Current Pharmaceutical Design, 2011, 17, 4121-4131 4121

Inflammation in Hypertension: Current Therapeutic Approaches

Emmanuel Androulakis#, Dimitris Tousoulis#, Nikolaos Papageorgiou*, George Latsios, Gerasimos Siasos,
Costas Tsioufis, Anastasios Giolis and Christodoulos Stefanadis

1st Cardiology Unit, Hippokration Hospital, Athens University Medical School, Greece

Abstract: The role of inflammation as crucial underlying process contributing to the initiation and the progression of atherosclerosis as
well as its clinical manifestations is well established. Recent data have demonstrated also a strong association between essential hyper-
tension and inflammatory process. In addition, several studies have shown that tissue expression and plasma concentrations of several in-
flammatory biomarkers/mediators are related to increased risk of hypertension. The determination of markers such as acute phase pro-
teins (C-reactive protein), adhesion molecules such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and chemoki-
nes is crucial in determining therapeutic responses and clinical outcomes of hypertensive patients. In addition, several therapeutic ap-
proaches targeting blood pressure may have also beneficial effects in terms of inflammation and thus further clinical benefits. Although
the available data are encouraging, further large scale studies are required to evaluate the reported anti-inflammatory effects in manage-
ment and treatment of arterial hypertension.

Keywords: Hypertension, inflammation, therapy, cytokines, blood pressure.

INTRODUCTION THE INFLAMMATORY ASPECTS OF ESSENTIAL HY-

Inflammation is a crucial underlying process strongly related to
the initiation, progression and clinical manifestations of atheroscle-
rosis. Increasing evidence suggests that inflammatory process is
also closely associated with essential hypertension. The renin-
angiotensin-aldosterone system (RAAS) activation and the in-
creased production of angiotensin II (Ang II) are also involved in
the pathophysiology of inflammation. On the other hand, hyperten-
sion is a major risk factor for cardiovascular disease, which grants a
threefold increased risk over that of normal blood pressure (BP)
levels [1]. In addition, studies have shown that hypertension con-
tributes to the acceleration of atherosclerosis through activation of
RAS [2-5]. Activation of RAS and increase in the local production
of Ang II have been implicated in this process [6].
Moreover, studies have shown that chronic inflammation may
play a significant role in the pathophysiology of increased blood
pressure (BP) [7-9]. This is mediated through a series of interac-
tions between inflammatory cells, leading to enhanced expression
of mediators/biomarkers such as growth factors, adhesion mole-
cules, cytokines, matrix metalloproteinases and chemokines. Such
markers have been found to be associated with increased risk of
hypertension and could be useful tools in the diagnosis of hyperten-
sion in the future [10]. Furthermore, inflammatory process appears
to be a potential therapeutic target, given recent advances, suggest-
ing that hypertension-associated chronic inflammation may be
linked to increased cardiovascular risk. Current anti-hypertensive
approaches including angiotensin converting enzyme (ACE) inhibi-
tors, angiotensin receptor blockers (ARBs) and Calcium antagonists
or their combination with other agents like statins or hypoglycemic
agents, as well as other modifications seem to exert beneficial car-
diovascular effects, due to their anti-inflammatory properties [11-
15].
In the present article we will review the available literature
regarding the mechanisms of inflammatory process/biomarkers and
their association with essential hypertension. Additionally, we will
discuss the potential anti-inflammatory pharmaceutical approaches
in states of essential hypertension.
*Address correspondence to this author at the 1st Cardiology Unit, Hippok-
ration Hospital Athens University Medical School, Greece;
Tel: +30-210-7782446; Fax: +30-210-7784590;
E-mail: drnpapageorgiou@yahoo.com
#
Equally contributed.
PERTENSION
It is well known that the pathogenesis of hypertension is medi-
ated via neural or humoral stimuli, promoting changes in pressure-
natriuresis in the kidneys, initiation of the autoregulatory response
and vasoconstriction as a result of vascular hypertrophy [16, 17].
