In your current study, vasorelaxant impact produced through the aqueous
extract regarding Melissa officinalis L. ssp. officinalis (MOO) (Lamiaceae) and
its possible mechanism within isolated rat aortic rings precontracted with
phenylephrine were examined. in the very first series of experiments, effect
of MOO on the baseline and phenylephrine ([10.sup.-5] M) precontracted
arteries was investigated, although within the 2nd group associated with experiments,
endothelium intact as well as endothelium denuded impact had been determined. The
agents used were [N.sup.[omega]-nitro-L-arginine (l-NAME), an
irreversible inhibitor of nitric oxide (NO) synthase, indomethacin (10
[mu]M), any cyclooxygenase (COX) inhibitor, and glibenclamide (10 [mu]M),
an ATP-sensitive potassium channel blocker. The Actual extract was found to
exert a vasorelaxant effect as well as rosmarinic acid quantity, the
characteristic compound with the plant, ended up being analyzed by simply reversed-phase
high-performance liquid chromatography (18.75%), along with had been further
confirmed through LC-MS analysis giving the prominent [M.sup.+1] molecular ion
peak in m/z 365. Total phenol amount within the extract was determined using
Folin-Ciocalteau reagent (0.284 mg/mg extract). Vasorelaxant effect of
the extract had been totally dependent around the existence involving endothelium and
was abolished through pretreatment with l-NAME, whereas pretreatment with
indomethacin and glibenclamide reduced your relaxation into a minor extent.
Rosmarinic acid has been in addition tested inside the identical manner as the extract and
was found to exert vasorelaxant effect. These kind of outcomes claim that the
aqueous extract associated with MOO vasodilates by approach of nitric oxide pathway with the
possible involvement regarding prostacycline as well as endothelium-derived
hyperpolarizing factor (EDHF) pathways as well.
[C] 2008 Elsevier GmbH. Most legal rights reserved.
Keywords: Melissa officinalis ssp. officinalis; Lamiaceae;
Vasorelaxant effect; Endothelium; Rat aorta; Rosmarinic acid
The final decade features witnessed the developing curiosity about complementary
therapies, specially phytotherapy. Parallel for the public interest,
researchers have got furthermore paid focus on herbal remedies within latest years.
Therefore, many traditionally used herbs have been investigated within many
different within vitro and in vivo studies.
Melissa officinalis L. (Lamiaceae), in addition referred in order to as "lemon
balm", is definitely an aromatic perennial herb native in order to outer parts of
Anatolia along with Mediterranean region re garding Turkey where it's got been
traditionally used as tea pertaining to its sedative, carminative, along with antiseptic
properties (Baytop, 1999). Throughout early epochs, the guarana plant has been furthermore reported
to end up being used for psychosomatic cardiac disorders along with coronary heart failure by
Paracelsus along with Avicenna (Wichtl, 1994; Babulka, 2005). The
characteristic constituents throughout lemon balm are already so far reported as
hydroxycinnamic acid derivatives (rosmarinic and caffeic acids) (Caniova
and Brandsteterova, 2001; Toth et al., 2003; Ziakova et al., 2003;
Boyadzhiev as well as Dimitrova, 2006), essential oil (Enjalbert et al., 1983;
Sadraei et al., 2003; Mimica-Dukic et al., 2004; Basta et al., 2005),
flavonoids (Mulkens as well as Kapetanidis, 1987; Heitz et al., 2000) as well
as acidic triterpenes (Herodez et al., 2003).
In the present study, our objective ended up getting to look at possible
vasorelaxant impact in the aqueous extract associated with Melissa officinalis L.
ssp. officinalis (MOO) inside rat isolated thoracic aorta. Besides,
rosmarinic acid amount was analyzed through reversed-phase high-performance
liquid chromatography (RP-HPLC) too as liquid chromatography mass
spectrometry (LC-MS) as well as total phenol content of the extract was
determined using Folin-Ciocalteau reagent.
