The Effects of Celiprolol on Serum Concentrations of Proinflammatory

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Pharmacological Reports 66 (2014) 68–73

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Original research article

The effects of celiprolol on serum concentrations of proinﬂammatory cytokines in

hypertensive (SHR) and normotensive (WKY) rats

Dariusz Andrzejczak *, Dorota Go´ rska

Department of Pharmacodynamics, Medical University of Lodz, Lodz, Poland

A R T I C L E I N F O A B S T R A C T

Article history: Background: A growing body of evidence suggests that some cardiovascular drugs could modulate the

Received 9 January 2013

level of proinﬂammatory cytokines. Therefore, the aim of the present study was to investigate whether

Received in revised form 30 July 2013

celiprolol, a third generation b-adrenoceptor blocker, affects lipopolysaccharide (LPS)-induced serum

Accepted 13 August 2013

concentrations of TNF-a, IL-1b, IL-6 in normotensive (WKY) and spontaneously hypertensive (SHR) rats.

Available online 1 February 2014 À1

Methods: Celiprolol (150 mg kg ) or vehicle was administered by gavage once daily for 21 days. Arterial

blood pressure was measured in conscious rats, using the tail-cuff method. Serum concentrations of

Keywords:

proinﬂammatory cytokines were measured with enzyme-linked immunosorbent assay kits. Addition-

Celiprolol

ally, plasma concentrations of total cholesterol, HDL-cholesterol and triglycerides were evaluated.

Proinﬂammatory cytokines

Lipids Results: In normotensive WKY rats celiprolol did not affect heart rate, blood pressure, or the serum

SHR concentrations of triglycerides, total cholesterol or HDL-cholesterol. In hypertensive animals the drug

WKY decreased lipid parameters, increased diastolic and mean blood pressure after the ﬁrst week of

administration, and produced a small but signiﬁcant decrease in heart rate after the ﬁrst two weeks of

the treatment. In both groups of animals, celiprolol decreased LPS-stimulated serum concentration of IL-

6 but did not affect levels of TNF-a and IL-1b.

Conclusions: It is suggested that the IL-6-modulating properties of celiprolol could provide additional

value to the therapeutic effectiveness of the drug in the treatment of hypertension.

ß 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp.

Introduction blockade of a1-adrenoceptors [32,43]. Other desirable effects of

celiprolol include an increase in insulin sensitivity in healthy

Increased airway resistance, peripheral and coronary vasocon- volunteers and patients with an insulin-resistance state, and

striction, proatherosclerotic action, and increased insulin resistance improvement of the serum lipid proﬁle, i.e. a decrease in

are the most important side effects of conventional b-blockers, concentrations of triglycerides and LDL-cholesterol, and an increase

limiting their therapeutical usefulness [23,26]. A large body of in HDL-cholesterol [43].

clinical data has demonstrated that the contraindications of Accumulating experimental evidence indicates the functional

celiprolol, a selective b1-blocker endowed with b2-adrenomimetic importance of an interplay between the autonomic nervous

activity, are markedly lower than those displayed by the ﬁrst system and the immune system [15]. b-Adrenoceptors are

generation of b-adrenolytic drugs. For example, celiprolol is safer expressed by various immune cells, such as lymphocytes,

than conventional b-blockers in the treatment of asthmatic patients macrophages, neutrophils, eosinophils, and basophils. Stimulation

because of lower inﬂuence on the airway function [8,32]. Moreover, of these receptors can lead to changes in the production of

celiprolol does not produce venodilatation, and has negligible proinﬂammatory cytokines [42,52]. We have previously demon-

vasoconstricting effects on stenotic and normal coronary arteries. strated that propranolol and atenolol, non-selective and cardio-

The vascular action of the drug is associated with the activation of selective antagonists of b-adrenergic receptors, respectively, are

b2-adrenoceptors, NO release from the endothelium, and weak endowed with immunomodulating properties [2,3]. This study

analyzes the effects of celiprolol on lipopolysaccharide (LPS)-

stimulated levels of proinﬂammatory cytokines, namely tumor

necrosis factor alpha (TNF-a), interleukin (IL)-1b and IL-6, in

Abbreviations: IL, interleukin; LPS, lipopolysaccharide; SHR, spontaneously hyper-

normotensive (Wistar-Kyoto; WKY) and spontaneously hyperten-

tensive rats; TNF-a, tumor necrosis factor alpha; WKY, Wistar-Kyoto rats.

sive (SHR) rats. In addition, the effects of celiprolol on heart rate,

* Corresponding author.