Further to the previous, data have suggested that there is also a
pathway which connects many of the proposed hypotheses on the
pathophysiology of hypertension and involves two main phases.
More specifically, during the first phase renal vasoconstriction
takes place, as a result of the activation of the RAS system and the
hyperactivation of the sympathetic nervous system [18, 19]. In the
second phase there is preglomerular vascular disease and intrarenal
vasoconstriction resulting from tubulointerstitial inflammation,
which is strongly related to interstitial T cell and macrophage re-
cruitment, local Ang II formation and generation of ROS. Such
processes promote salt retention and maintain fluid imbalance and
contribute to the initiation of hypertension [20, 21].
Although several studies have examined thoroughly the patho-
genesis of hypertension, its’ pathophysiology is rather multifacto-
rial and still remains obscure. Regarding mechanisms related to the
pathogenesis of immune response, T cells have been found to par-
ticipate actively to the initiation of hypertension. The latter appear
to be regulated a renin-angiotensin system endogenously affecting
the activity of nicotinamide adenine dinucleotide phosphate oxidase
(NADPH) and the production of pro-inflammatory cytokines [22].
In addition, experimental data have reported that a lack of T and B
cells may be associated with blunted hypertension and absence of
vascular impairment after infusion of Ang II [23]. Furthermore,
experimental and human studies have demonstrated enhanced adhe-
sion of monocytes to endothelial cells and increased monocyte
number [24, 25]. Other studies have shown elevated C-reactive
protein (CRP) levels in patients exhibiting essential hypertension,
without previous anti-hypertensive medication, thus evaluating the
close relation between inflammatory process and BP [26]. Such
results have raised speculation for the potential causal association
between CRP and hypertension, especially due to the linkage with
indexes of arterial stiffness [27].
HYPERTENSION AND INFLAMMATORY PROCESS: IN-
SIGHT TO MECHANISMS
During the last years several mechanisms and pathways have
been proposed and identified to link increased inflammatory proc-
ess and essential hypertension (Fig. 1).

1873-4286/11 $58.00+.00 © 2011 Bentham Science Publishers

4122 Current Pharmaceutical Design, 2011, Vol. 17, No. 37
Fig. (1). Inflammatory mechanisms implicated in hypertension.
Association between Inflammatory Process and the Renin-
angiotensin-aldosterone System (RAAS)
It is well known that increased levels of blood pressure stimu-
late inflammatory response which consists of processes such as
vascular permeability, leukocyte adhesion, transmigration, chemo-
taxis and cell growth as well as fibrosis.
Vascular permeability and inflammation
Increased vascular permeability along with exudation of pro-
tein-rich fluid and cell infiltration comprise the basic phase of in-
flammatory process. Angiotensin II is a factor which regulates in-
flammation through the mechanical injury due to increased blood
pressure and via the promoting effect on the release of several sub-
stances/mediators [28]. In addition, Ang II is capable to stimulate
many underlying mechanisms where leukotriene C4, prostaglandin
E2 and vascular endothelial cell growth factors (VEGFs) play an
important role [29]. The role of VEGFs in vasculogenesis and ab-
normal angiogenesis and inflammation is well evaluated. Again
Ang II participates actively and contributes to enhanced VEGF
mRNA expression in vascular smooth muscle cells, endothelial
cells, mesangial cells and cardiac myofibroblasts, mainly through
the interaction with the AT1 receptor. [30]. It is thus obvious that
Ang II contributes to the early stages of vascular inflammation
independently of hemodynamic changes [29, 30].
The Impact of Angiotensin II on Adhesion Molecules
Several biological molecules such as integrins, selectins, cellu-
lar adhesion molecules and cytokines are upregulated by Ang II,
thus supporting leukocyte tethering, rolling, adhesion and transmi-
gration through the vascular wall.
Adherence of circulating leukocytes to the endothelium and
their transmigration into the arterial wall represent crucial events of
atherogenesis [31, 32]. Adhesion is a complex process character-
ized by rolling and tethering of leukocytes to the endothelial surface
Androulakis et al.
