Pharmaceutical Biology

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The beneficial effects on blood pressure,

dyslipidemia and oxidative stress of Sambucus
nigra extract associated with renin inhibitors

Manuela Ciocoiu, Magda Badescu, Oana Badulescu & Laurentiu Badescu

To cite this article: Manuela Ciocoiu, Magda Badescu, Oana Badulescu & Laurentiu Badescu
(2016) The beneficial effects on blood pressure, dyslipidemia and oxidative stress of Sambucus
nigra extract associated with renin inhibitors, Pharmaceutical Biology, 54:12, 3063-3067, DOI:
10.1080/13880209.2016.1207088

To link to this article: https://doi.org/10.1080/13880209.2016.1207088

Published online: 14 Jul 2016.

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PHARMACEUTICAL BIOLOGY, 2016
VOL. 54, NO. 12, 3063–3067
http://dx.doi.org/10.1080/13880209.2016.1207088

RESEARCH ARTICLE

The beneficial effects on blood pressure, dyslipidemia and oxidative stress of

Sambucus nigra extract associated with renin inhibitors
Manuela Ciocoiua, Magda Badescua, Oana Badulescua and Laurentiu Badescub
a
Department of Pathophysiology, Faculty of Medicine, University of Medicine and Pharmacy ‘Grigore T. Popa’ Iasi, Romania; bDepartment of
Cellular and Molecular Biology, University of Medicine and Pharmacy ‘Grigore T. Popa’, Iasi, Romania

ABSTRACT ARTICLE HISTORY

Context: The health effects of Sambucus nigra L. (Caprifoliaceae) could be due to polyphenols whose Received 21 December 2015
modes of action differ from the traditional one proposed for exogenous antioxidants. Accepted 24 June 2016
Objective: The study emphasizes the effects of the association between the renin inhibitor and the poly- Revised 16 June 2016
phenolic extract on biochemical parameters and systolic (TAS) and diastolic (TAD) blood pressure within an Published online 14 July 2016
L NAME-induced experimental model of arterial hypertension (AHT).
KEYWORDS
Materials and methods: The polyphenols are extracted with ethanol from isolated and purified vegetable Blood pressure; aliskiren;
material represented by the mature fruit of the S. nigra with a dosage of 0.046 g/kg body weight (PS), polyphenols; oxidative stress
every 2 days, for 8 weeks. The dose represents 1/20 of LD50. The Wistar white rat blood pressure values
were recorded using a CODATM system, which uses a non-invasive blood pressure measuring method.
Results and discussion: The total antioxidant capacity levels were significantly decreased (p < 0.001) in
AHT group as compared to the rats in the AHT þ PS group. A combination of a renin inhibitor (Aliskiren)
and polyphenolic extract generated a superior antioxidant effect compared to administering the two separ-
ately. Both TAS and TAD in rats with drug-induced hypertension were reduced by polyphenolic extract.
The homogeneous values of TAS record a significant decrease (p < 0.001) of the average values in
AHT þ PS group or AHT þ Aliskiren group.
Conclusion: The combination of two different classes of substances, namely, renin inhibitors and natural
polyphenol extracts, reduces arterial pressure and also might reduce the side effects of the major classes
of antihypertensive agents and improve the quality of live.

