vasorelaxant properties
of Cistus extracts also suggest their possible use in vascular
conditions such as hypertension.

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