(mediated by selectins). Activation and adhesion depend on interac-
tions between molecules such as vascular cell adhesion molecule-1
(VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) on the
endothelial surface and activated integrins on neutrophils. Transmi-
gration of adherent cells through the junctions of endothelial cells,
requires chemotaxis and involvement of another CAM, the plate-
let/endothelial cell adhesion molecule 1 (PECAM-l) [31, 32].
Moreover, there are experimental studies in states of hyperten-
sion which have evaluated the inflammatory activity of Ang II and
this was exerted directly to the vasculature. More specifically, there
was an increased leukocyte rolling, adhesion and migration after
Ang II infusion in the rat mesenteric microcirculation. In addition,
Ang II enhanced the expression of adhesion molecules such as
ICAM-1 and VCAM-1 via redox-dependent mechanisms in cultures
of endothelial cells [33].
The Impact of Angiotensin II on Proinflammatory Cytoki-
nes/Chemokines
It has been well established that circulating levels of adhesion
molecules, cytokines and chemokines are increased and arterial
hypertension is recurrently associated with inflammation of the
endothelium as a result of the upregulation of these functional
molecules. The role of chemokines in atherosclerosis has been fur-
ther supported by several studies. Low-density lipoprotein particles
are potent inducers of chemokines in various cells such as macro-
phages and vascular smooth muscle cells (SMC), suggesting that
chemokines may represent a link between various types of cells.
Proliferation, enzyme secretion, induction of reactive oxygen spe-
cies, and promotion of foam cell formation have been also observed
in vitro after chemokine stimulation [34]. Moreover, beyond their
effects on leukocytes, chemokines may also interfere with SMC
migration and growth as well as platelet activation [35, 36]. Inter-
estingly, although it has been shown that Ang II promotes the pro-
duction of cytokines/chemokines including interleukin-6 (IL-6) and
monocyte chemoattractant protein-1 (MCP-1)(an important
Hypertension and Inflammation
chemokine responsible for the migration of monocytes to the in-
tima) [37], it is still obscure whether MCP-1 maintains the inflam-
matory state in endothelial cells (ECs), thus contributing to the
progression of cardiovascular injury. In addition, the expression of
both MCP-1 and the cell chemoattractant receptor 2 (CCR2) has
been evaluated in ECs and MCP-1 levels were significantly in-
creased in patients exhibiting atherosclerosis [38]. Experimentally it
has been found that infusion of Ang II enhances TNF-a: tumor ne-
crosis factor-a (TNF-a), IL-6 and MCP-1 gene expression both in
renal cells, cardiac fibroblasts and vascular cells respectively [39,
40]. Further studies showed that Ang II stimulated the gene expres-
sion of osteopontin in cultured cerebrovascular smooth muscle cells
[41].
Inflammation in Adipose Tissue
It has been suggested that adiposity contributes to the insulin
resistance and endothelial dysfunction of hypertensive patients.

Moreover, adipocytes of untreated hypertensive patients may par-
ticipate in the expression of inflammatory and metalloprote-
ase/tissue inhibitor of metalloprotease molecules (MMP/TIMP).
More specifically, Madec et al. measured several inflammatory and
MMP/TIMP molecules in adipocytes isolated from samples of vis-
ceral and subcutaneous adipose tissue of 30 nonobese, untreated
hypertensive patients and 20 normotensive controls. Interleukin-6,
PAI-1, and tumor necrosis factor-alpha were elevated, and TNF-
beta was decreased in hypertensive compared to controls, changes
which were paralleled by higher circulating IL-6 and PAI-1 levels
in hypertensive patients. In adipocytes expression of MMP/TIMP
molecules showed a compatible pattern with the raised circulating
levels of inflammatory markers and an inverse relation to the blood
pressure [42].
THE ASSOCIATION BETWEEN ALDOSTERONE AND
VASCULAR INFLAMMATION
The oxidative and inflammatory character of aldosterone is well
established [43]. It has been shown that administration of aldoster-
one results to inflammatory arterial lesion accompanied by perivas-
cular macrophages in the heart of animal model, while it enhanced
the expression of ICAM, osteopontin and MCP-1. These effects
were suppressed by mineralocorticoid receptor (MR) blockade [44].