Materials along with methods
The plant ended up being collected through certainly 1 of us (S.E.) via Biyikali village
of Tekirdag province (Turkey) in June 2006 along with identified as Melissa
officinalis L. ssp. officinalis through Prof. Dr. Hayri Duman from Department
of Biology, Faculty associated with art along with Science, Gazi University, Ankara
(Turkey). The Actual voucher specimen can be preserved in the Herbarium involving Faculty
of Pharmacy associated with Gazi University, Ankara (Turkey).
The leaves involving M. officinalis L. ssp. officinalis ended up being dried in
shade, chopped, along with extracted with boiling distilled water. After
filtration, the particular aqueous cycle was collected along with lyophilized to give a
crude aqueous extract.
Experiments upon MOO were completed utilizing adult male Wistar rats
weighing among 250 as well as 350 g. Most animals had been received in accordance
to your "Guide for your Case and Use associated with Laboratory Animal
Resources". the rats were acclimatized to some 12-h light: 12-h dark
cycle in 25 [degrees]C along with supplied together with regular laboratory diet program and
tap h2o advertisement libidum. They Will had been brought every day to the laboratory regarding the
experiments, which usually complied with all the guide for the care and also Use of
Laboratory Animals (NIH Publication No. 85-23, revised 1996) and were
approved through the Ethics Committee regarding Gazi University.
All drugs had been obtained coming from Sigma Chemical Co. (St. Louis, MO,
USA). The stock remedy involving noradrenaline has been ready in 0.001 N HC1 and
ascorbic acid had been included with avoid oxidation. Acetylcholine was
dissolved in 0.001 N HC1, glibenciamide had been dissolved in
di-methylsulfoxide (DMSO), indomethacin has been dissolved throughout 150mM
[NaHCO.sub.3], whereas most oLher drugs were dissolved inside saline (0.9%).
All subsequent dilutions were prepared in Krebs-Henseleit remedy and
kept inside a cold along with dark medium. The Particular vehicles were located to get no
effect about the relaxation responses.
On another hand, rosmarinic acid regarding HPLC analysis had been purchased
from Sigma-Aldrich (Fluka-44699, Buchs, Switzerland). Chromatographic grade-double distilled water, HPLC grade methanol (Merck-1, 06007),
isopropyl alcohol (Merck-101040), along with analytical grade ortho-phosphoric
acid 85% (Mcrck-563) were used. Gallic acid as well as Folin-Ciocalteau's
reagent had been obtained from Sigma-Aldrich Chemie GmbH (Taufkirchen,
Determination associated with vasorelaxant effect
The rats had been sacrificed after ether anesthetized and the thoracic
aorta had been removed, cleaned off adherent connective tissues, and cut into
rings involving 4-5 mm long. Segments were suspended inside a water-jacketed organ
bath regarding ten ml filled with Krebs-Heinseleit remedy (37 [degrees]C) of
the subsequent composition inside mM: Na Cl 119; NaHC[O.sub.3] 25; KCl 4.6;
MgCl 21.2; K[H.sub.2]P[O.sub.4] 1.2; Ca[Cl.sub.2] 2.5; and also glucose 11.
The remedy had been aerated using a gasoline mixture containing 95% [O.sub.2]:5%
[CO.sub.2]. the rings had been suspended on the couple of stainless-steel hooks,
one of which in turn was fixed for an L-shaped rod inside the actual chamber as well as the
other to a isometric transducer (PowerLab ML750) below optimum resting
force. The Actual stainless-steel hook had been connected towards the force displacement
transducer. Isometric contractions had been measured and also recorded
continuously inside a computer by making use of your Labsys computer plan w17x.
Arterial rings were equilibrated inside Krebs-Heinseleit solution for 1 h at
1 g optimum resting force. In a few rings, the endothelium ended up being removed
gently simply by rubbing your luminal surface with the ring having a rough ened
polyethylene tube. In the end with the equilibration period of one h,
viabilities in the arteries segments together with and also without endothelium were
checked by KC1 (60mM) along with phenylephrine ([10.sup.-5]M). The
effectiveness of endothelium removal ended up being confirmed from the inability of
acetylcholine ([10.sup.-6]M) in order to induce relaxation on phenylephrine
precontracted rubbed rings and confirmed by a less than 10% relaxation.