Introduction hyperoside) (up to 3.0%), triterpenes (about 1%), sterols (about

Polyphenols (flavonoids, lignans, stilbenes, etc.) are the most
diverse group of phytochemicals distributed in vegetables, fruits,
olive oil and wine, and exhibit wide range of protective roles such
as hypolipidemic, antioxidative, antiproliferative and anti-inflam-
matory effects to reduce the onset of disease progression (Liu
2003; George et al. 2009).
Among the great family of polyphenols, flavonoids play an
important role. Bioflavonoids are biologically active compounds
that, once inside the human body, determine a positive biologic
response (Mennen et al. 2004). Bioflavonoids are recommended
as supplement in preventing and treating those deficiencies that
involve capillary fragility and permeability (Yao et al. 2004).
Several epidemiological studies (Dauchet et al. 2005; Bayard
et al. 2007) suggest that regular consumption of foods and bever-
ages rich in polyphenols is associated with a reduction in the risk
of a range of pathological conditions, such as arterial hypertension
(AHT), coronary heart disease, stroke, diabetes mellitus and can-
cer. Co-active compounds identified in the fresh berries of
Sambucus nigra L. (Caprifoliaceae) (Elderberry) known as
European elder include proteins and several vitamins (e.g., vita-
mins C, folic acid and pantothenic acid) (Sidor & Gramza-
Michałowska 2015). This fruit contains many primary metabolites,
as sugars and organic acids, and secondary metabolites, as flavo-
noids (kaempferol, astragalin, quercetin, rutin, isoquercetin,
1%), phenolic acids (about 3%) and essential oil (up to 0.15%)
(Ghosh & Scheepens 2009; Cunha et al. 2016).
The renin–angiotensin–aldosterone system (RAAS) plays a key
role in the regulation of blood pressure and volume homeostasis.
The renin inhibitors (Aliskiren) could be an alternative of the
angiotensin-converting enzyme inhibitors (ACEI) or the angioten-
sin receptor blockers (ARB), in treating AHT and it could also
accomplish a multi-protection of the organs (heart, kidney, brain)
(Gradman et al. 2005). Since ACEI and ARB increase the level of
plasma renin, Aliskiren combination can be beneficial because it
reduces plasma renin activity (Allikmets 2007).
The purpose of the study was to emphasize the effects of the
association between the renin inhibitor and the S. nigra extract on
biochemical parameters and heart rate, systolic and diastolic blood
pressure.
Materials and methods
Ripe berries of S. nigra were shade-dried at room temperature for
1 week. Dried berries (100 g) were chopped into small pieces and
extracted with 3  700 mL ethanol using a magnetic stirrer (FALC
F30ST), each time for 3 h. The combined extracts were taken to
dryness by evaporation under reduced pressure (BUCHI € R-210
€ €
rotavapor, BUCHI V-850 vacuum controller, BUCHI V-700