E-mail address: [email protected] (D. Andrzejczak). arterial blood pressure, and serum lipid proﬁle were examined.

1734-1140/$ – see front matter ß 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved. http://dx.doi.org/10.1016/j.pharep.2013.08.006

D. Andrzejczak, D. Go´rska / Pharmacological Reports 66 (2014) 68–73 69

Materials and methods tion was chosen according to Dredge et al. [13]. The blood was

allowed to clot overnight at 4 8C, and then the samples were

Animals and treatment centrifuged for 20 min at 2000 Â g. The serum was removed and

stored at À20 8C until used for biochemical measurements.

The study was conducted on 12–14 weeks old spontaneously

hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) male Arterial blood pressure and heart beat measurements

rats. The rats were housed in standard plastic cages, 10 animals per

cage, at a constant temperature of 21 Æ 1 8C, and under an Arterial blood pressure was measured in conscious rats by a

illumination cycle of 12 h light–dark (lights on between 7.00 and manometer manufactured by LETICA (Panlab S.L., Spain), using a

19.00). The animals, with an initial body weight 280–310 g, had free tail-cuff method as described in details by Go´ rska and Andrzejczak

access to standard food and tap water. In order to select the rats for [17]. Before the measurements, in order to calm the animals and

experimentation, preliminary examinations were carried out at the dilate the tail blood vessels, the rats were placed inside a warming

end of the second and third weeks of their adaptation. The animals chamber (about 34 8C) for 30 min. The measurements of arterial

with high blood pressure ﬂuctuations were excluded from the study. blood pressure (systolic, diastolic and mean) were carried out at

Experiments were conducted between 8 a.m. and 4 p.m. All least three times for each animal, and the mean values of several

experimental procedures were performed in accordance with the successive measurements were used for further analysis. Changes

Polish governmental regulations concerning experiments on animals in blood pressure were expressed as the percentage of baseline

(Dz.U.05.33.289) and were approved by the Local Ethics Committee values. The heart rate was measured by the same apparatus

for Experimentation on Animals. automatically and was registered as beats per minute.

Celiprolol (Celipres, Ranbaxy Laboratories Ltd., India;

À1

150 mg kg body weight) was suspended in 1% solution of Lipid proﬁle determination

methylcellulose (Sigma–Aldrich, Poznan, Poland) and administered

À1

by gavage at a volume of 2 ml kg b.w. once daily for 3 weeks. Total serum cholesterol concentration was determined by the

À1

Control rats received a 1% solution of methylcellulose (2 ml kg cholesterol oxidase method using a commercially available kit

b.w.). Measurements of arterial blood pressure were carried out after (Cholesterol CHOD PAP, Biolabo, Maizy, France) according to the

7, 14, and 21 days of administration of celiprolol or vehicle. manufacturer’s instructions. To measure HDL-cholesterol, low

Preliminary studies showed no detectable levels of cytokines in density lipoproteins, very low density lipoproteins, and chylomi-

the serum of SHR rats. Thus, in order to achieve a measurable crons were precipitated from serum samples by phosphotungstic

cytokine level, 24 h after the last administration of celiprolol or acid and magnesium chloride. Following that, HDL-cholesterol was

vehicle, the rats received ip a small dose of LPS from Escherichia coli measured with the aid of commercially available kit (HDL-

À1

serotype 055:B5 (Sigma–Aldrich, Poznan, Poland; 0.1 mg kg b.w. cholesterol-PTA, Biolabo, Maizy, France). Triglycerides were

À1

in 1 ml of saline kg b.w.). After 2 h, the animals were anesthetized measured using a commercially available kit (Triglycerides GPO

with ethyl ether, and the blood samples were collected by heart Method, Biolabo, Maizy, France) according to the manufacturer’s

puncture. The time of blood sample collection after LPS administra- instructions.