The latter is capable to decrease experimentally inflammatory proc-
ess in the aorta, fibrosis and myocardial hypertrophy. Additionally,
it decreased TNF-a and MCP-1 expression implicating a role in the
regulation of inflammation and oxidative stress status and plays a
critical role in the profibrotic process [45, 46]. Other studies have
shown that systemic administration of aldosterone is capable to
increase oxidative stress in animal model hearts, vasculature and
kidneys and thus increasing inflammation via activation of the re-
dox sensitive nuclear factor-B (NF-B) [47].
Regarding to the in vivo pro-inflammatory effects of aldoster-
one, studies focus on the measurements of circulating biomarkers of
inflammation, including TNF-a, MCP-1 and CRP [48]. Luther et al.
showed that although aldosterone did not affect blood pressure or
CRP, it enhanced IL-6 levels [49]. Importantly, aldosterone block-
ade attenuated urinary MCP-1, a chemokine that may contribute to
progression of various nephropathies, and oxidative stress in pa-
tients with type 2 diabetes [50]. The results of the study showed that
urinary MCP-1 is correlated with oxidative stress as measured by
urinary 8-iso-PGF2alpha and that spironolactone can decrease uri-
nary MCP-1 and oxidative stress. Although many studies have
shown that MR antagonists suppress the inflammatory effects of
aldosterone, other studies have suggested a MR-independent pro-
inflammatory impact of aldosterone, as this is indicated by the ab-
sence of specific molecular pathways blockade which leads in pro-
duction of cytokines and chemokines [51]. It is possible that aldos-
terone may contribute to increased inflammation in the vasculature
both via MR-dependent and independent mechanisms through its
non-hemodynamic effects.
Current Pharmaceutical Design, 2011, Vol. 17, No. 37 4123
ET-1-INDUCED INFLAMMATION
There is growing evidence supporting the role of endothelin-1
(ET-1) as an important mediator of chronic inflammation in the
vasculature. In patients with untreated hypertension, plasma ET-1
activity may be associated with elevated inflammatory markers of
monocyte-endothelial cell adhesive interaction in comparison to
normotensives [52]. According to experimental data, ET-1 seems to
induce chronic inflammation accompanied by increased tissue
macrophages and lymphocytes infiltration, as well as expression of
inducible NOS (iNOS) [53]. Furthermore, in a model of endothelial
cell-restricted preproendothelin-1 overexpression, ET-1 induces
vascular inflammation by multiple pathways, such as activation of
activator protein-1 (AP-1) and NF-B in the absence of blood pres-
sure elevation or systemic inflammation [54]. Endothelin-1 might
be implicated in the inflammatory process mediated by NF-,
given that in an experimental inhibition of NF-, there was a par-
allel suppression of ET-1 [55]. Moreover, it has been suggested that
CRP actively promotes proatherosclerotic and inflammatory proc-
esses potentially mediated by the action of ET-1 and IL-1 [56]. Of
note, experimental models showed that vascular remodeling, in-
creased oxidative stress ad endothelial dysfunction occurred in
animals with endothelium targeted-overexpresion of pre-pro-ET-1
[57]. Recently, Amiri et al. provided evidence that ET-1 overex-
pression when associated with high-salt intake leads to enhanced
endothelial dysfunction and vascular remodeling and contributes to
elevated blood pressure, via ET(A) receptor (ET(A)R) and ET(B)R
[58].