CONTACT Magda Badescu magda.badescu@gmail.com Department of Pathophysiology, University of Medicine and Pharmacy ‘Grigore T. Popa’, 16, Universitatii
Street, 700115 Iasi, Romania
ß 2016 Informa UK Limited, trading as Taylor & Francis Group
3064 M. CIOCOIU ET AL.
vacuum pump). Total phenolics quantification was performed by
Folin-Ciocalteu method. The absorbance was measured at 765 nm
after 2 h of incubation at room temperature. A calibration curve
was plotted using gallic acid as standard. The amount of total phen-
olic content was expressed as gallic acid equivalents (GAE)/100 g
extract. The absorbencies of all the solutions were determined by
using a V-550 Able Jasco UV-VIS spectrophotometer. The result is
the mean of triplicates ± standard deviation. The total content of
polyphenols was 7.63 ± 0.12 mg GAE/100 g from S. nigra extract.
The experiment used active therapeutic doses, well-determined
fractions of LD50 on an experimental model of AHT. Fractions of
LD50 are doses representing 1/5, 1/10, 1/20, 1/40 of LD50. The dose
representing 1/20 of LD50 was chosen, as it is the smallest dose that
determined the pharmacodynamic effect that is being researched,
without producing significant toxic effects. S-Sambunigrin contains
hydrogen cyanide (HCN), which is toxic (3 to 17 mg HCN/100 g
fresh weight in leaf and 3 mg HCN/100 g of fruit) (www.ema.eur-
opa.eu, 2013). Elderberry extracts used in our experiment are gen-
erally without side effects when taken in the suggested dosages.
The research was performed on Wistar white rats, with an
average weight of 250–280 g, which were divided into 6 groups of
12, namely: W Group – control, normal animals, that did not
receive natural polyphenols; PS Group – animals that were
administered polyphenols under the form of solution, from the
extract obtained from the S. nigra fruit, with a dosage of 0.046 g/
kg body, p.o. (by tube feeding), at every 2 days, for 8 weeks. The
dry polyphenol extract was diluted in DMSO, 100 mL poly-
phenolic solution containing 840 mg natural polyphenols, 95 mL
distilled water and 5 mL DMSO; AHT Group – animals which
were administered N(G)-nitro-L-arginine-methyl ester (L-NAME)
40 mg/kg body/day, i.p., at every 2 days, for 8 weeks; AHT þ PS
Group – animals which were administered polyphenols in the
dosage mentioned p.o. at every 2 days, concomitantly with L-
NAME, for 8 weeks; AHT þ Alisk Group – animals with AHT
induced by L-NAME, that were given Aliskiren 30 mg/kg body/
day, administered s.c. for 8 weeks; AHT þ Alisk þ PS Group – ani-
mals with AHT that were given Aliskiren and polyphenols in the
above-mentioned dosage, for 8 weeks.
The in vivo experiments, on experimental animal sample, were
carried out in specially equipped premises, where conditions of
habitat in accordance with standard norms were created. Between
experiments, the rats were kept in individual cages and were given
food and water. A 12-h light/dark cycles was employed.
The experiments on murine model complied with the ethical
norms in experimental research, yet also with the terms enforced
by the Iasi ‘Grigore T. Popa’ University of Medicine and
Pharmacy Commission of Bioethics. At the same time, the EU
norms concerning lab rats were taken into consideration (the
Directive of the European Council Committee 86/609/EEC).
For the extracellular response the total antioxidant capacity
(TAC) was determined by using a RANDOX kit for manual use
by Randox Laboratories Ltd. The major advantage of this test is
to measure the antioxidant capacity of all antioxidants in a bio-
logical sample and not just the antioxidant capacity of a single
compound. The method is based on formation of the
ABTS•þ cation [2,20 -azinobis (3-ethylbenzothiazoline-6-sulphonic
acid)] and its scavenging by antioxidant sample constituents (e.g.
serum or food) measured by spectrophotometry (decay of green/
blue chromophore absorbance is inversely associated with antioxi-
dant sample content and the control antioxidant is Trolox, a
hydrophilic vitamin E analogue).
Ceruloplasmin determination was performed on an EOS
BRAVO automatic analyser. Uric acid determination was carried
out by means of Siedel’s modified colorimetric method. The
exploration of the lipid profile included the measurement by pho-
tocolorimetry, in the serum obtained after separation, of high-
density lipoproteins (HDLc) (Lopes-Virella 1977), for all the ani-
mals included in the experiment.
The rat blood pressure values were recorded using a CODATM
system purchased from Kent Scientific Corporation (Torrington,
CT), which uses a non-invasive blood pressure measuring
method. It records the blood volume–pressure by a band attached
to the tail, homologated by Bland-Altman testing designed to
reveal conformity with an invasive method (radiotelemetry),
which enjoys proven accuracy, yet it is difficult to use in our
study. The method is also recommended by the AHA in its blood
pressure measuring guide for laboratory animals. The actual
experiment consists of performing at least six blood pressure
measurements in each laboratory animal, data collection by means
of the CODATM software and subsequent data processing.
Statistical data interpretation
All the data are shown as mean value ± standard error of the
mean (SEM). In order to assess the normal distribution of the
groups, Shapiro–Wilk test was performed. Statistical data inter-
pretation considered the corresponding differences for a given sig-
nificance threshold: p > 0.05, statistically insignificant; p < 0.05,
statistically significant; p < 0.01, strong statistical significance;
p < 0.001, very strong statistical significance.
Results
The TAC levels were significantly decreased (p < 0.001) in AHT
group (1.31 ± 0.16 mmol/L) as compared to the rats in the W
(1.55 ± 0.29 mmol/L) and AHT þ PS (1.53 ± 0.27 mmol/L) groups.
As expected, severe oxidative stress disturbs the antioxidant bal-
ance by generating reactive species and decreasing the TAC in the
extracellular space. There are similar TAC values in group W and
group PS (1.58 ± 0.31 mmol/L) and the differences between the
AHT and AHT þ PS groups are statistically significant (p < 0.01).
The highest average values of HDLc can be found in W group,
very significantly higher (p < 0.001) compared to the AHT group.
PS group has average values of HDLc significantly higher
(p < 0.001) than those recorded in the AHT, AHT þ PS and
AHT þ Alisk groups. The lowest average values are noticed for
the rats in AHT group (Figure 1). Supplementing the diet with S.
nigra determines average values of HDLc close to those recorded
in the W group. Significant correlations of the individual values
of HDLc with blood pressure have been met only in the groups:
AHT þ Alisk þ PS with systolic blood pressure values (TAS) a
weak indirect correlation (r ¼ 0.11) (Figure 2);
AHT þ Alisk þ PS with diastolic blood pressure values (TAD) a
moderate indirect correlation (r ¼ 0.50).
The lowest average values of the ceruloplasmin have been
recorded in the AHT group. The highest average values of the
ceruloplasmin have been recorded in the W group and in the
groups treated with S. nigra. Administration of S. nigra led to
similar average values to those found in the W group, which sug-
gests it is the most efficient administration.
The highest average values of the uric acid have been recorded
in AHT group, significantly higher than in the other groups. The
lowest average values of the uric acid have been recorded in the
groups treated with S. nigra and in the W group, significantly
lower than those registered in the other researched groups. The
statistical processing confirms the homogeneity of the uric acid
 PHARMACEUTICAL BIOLOGY 3065