Table 1

À1

Effects of the repeated administration of celiprolol (150 mg kg ) on systolic (A), diastolic (B) and mean blood pressure (C) in normotensive (WKY) and hypertensive (SHR)

rats.

Time after drug administration (week) Mean changes in systolic blood pressure (% of initial values)

WKY SHR

Vehicle (n = 10) Celiprolol (n = 15) Vehicle (n = 10) Celiprolol (n = 15)

(A)

1 99.4 Æ 1.6 96.9 Æ 2.0 99.8 Æ 2.3 97.0 Æ 2.6

2 96.9 Æ 1.9 98.9 Æ 2.2 95.6 Æ 2.6 97.2 Æ 3.7

3 101.5 Æ 1.1 98.4 Æ 2.6 98.9 Æ 3.9 101.7 Æ 2.1

Time after drug administration (week) Mean changes in diastolic blood pressure (% of initial values)

WKY SHR

Vehicle (n = 10) Celiprolol (n = 15) Vehicle (n = 10) Celiprolol (n = 15)

(B)

1 97.8 Æ 4.4 105.5 Æ 4.4 97.1 Æ 3.7 110.6 Æ 3.9

2 103.1 Æ 1.4 108.8 Æ 3.6 102.6 Æ 3.6 112.0 Æ 2.3

3 101.6 Æ 3.6 109.2 Æ 5.7 98.3 Æ 3.7 102.6 Æ 2.3

Time after drug administration (week) Mean changes in mean blood pressure (% of initial values)

WKY SHR

Vehicle (n = 10) Celiprolol (n = 15) Vehicle (n = 10) Celiprolol (n = 15)

(C)

1 98.3 Æ 3.0 101.9 Æ 3.2 100.3 Æ 2.8 107.3 Æ 1.3

2 101.1 Æ 1.3 105.7 Æ 2.6 99.2 Æ 3.1 105.4 Æ 2.1

3 101.0 Æ 2.3 104.3 Æ 4.0 99.3 Æ 3.5 102.3 Æ 1.1

Values are means Æ SEM.

p < 0.05 in comparison with vehicle-treated control animals.

Baseline values of blood pressure (mmHg) for WKY rats in vehicle-treated group: systolic 117.0 Æ 2.0; diastolic 84.6 Æ 1.7; mean 95.8 Æ 1.5.

Baseline values of blood pressure (mmHg) for WKY rats in celiprolol-treated group: systolic 118.1 Æ 2.2; diastolic 85.1 Æ 1.8; mean 96.8 Æ 1.8.

Baseline values of blood pressure (mmHg) for SHR in vehicle-treated group: systolic 237.3 Æ 3.2; diastolic 128.2 Æ 2.7; mean 165.2 Æ 3.0.

Baseline values of blood pressure (mmHg) for SHR in celiprolol-treated group: systolic 235.6 Æ 2.4; diastolic 129.2 Æ 1.9; mean 164.3 Æ 2.0.

70 D. Andrzejczak, D. Go´rska / Pharmacological Reports 66 (2014) 68–73

Serum cytokine levels

Serum TNF-a, IL-1b and IL-6 concentrations were measured in

duplicates with a commercially available enzyme-linked immu-

nosorbent assay kit (Quantikine, R&D Systems, Minneapolis, USA)

according to the manufacturer’s instructions.

Analysis of data

The results are expressed as the mean Æ SEM values. The

normality of distribution was checked by means of a combination of

the Kolmogorov–Smirnov test and the Lilliefors test. The data were

analyzed for statistical signiﬁcance by one-way ANOVA followed by a

post hoc Least Signiﬁcant Differences (LSD) test, using StatSoft, Inc.

(2010) STATISTICA version 9.1. If the data were not normally

distributed, statistical evaluation was performed by using ANOVA

(Kruskall–Wallis) and the Mann–Whitney U test. The statistical

analysis of data presented in Table 2 was performed with the aid of a

t-Test for Dependent Samples. Differences were considered statisti-

cally signiﬁcant when p < 0.05. The initial values of arterial blood

pressure were assumed as 100%.