The aqueous extract involving MOO has been dissolved in distilled drinking water (l mg
[ml.sup.-1]), as well as dilution (0-001-1 mg [ml.sup.-1]) was produced by
Krebs-Henseleit solution. Inside the really first scries regarding experiments, effect of
the extract about the baseline along with phenylephrine ([10.sup.-5] M)
precontracted arteries was investigated, whilst endothelium intact or
endothelium denuded impact ended up being establ ished within the 2nd team of
experiments. Finally, we investigated vasorelaxant mechanisms associated with MOO on
endothelium intact arteries. Within this series of experiments, endothelium
intact arteries had been incubated with regard to 30min with inhibitors regarding production
of diverse endothelium-derived relaxing elements before preconviction
with phenylephrine. An irreversible nitric oxide (NO) synthase
inhibitor; l-NAME ([N.sup.[omega]-nitro-L-arginine-2.5 x [10.sup.-4]M),
a cyclooxygenase (COX) inhibitor; indomethacin (10[mu]M), as well as an
ATP-sensitive potassium channel blocker; glibenclamide (10[mu]M) were
tested separately. both control along with treated rings precontracted as well as the
MOO extract cumulative concentration-response curve was made. Rosmarinic
acid was also tested pertaining to its vasorelaxant impact applying the particular same
Rosmarinic acid analysis has been performed by getting an LC system consisting
of an HP Agilent 1100 series quaternary pump with a degasser and
photodiode array detector. the examples were injected to a HP Agilent
1100 Autosamplers with thermostatted column compartment on a
Phenomenex-Hyperclone ODS Cig column (5 [mu], 250 mm; 4.6 mm) at 30
[degrees]C. The Particular system was controlled and data analysis has been performed
with Agilent ChemStation software. Almost All the actual calculations relating to the
quantitative analysis had been performed together with external standardization by
measurement with the peak areas.
HPLC analysis was performed by means of a gradient elution along with flow rate of
l.Oml [min.sup.-1] as described elsewhere (Kan et al., 2007). Briefly
describing, your mobile phase has been delivered through 3 separate
containers along with gradient elution program. The first container was
ophosphoric acid 0.085% inside h2o (solution A) along with the next container
was o-phosphoric acid 0.085% in methanol (solution B), as the third
one had been o-phosphoric acid 0.085% in 2-propanol (solution C). All
solvents had been filtered via any 0.45 urn Millipore filter prior to use
and degassed throughout an ultrasonic bath. The gradient system using o-phosphoric
acid 0.085% inside water (A), o-phosphoric acid 0.085% throughout methanol (B), and
o-phosphoric acid 0.085% within 2-propanol (C) were used.
Total phenol content
Phenolic compounds were assayed according towards the Folin-Ciocalteau
method (Singleton along with Rossi, 1965). Briefly, the particular samples (150 [mu]1)
were put directly into test tubes; 750 [mu]1] associated with Folin-Ciocalteaifs reagent and
600 [mu]1 regarding sodium carbonate (7.5%) had been added. the tubes had been vortexed
and incubated in 40 [degrees]C pertaining to 30min. Later, absorption has been measured
at 760 nm. Your total phenolic content was expressed as gallic acid
All biological exercise information had been expressed because the suggest [+ or even -]
SEM for your variety of experiments indicated. the relaxations to be able to MOO and
rosmarinic acid were expressed as the percent decreases in volving the
precontraction for you to KC1. Your sensitivity of arteries to MOO can be expressed
as the actual effective concentrations in which elicited 50% of the maximal
responses ([EC.sub.50] and maximal decrease in tension
([E.sub.max]).([EC.sub.50]) values had been expressed as negative log M. The
responses were quantified within regards to [EC.sub.50] values, obtained from
the concentration-response curve with regard to MOO by simply nonlinear curve fitting,
using the actual Prism 3 Graph Pad program. Statistical analysis had been performed
by Student's-t test to end up being able in order to assess the distinction among two
groups in the identical moment as well as the one-way ANOVA. Values were considered to
be significantly various if the P worth ended up being under 0.05.