40

35

30

mg/dL
25

20

15
W PS AHT AHT+PS AHT+Alisk AHT+Alisk+ PS
Study groups
Figure 1. Average values of HDLc on study groups.

AHT + PS Group AHT+ Alisk + PS Group

175 175
y = −0.25x + 148.25
R2 = 0.0126
150 150
y = −0.5607x + 165.36
TAS/TAD

TAS/TAD

R2 = 0.1047
125 125
y = −0.9583x + 126.79
R2 = 0.2524
100 100
y = −0.8218x + 122.25
R2 = 0.3244
75 75
10 20 30 40 10 20 30 40
HDLc (mg/dL) HDLc (mg/dL)
Figure 2. Correlation of HDLc with TAS in AHT þ PS and AHT þ Alisk þ PS groups. Group AHT þ Alisk þ PS shows a weak, indirect correlation between HDLc with TAS
and a moderate indirect correlation between HDLc with TAD. TAS: systolic blood pressure; TAD: diastolic blood pressure.

average values in the groups treated with S. nigra no matter of 450

the association, or not, with AHT.

The highest average values of heart rate were recorded in the 425
AHT group, significantly higher than in other investigated groups.
At the significant limit of 95%, the average values of the heart 400
rate in AHT, AHT þ PS, AHT þ Alisk groups were significantly
higher compared to those recorded in W and PS group
Heart rate

375
(Figure 3). AHT þ Alisk þ PS group has average values that are
significantly lower than the AHT group. To be noted that in
groups with AHT the association with Aliskiren and/or polyphe- 350

nols reduces the heart rate. In the PS group, the average values of
heart rate are comparable to those recorded in the W group. 325
The highest average values of TAS can be found in the AHT
group, presenting strong differences, statistically significant com-
300
pared to other investigated groups. Depending on the investigated W PS AHT AHT+PS AHT+Alisk AHT+Alisk+PS
group, the homogeneous values of TAS record a significant Study groups
decrease (p < 0.001) of the average values in AHT þ PS group or Figure 3. Average values of the heart rate on study groups.
AHT þ Alisk group (Figure 4). The highest TAD can be found in
the AHT group, significantly higher (p < 0.001) than other analysed neurological pathologies (Ferrari & Torres 2003). Various epi-
groups. The PS and AHT þ Alisk þ PS groups has average values of demiological studies have shown an inverse association between
TAD comparable to those recorded in the W group (Figure 5). the consumption of polyphenols or polyphenol-rich foods and
the risk of cardiovascular diseases (Bell & Gochenaur 2006;
Pascual-Teresa & Sanchez-Ballesta 2008). In this sense, research-
Discussion
ers had materially proved that following consumption of diets
The role of antioxidant nutrients in fighting against oxidative stress rich in fruits and vegetables there was an increase in serum
is well-established in several diseases including cardiovascular and TAC (Cao et al. 1998).
3066 M. CIOCOIU ET AL.

180 Phytochemicals like curcumin, resveratrol, epigallocatechin-3-

gallate and isothiocyanates share common properties and play an
170
important role to activate the phase II detoxifying and antioxidant
enzymes like heme oxygenase-1 (HO-1), glutathione-peroxidase
and glutathione-S-transferase by targeting the common transcrip-
160
tion factor Nrf2 [nuclear factor (erythroid derived 2) related fac-
tor] (Liby et al. 2007; Tosetti et al. 2009).
TAS, mmHg