Results

Blood pressure and heart rate

In WKY rats, which were chosen as a control strain, the

following values (in mmHg) of arterial blood pressure were found:

systolic, 119.7 Æ 1.4; diastolic, 85.7 Æ 1.6; mean, 96.8 Æ 1.5

(n = 10 animals/group). The SHR selected for the study had initial

arterial blood pressure (in mmHg): systolic, 235.7 Æ 2.9; diastolic,

129.8 Æ 1.7; mean, 164.6 Æ 1.7 (n = 15 animals/group). They were

signiﬁcantly higher than the corresponding values determined in

WKY animals. SHR rats also had a signiﬁcantly higher basal heart beat

À1

Fig. 1. Effects of the repeated administration of celiprolol (150 mg kg ) on serum

rate (332.0 Æ 1.9 beats/min; n = 15) compared to WKY rats

concentration of triglycerides, total cholesterol and HDL-cholesterol in WKY and

(297.9 Æ 1.1 beats/min; n = 10).

SHR rats. Values are means Æ SEM. *p < 0.05 in comparison with control group

À1

Celiprolol (150 mg kg b.w.) did not affect blood pressure and (vehicle-treated rats).

heart rate in normotensive WKY rats (Tables 1 and 2). Administration

of the drug to SHR rats resulted in a small, but statistically signiﬁcant, hand, in SHR rats, celiprolol signiﬁcantly decreased all lipid

increase in diastolic blood pressure, by 10% and 12% after the ﬁrst and parameters by 23–27% (Fig. 1).

the second weeks, respectively, and mean blood pressure, by 7% after

the ﬁrst week (Table 1). Following one week of treatment with Serum cytokines

celiprolol, small but statistically signiﬁcant decrease in heart rate of

5% was observed, and after two weeks this grew to 8% (Table 2). As concentrations of TNF-a, IL-1b and IL-6 in the serum of SHR

rats were found to be below the limits of detection in preliminary

À1

Lipid proﬁle experiments, a small dose of LPS (0.1 mg kg b.w.) was used in

order to stimulate the production of cytokines to measurable

In WKY rats celiprolol did not modify serum concentrations of levels. Celiprolol did not affect LPS-induced serum level of TNF-a

total cholesterol, HDL cholesterol, and triglycerides. On the other

Table 3

À1

Effects of the repeated administration of celiprolol (150 mg kg ) on serum Table 2

À1

concentration of TNF- , IL-1 and IL-6 in normotensive (WKY) and hypertensive

Effects of the repeated administration of celiprolol (150 mg kg ) on heart rate in a b

(SHR) rats.

normotensive (WKY) and hypertensive (SHR) rats.

Serum concentration of WKY rats

Time after drug Mean changes in heart rate (beats per min)

administration cytokines (pg/ml)

WKY SHR Vehicle (n = 10) Celiprolol (n = 15)

(week)

Vehicle Celiprolol Vehicle Celiprolol TNF-a 2325.3 Æ 122.2 1900.7 Æ 203.3

(n = 10) (n = 15) (n = 10) (n = 15) IL-1b 138.2 Æ 27.3 121.3 Æ 25.9

IL-6 7531.1 Æ 631.3 3438.3 Æ 849.8

1 296.7 Æ 1.5 298.5 Æ 2.3 333.3 Æ 2.2 315.2 Æ 3.0

Serum concentration of SHR rats

2 295.8 Æ 1.4 300.8 Æ 2.4 329.8 Æ 3.8 306.3 Æ 2.9

cytokines (pg/ml)

3 296.5 Æ 1.0 301.2 Æ 2.1 328.8 Æ 3.1 329.0 Æ 4.3

Vehicle (n = 10) Celiprolol (n = 15)

Values are means Æ SEM.

* TNF-a 2227.9 Æ 24.2 2055.1 Æ 272.9

p < 0.05 in comparison with baseline value (‘‘0’’) in celiprolol-treated SHR rats.