The aqueous extract regarding MOO (1-1000 [mu]g/ml) produced
concentractio n-dependent relaxation throughout phenylephrine-precontracted
endothelium intact thoracic aorta rings [E.sub.max]: 91[+ or perhaps -]
1.5%,--log[EC.sub.50]: 1.64 [+ or perhaps -] 0.02, n = 6), while abolished in
de-endothelised rings in all doses [E.sub.max]: 1.5 [+ or perhaps -] 0.3%,
-log[EC.sub.50]: 1.61 [+ or perhaps -] 0.038, n = 8). Your extract caused
concentraction-dependent relaxations throughout endothelium-intact aortic rings
precontracted using phenylephrine [Fig. 1). The Actual relaxation effects of MOO
was significantly abolished by simply L-NAME (2.4 X [10.sup.-4] M)
([E.sub.max]: 7.32 [+ as well as -] 0.34%,--log[EC.sub.50]: 1.4 [+ or perhaps -] 0.34; n
= 8) (Fig. 1). Glibeneclamide as well as indomethacin significantly reduced the
vasorlaxant impact associa ted with MOO in 1 and 0.3 mg [ml.sup.-1] doses [E.sub.max]:
53.4 [+ as well as -] 0.12%,--log[EC.sub.50]: 2.0 [+ or perhaps -] n = 8, and
[E.sub.max]: 50 [+ or -] 0.44%;--log[EC.sub.50]: 1.95 [+ as well as -] 0.02, n =
8, respectively). Rosorelaxant effect inside the exact same experiment as seen in
[FIGURE 1 OMITTED]
Quantity associated with rosmarinic acid analyzed through RP-HPLC is discovered for you to be
18.75% in the aqueous extract involving MOO. The Actual extract possessed 0.284 mg/mg
extract involving total phenol quantity as gallic acid equivalent using
We herein studied the actual aqueous extract involving MOO within thoracic aorta
strips and also observed any concentration-dependent vasorelaxant effect in
arteries precontracted with phenylephrine. damaging the particular intima regarding aorta
strips or eve n pretreatment using l-NAME virtually abolished MOO-induced
relaxation, whereas pretreatment with indomethacin as well as glibenclamide
only decreased your relaxation at higher concentration with the extract.
Although M. officinalis,, as getting a medicinal plant, continues for you to be recorded
for its utilization against a range of cardiac disorders, there can be certainly restricted
knowledge regarding its cardiovascular activity. In case the particular biochmical study
performed upon hypolipidemic rats in which the M. officinalis extract
exerted a hypolipidemic effect is actually excluded (Bolkent et al., 2005), there
are limited studies in literature investigating its cardiac activity. In
one study which usually ended up being performed around the isolated hearts of rats, M.
officinalis extract provoked significant cardiac price reduction nevertheless did
not modify the contractile force (Gazola et at., 2004).
The vascular endothelium performs the wide variety of homeostatic features within regular blood vessels. located between the vascular
lumen as well as the smooth muscle cells in the vessel wall, the particular monolayer of
endothelial cells can be able to transduce blood-brone signals, sense
mechanical forces inside the lumen, as well as regulate vascular tone through
the production of a variety of factors. Endothelium produces potent
vasodilators, for example endothelium-derived relaxing aspect (EDRF, NO),
ptostacyclin and endothelium-derived hyperpolarizing factor (EDHF).
Perhaps, the most crucial vasodilator substance produced by
endothelial cells can be endothelium-derived relaxing element (EDRF), which
has been identified because the nitric oxide (NO) radical (Ganz and Ganz,
2001). Zero is the predominant mediator inside big conduit arteries, whereas
EDHF along with prostacyclin are more prominent in smaller vessels for example the
mesenteric vessels, coronary arteries, and peripheral resistance vessels
(Shimokawa et al., 1996).
Up for you to date, innumerable studies have been reported in herbal
extracts and some of these created conclusion in regards to become able to the active component(s)
responsible for that vesorelaxant effect associated with individuals extracts. Throughout those
studies in which the herbal extracts confirmed vasodilator effect in isolated
aorta strips, as a results of investigating the particular underlying mechanism,
some were suggested to be efficient by simply releasing NO by means of endothelium,
while numerous other people were suggested to demonstrate their own vasorelaxant effect
not only by approach of NO pathway, but also EDHF and/or prostacyclin pathways
which play an important role within th e process. in your current study, we
also suggest that the aqueous extract of MOO has an
endothelium-dependent vsorelxant effect via NO pathway, involving EDHF
and prostacyclin pathways as well.