Nuclear Factor-kappa B (NF-
B)
uclear factor-B is particularly important in vascular inflam-
mation, as it regulates the transcription levels of several pro-
inflammatory genes. Ruiz-Ortega et al [59] have demonstrated that
Ang II activates NF-B via angiotensin receptor 1 (AT1) and AT2
in VSMCs, although NF-B–mediated transcription occurred
mainly through AT1. In turn, NF- stimulates angiotensinogen
and Ang II gene expression, thereby participating in the inflamma-
tory responses related with Ang II. The importance of NF- in
inflammation has been suggested by experimental models of athe-
rosclerosis and hypertension, demonstrating that NF-B inhibition
reduces Ang II-induced expression of IL-6, vascular cell adhesion
molecule-1 (VCAM-1) and MCP-1 [60, 61]. In VSMC from AT1a
receptor knockout mice, Ang IV, an angiotensin related peptide,
also activated NF-B pathway via AT4 receptors and increased the
expression of proinflammatory factors under NF-B control, such
as MCP-1, IL-6, TNF-a, ICAM-1, and tissue plasminogen activator
inhibitor-1 (PAI-1) [62]. In addition, NF- has also a key role in
other phases of inflammation, such as in Ang II induced migration
and proliferation of VSMCs, both under normal physiological con-
ditions, and following vascular injury [63].
Reactive Oxygen Species and Vascular Inflammation
Intense research on experimental models of hypertension has
shown an established relationship between oxidative stress and
blood pressure. Increased reactive oxygen species (ROS) are mainly
produced by NADPH of ECs, VSMCs, fibroblasts and mono-
cytes/macrophages [64, 65]. It has been previously shown that mice
lacking endothelial nitric oxide synthase (eNOS), which catalyses
the production of nitric oxide (NO) from L-arginine, have de-
creased blood pressure, decreased heart rate and increased plasma
renin activity, and also that patients with essential hypertension
have reduced production of NO compared with normotensive indi-
viduals [66]. Furthermore, Ang II potentially participates in the
production of .O2 via activation of NADH/NADPH oxidase, thus
affecting the balance between relaxing and contracting factors re-
leased from the endothelium [67]. At this point it is important to
note that ROS may directly alter vascular function and tone by sev-
eral mechanisms including altered NO bioavailability or signaling,
4124 Current Pharmaceutical Design, 2011, Vol. 17, No. 37
and significant evidence indicates that they also have a causal role
in the molecular processes leading to hypertension [68]. Also, ge-
netic polymorphisms of NADPH oxidase have been associated with
increased atherosclerosis and hypertension. For example, the
C242T CYBA polymorphism is associated with essential hyperten-
sion, NADPH oxidase-mediated oxidative stress and endothelial
damage while hypertensive patients carrying the -930(A/G) poly-
morphism are more susceptible to oxidative stress [69, 70].
Oxidative stress is a multisystem phenomenon, implicated in
every stage of inflammation, as well as endothelial dysfunction,
hypertrophy, apoptosis, migration, fibrosis, angiogenesis and in
processes related with vascular remodeling in hypertension [71].
More specifically, oxidative stress results in stimulation of the in-
flammatory process, endothelial dysfunction and altered vasodila-
tion via multiple intracellular proteins, enzymes and transcription
factors activated by ROS [72, 73]. Angiotensin II plays crucial role
in cascades leading in VSMC growth and migration, expression of
pro-inflammatory mediators and modification of extracellular ma-
trix. Angiotensin II signaling is upregulated in VSMC of hyperten-
sive patients, thus vascular NADPH oxidase is activated, and the
produced ROS contribute to the activation redox-sensitive inflam-
matory genes, such as those encoding MCP-1 and IL-6 [74, 75].
Interestingly, the role of an advanced glycation end prod-
uct/receptor for advanced glycation end product (AGE/RAGE)
system activation in endothelium is known to be associated with
reactive oxygen species generation, activation of NF-kB, increased
secretion of proinflammatory cytokines and cell adhesion molecules
as well as recruitment of proinflammatory cells, however it role has
not yet clarified [76]. Interaction of AGE with RAGE leads to in-
tracellular signalling, and subsequent expression of pro-inflam-
matory molecules and up-regulation of RAGE itself thus, a circulus
vitious may be initiated and accelerated [77]. This interaction may
contribute to pathophysiology of accelerated atherosclerosis and
coronary artery disease [77, 78] and suggests a mechanism for
chronic vascular dysfunction [79]. These considerations support the
notion that AGE/RAGE system may be an important target for
therapeutic intervention in cardiovascular diseases, such as hyper-
tension, given its association with inflammation [80].