IL-1b 132.4 Æ 40.9 134.3 Æ 25.8

Baseline heart rate values in vehicle-treated WKY 297.9 Æ 1.1 beats/min and *

IL-6 5404.4 Æ 596.8 2579.1 Æ 605.0

celiprolol-treated WKY 298.9 Æ 1.8.

Baseline heart rate values in vehicle-treated SHR rats 332.0 Æ 1.9 beats/min and Values are means Æ SEM.

celiprolol-treated SHR 331.5 Æ 2.9. p < 0.05 in comparison with control, vehicle-treated rats.

D. Andrzejczak, D. Go´rska / Pharmacological Reports 66 (2014) 68–73 71

and IL-1b in WKY and SHR rats. On the other hand, in both strains with isoprenaline, a non-selective b-adrenoceptor agonist, prior to

of animals, the drug decreased IL-6 serum level by approximately LPS administration resulted in a signiﬁcant elevation of IL-6

54% (Table 3). plasma level in mice [42]. The action of celiprolol on IL-6

presumably did not also result from its b1-adrenolytic activity,

Discussion as results from our laboratory have previously demonstrated that

prolonged treatment of rats with atenolol, a selective b1-blocker,

Hypertension is a multifactorial disease with a very complex increases serum IL-6 levels [3].

etiology. An accumulating body of experimental data suggests the IL-6 is a proinﬂammatory cytokine with pleiotropic activity

involvement of the immune system and a low-grade inﬂammation [29]. A growing body of experimental evidence indicates that IL-6

process in the development of hypertension and in the cardiovas- plays an important role in mediating inﬂammatory and blood

cular complications associated with it [20,21]. Furthermore, ample pressure response to angiotensin II. Thus, treatment of C57BL/6J

evidence links proinﬂammatory cytokines with hypertension, but mice with IL-6 increased vascular AT1 receptor expression,

whether elevated levels of cytokines precede or follow the angiotensin II-induced vasoconstriction in aortic segments,

development of hypertension remains to be elucidated [41,46]. enhanced vascular superoxide production and impaired endothe-

Taking into account the above facts, an additional anti-inﬂamma- lium-dependent vasodilatation [48]. During two weeks of angio-

tory activity of a drug used in the treatment of hypertension could tensin II infusion, the IL-6 knockout mice had signiﬁcantly lower

be considered as its therapeutically important property. blood pressure than wild type animals. This observation led Lee

b-Adrenergic blockers are widely used in the treatment of et al. [25] to suggest that hypertension caused by angiotensin II and

various cardiovascular diseases, including hypertension. At pres- by a high-salt diet could result, to some extent, from the action of

ent, little is known about the effects of this group of drugs on IL-6. Similar results were presented by Coles et al. [11].

À1

inﬂammatory mediators in hypertension. Nemati and coworkers Subcutaneous administration of angiotensin II (1.1 mg kg /day)

[33] analyzed the effects of various hypotensive drugs, including to wild type mice evoked hypertension and cardiac hypertrophy.

atenolol, on LPS-induced IL-1b secretion from peripheral blood Such effects were not observed in IL-6 knockout mice. A study by

polymorphonuclear leukocytes isolated from normotensive indi- Schrader et al. [39] on mice showed that IL-6 could be essential for

viduals and from patients with essential hypertension. They found angiotensin II-induced endothelial dysfunction, i.e. production of

no signiﬁcant effect of this selective b1-blocker on the secretion of reactive oxygen species and reduction of endothelial nitric oxide

cytokine by cells from hypertensive subjects. An eight-week synthase mRNA expression. In Sprague-Dawley rats, IL-6 caused a

treatment of hypertensive postmenopausal women with atenolol pattern of myocardial remodeling similar to that seen in

did not affect serum IL-6 level and slightly increased the level of hypertension [31]. It should be emphasized that an association

TNF-a [37]. On the other hand, Madej et al. [28] demonstrated that between IL-6 levels and elevated blood pressure/hypertension

treatment of hypertensive patients with bisoprolol decreased TNF- [9,10], and increased risk of myocardial infarction [38] have been

a, IL-1b and IL-6 secretion from peripheral blood mononuclear demonstrated in man.

