Kamis, 04 Mei 2017

Endothelium-dependent induction of vasorelaxation by Melissa officinalis L. ssp. officinalis in rat isolated thoracic aorta.


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

Plant material

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).

Extract preparation

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

experimental protocol.

HPLC apparatus

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.

Chromatographic conditions

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


Statistical analysis

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

Fig. 1.


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

Folin-Ciocalteau reagent.

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.


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

Ankara, Turkey

(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).

0944-7113/$- discover front issue [c] 2008 Elsevier GmbH. Just About All rights


doi: 10.1016,(j .phymed.2008.05.007

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