Many earlier studies along with plant extracts which could have used similar
experimental models proved that phenolic constituents such as
flavonoids, glucose derivatives, coumarines, phenylethanoids, and other
polyphenols are potentially accountable with regard to vasorelaxant activity (Ko et
al., 1991; Goto er al., 1996; Lee et al., 2002; Legssyer et al., 2004;
Brixius et al., 2006; Yoshikawa et al., 2006; Rocha et al., 2007; Anselm
et al., 2007).
These numerous studies have indicated in which in addition to be able to and also independently
from his or her antioxidant effects, polyphenols enhance the particular productions of
vasodilating factors; NO, endothelium-deriv ed aspect (EDHF), together
with prostacyclin along with inhibit the synthesis involving vasocontrictor
endothelin-1 throughout endothelial cells. Besides, some other probable mechanisms
are the elevated amount of [Ca.sup.2+] as well as redoxsensitive activation of
the phosphoinositide-3 (PI3)-kinase/Akt pathway (leading for you to rapid and
sustained activationo regarding NOS and formation involving EDHF) as well as enhanced
expression associated with NOS (Stoclet et al., 2004).
In our study by which the particular aqueous extract involving MOO was revealed to
exert an endothelium-dependent vasorelaxation throughout rat thoracic aorta, the
extract has been further reviewed by simply distinct analytical methods. Total
phenolic content in the extract (0.284mg/mg extract) emphasized that will the
extract can be quite rich inside phenolics along with HPLC analysis supported as well
t hat rosmarinic acid was the particular dominant phenolic acid (18.75%). In
addition, LC-MS information indicated the presence regarding rosmarinic acid once more in
the extract as the main component giving the single abundant pack in
total ion chromatogram (TIC) which emerged in 3.47 min (Fig. 2). Mass
spectrum in the peak scanned in positive mode together with electron-spray mass
detector gave the prominent [[M.sup.+1]] molecular ion peak at m/z 365
which clearly defined the actual moccular with a prior report (Almela et
al., 2006). As rosmarinic acid ended up being one with the most abundant within the MOO extract,
we furthermore tested your compound regarding its possible vasorelaxant effect and
observed that will it exerted any dosedependent vasorelaxative effect.
[FIGURE two OMITTED]
In conclusion, our results demonstrated the aqueous extract of
MOO possessed the ac tual concentration-dependent vasorelaxant in
phenylephrine-precontracted thoracic aorta rings along with endothelium. This
vasorelaxant activity will be caused from the stimulation of endothelial nitric
oxide formation with all the feasible involvements regarding prostacyclin along with EDHF
activation as well. Your phytochemical analysis with the extract clearly
showed the particular existence involving phenolic compounds using rosmarinic anid as the
main compound. Since pure rosmarinic acid furthermore produced vasorelaxation
in the identical experimental model. we claim that your vasorelaxation
produced through the MOO extract might most likely become thanks to phenolic compounds,
with rosmarinic acid because the significant contributor for the pointed out effect.
To the best in our knowledge, we herein document the initial research on
vasorelaxant impact associated with MOO and also rosmarini c acid inside isolated rat thoracic
aorta. Finally, we would like to include which beneath your illuminations of the
findings above, M. officinalis ssp. officinalis could possibly be considered as a
phytotherapeutic co-medication for that remedy associated with cardiovascular
diseases. Supplementary studies ought to be carried out to analyze its
cardioprotective potency within a lot more details.
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S. Ersoy (a), I. Orh an (a), *, N.N. Turan (b), G. Sahan (b), M. Ark
(b), F. Tosun (a)
(a) regarding Pharmacognosy, Faculty regarding Pharmacy, Gazi University, 06330
(b) Department associated with Pharmacology, Faculty involving Pharmacy, Gazi
University, 06330 Ankara, Turkey
* Corresponding author. Tel.: +903122023186; fax: +90 3122235018.
E-mail address: iorhan(@gazi.edu.tr (I. Orhan).
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doi: 10.1016,(j .phymed.2008.05.007