cells. Using an animal model of hypertension, SHR rats, our The two other studied proinﬂammatory cytokines, TNF-a and

previous studies have demonstrated that atenolol does not modify IL-1b, have been proven to exert negative effects on the

the LPS-induced elevation of TNF-a and IL-1b blood levels, while endothelium. Thus, TNF-a could stimulate the angiotensinogen-

propranolol, a non-selective b-blocker, was found to reduce the encoding gene [6] and limit the half-life of eNOS mRNA [51],

stimulated IL-1b level [2,3]. whereas IL-1b has been shown to favor the development of

Celiprolol is generally described as a third generation b- atheromatous changes [27]. Increased IL-1b serum levels were

adrenoceptor antagonist. In addition to selective b1-adrenoceptor found in hypertensive patients [12]. Recent studies suggest that

blocking properties, the drug has b2 partial agonist properties, TNF-a and IL-1b could act on the brain to increase blood pressure,

exerts direct vasodilator effects, and does not depress the heart heart rate, and sympathetic nerve activity [49]. Of note, etanercept,

rate to the same extent as several other b-blockers. The a TNF-a antagonist used mainly in autoimmune diseases, such as

therapeutic indication for the use of celiprolol includes mainly rheumatoid arthritis, was shown to prevent the development of

hypertension and angina complicated by impaired glucose hypertension in fructose-fed rats [44].

tolerance or diabetes mellitus, peripheral vascular resistance There are a few published reports on effects of b-blockers on

and hyperlipidemia [14]. Data regarding cytokine-modulating serum levels of TNF-a and IL-1b. By analogy to celiprolol (present

properties of celiprolol are sparse. Hayashi et al. [22] observe that data), atenolol [3] and nebivolol [18], a b1-selective adrenergic

À1

celiprolol (100 mg kg /day) improved endothelial function in blocker with additional vasodilating properties, did not modify

Otsuka Long-Evans Tokushima Fatty diabetic rats. Furthermore, LPS-stimulated levels of TNF-a and IL-1b in normotensive as well

plasma concentrations of TNF-a were signiﬁcantly elevated in as in hypertensive rats. On the other hand, propranolol, a non-

vehicle- and atenolol-treated rats but not in animals receiving selective b-adrenoceptor antagonist, suppressed gene expression

celiprolol. In another study, Tsubokou et al. [45] demonstrate that of TNF-a in murine viral myocarditis [47], and decreased LPS-

celiprolol decreases upregulated transforming growth factor-b1 stimulated TNF-a and IL-1b levels in WKY and SHR rats [2].

(TGF-b1) expression in deoxycorticosterone acetate (DOCA)-salt After one and two weeks of celiprolol administration to SHR rats,

hypertensive rats. Of note, this activity of celiprolol has been a small (10–12%) but signiﬁcant increase in diastolic blood pressure

recently used in the treatment of vascular Ehlers-Danlos syn- was observed. This effect could be only partially explained by the

drome, where circulating TGF-b likely plays the role of an complex effect of the drugon the b1- and b2-adrenoceptors.Alvarez-

important pathogenic factor [5,7,24,35]. Guerra et al. [1] showed that celiprolol could antagonize, in a dose-

The results of the present study demonstrated, for the ﬁrst time, dependent manner, the hypotensive effects of salbutamol (a b2-

effects of celiprolol on LPS-induced proinﬂammatory cytokines adrenoceptor agonist), and even inhibit its own hypotensive effect in

concentration in normotensive and hypertensive animals. Al- male Sprague-Dawley rats. At present it might be speculated that the

though the drug did not modify LPS-induced TNF-a and IL-1b complex molecular mechanism of celiprolol action, loss of its

serum levels in SHR and WKY rats, it potently decreased IL-6 level selectivity for both antagonist and partial agonist effects [50], or

in both rat strains. It appears unlikely that the action of celiprolol increased peripheral resistance, consistent with the observed heart

on LPS-stimulated serum level of IL-6 is related to its partial b2- rate decrease, could contribute to the blood pressure changes in

sympathomimetic activity, as stimulation of b2-adrenoceptors hypertensive rats described in this study.

72 D. Andrzejczak, D. Go´rska / Pharmacological Reports 66 (2014) 68–73

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