150 The redox-sensitive transcription factor Nrf2 plays an import-

ant role in regulating induction of phase II detoxifying or antioxi-
dant enzymes (HO-1, SOD, etc.), which result in cellular defense
140
against oxidative stress and exert cytoprotective mechanism. A
cytoskeleton binding protein called Kelch-like erythroid CNC
130 homologue (ECH)- associated protein 1 (Keap1) binds to Nrf2
regulating its translocation to the nucleus or its activation (Lee-
Hilz et al. 2006). Following nuclear translocation, Nrf2 binds not
120
W PS AHT AHT+PS AHT+Alisk AHT+Alisk+PS
only to the specific consensus cis-element called antioxidative
responsive element (ARE) or electrophile response element (Na &
Study groups
Surh 2008) present in the promoter region of genes encoding
Figure 4. Average values of systolic arterial pressure (mmHg) on study groups.
many antioxidant enzymes, but also to other trans-acting factors
such as small Maf-F/G/K as well as the coactivators of ARE
140
including cAMP response element binding protein (CREB-binding
protein or CBP), p300 that can coordinately regulate the ARE-
driven antioxidant gene transcription (Dhakshinamoorthy &
Jaiswal 2000; Shen et al. 2004).
120
Endothelial dysfunction determines changes in cellular redox
characteristics. Starting from these premises and from previous
studies that have discussed the potential antioxidant extract of S.
nigra is proved that incorporation of anthocyanins from these
TAD, mmHg

100
80
60
W PS AHT AHT+PS AHT+Alisk AHT+Alisk+PS
Study groups
Figure 5. Average values of diastolic arterial pressure (mmHg) on study groups.
In this experimental model, all groups were put on the same
diet. The reduction in antioxidant mechanisms can be neutralized
through natural polyphenol compounds of S. nigra, which will
maintain TAC to levels capable of neutralizing ROS effects. The
TAC evaluation, used with other oxidative stress and antioxidant
defense biomarkers, constitutes the first step in search for a
healthy body status.
The beneficial antiradicalar effect of ceruloplasmin is suggested
by the fact that all groups present higher average values of cerulo-
plasmin compared to the hypertensive group. Through stimulat-
ing activity of ceruloplasmin, the polyphenols effect is favourable,
proving its additional antioxidant role. Moreover, low ceruloplas-
min values were associated with low HDLc values and increased
heart rate.
The ceruloplasmin and uric acid were determined as non-spe-
cific oxidative stress markers. Uric acid acts as a scavenger of free
radicals due to covalent bonds that can be set with singlet oxygen.
On animal testing, hyperuricemia predisposes to hypertension
through various mechanisms such as endothelial dysfunction,
inflammation and vascular changes in the renal microcirculation,
activation of the RAAS system (Manach et al. 2004; Schroeter
et al. 2010).
fruits into endothelial cells causes protective effect against oxida-
tive stress (Skoczynska et al. 2007).
Association within the inhibitor of renin hypertensive group
and separate polyphenols reveal an improvement in mean systolic
values of hypertension compared with values obtained in the
group that received only Aliskiren. Similar data were obtained for
diastolic component of hypertension.
The key question is whether this polyphenolic extract can be
used as both preventive and acute therapeutic agents in the treat-
ment of cardiovascular disease. In a preventive approach, S. nigra
may lower blood pressure and increased HDLc. Acutely, polyphe-
nols inhibit oxidative stress. Due to the pleiotropic properties of
the polyphenols and their potential synergies of action on vascular
endothelium, they appear to be good candidates for both the pre-
vention and treatment of cardiovascular diseases.
The use of the direct renin inhibitor in the therapy combined
with polyphenolic extract of S. nigra ensures an increased protec-
tion and improves the results in comparison with the mono-ther-
apy. The combined inhibition of RAAS may allow the use of
smaller doses of each component in order to obtain a more effi-
cient and more durable suppression of RAAS, and probably less
adverse effects.
Future studies are required to understand on the mechanisms
of the in vivo effects of polyphenolic extract. Additional aspects
about bioactivity, absorption and stability of dietary polyphenols
with respect to modulation arterial pressure by renin inhibitors
are also important areas of further research.
Conclusions
Both systolic and diastolic arterial pressure in rats with drug-
induced hypertension were reduced by polyphenolic extract from
S. nigra. When polyphenols are associated with renin inhibitor,
this occurrence is further enhanced. The polyphenolic extract has
both an antioxidant and hypolipemiant effect. In order to form

strategies for the intervention and prevention of cardiovascular
diseases, an understanding of the basic molecular mechanisms by
prophylactic agents is required.
Disclosure statement
The authors declare that they have no competing interests.
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