INFLAMMATORY BIOMARKERS ASSOCIATED WITH
HYPERTENSION
The risk factors for the development of arterial hypertension
remain, for the most part, unknown. Mild chronic inflammation, as
indicated by elevated cytokines plasma concentrations, may partici-
pate in the development of endothelial dysfunction, chronic im-
paired vasodilation, and subsequently in the incidence of arterial
hypertension. [81] (Table 1).
Cross-sectional independent associations between BP and
plasma levels of CRP, but no prospective evidence of these associa-
tions is currently available. According to significant data, CRP has
been closely associated with hypertension [82, 83]. Bautista et al.,
in a study of a random sample of 300 subjects from the general
population, showed for the first time that CRP level may be an in-
dependent risk factor for the development of hypertension [84].
Furthermore, CRP has been positively associated with BP variabil-
ity, a finding with significant importance, given that elevated BP
variability has been associated with target organ damage and ad-
verse cardiovascular events in hypertensive patients [85, 86].
Patients with essential hypertension exhibit also an altered pro-
file of inflammatory cytokines, indicative of monocyte activation in
the circulation. For example, it has been observed an increased IL-1
and IL-6 production capacity when whole blood was stimulated ex
vivo with lipopolysaccharide and elevated IL-1 receptor antagonist
(IL-1ra) circulating levels in essential hypertensive patients [87].
Other data suggest that TNF-alpha and IL-6 could be independent
risk factors for high BP in healthy subjects [88]. Additionally, in
newly diagnosed never-treated patients with essential hypertension,
Androulakis et al.
hs-CRP [2.24 (1.17-4.28), P<0.05] and urinary TNF-alpha [1.21
(1.02-1.44), P<0.05] were independently related to early target
organ damage (left ventricular hypertrophy and microalbuminuria)
[89]. Blood pressure variability potentially is associated with target
organ damage and cardiovascular events. Of note, this parameter
has been significantly associated with IL-6 and CRP, while an asso-
ciation between ambulatory BP and TNF-a levels was observed,
according to a recent cross-sectional study [90]. In agreement, ac-
cording to data obtained from the thoracic aorta of spontaneously
hypertensive rats (SHR), IL-8/CXCL8 plays an important role in
the pathogenesis of Ang II-induced hypertension and vascular le-
sions [91]. Significant experimental data also indicate that prenatal
IL-6 exposure may cause hypertension by altering the renal and
circulatory RAS and fluid balance, while exposure to lipopolysac-
charide, known for its inflammation-inducing properties, resulted in
alteration of the intrarenal RAS and renal damage [92, 93].
A number of data suggest an important role of adhesion mole-
cules and chemokines in mechanisms that participate to remodeling
of the vascular wall in states of hypertension. More specifically, it
may increase the expression of these cytokines (ICAM-1, MCP-1)
and induce a significant release of granulocyte-macrophage colony-
stimulating factor (GM-CSF), MCP-1, and macrophage inflamma-
tory protein-1alpha (MIP-1a) into the circulation of patients with
mild to moderate hypertension compared with healthy controls. It is
worth mentioning that this was greater in hypertensive patients with
significant hyperlipidemia, suggesting a potential association with
an atherosclerotic inflammatory process [94-96]. A growing body
of evidence suggests that patients with hypertension exhibit in-
creased circulating levels of interleukin 18 (IL-18). Increased levels
of IL-18 seem to be associated with increased carotid intima-media
thickness, an important predictor of cardiovascular events in pa-
tients with coronary artery disease. Furthermore, experimental evi-
dence has demonstrated that catecholamines or angiotensin, two
factors well-known for their participation in pathophysiology of
hypertension, potentially induce the expression of IL-18 and/or its
receptor [97]. Thus, several inflammatory markers are associated
with increased risk of hypertension and may be proved an important
tool in the management of arterial hypertension.
IMPACT ON CLINICAL PRACTICE
Given that inflammation is closely related to hypertension, it is
relevant to mention some recent findings with respect to clinical
practice. This is nicely exemplified by a recent study in Japanese
general population, which demonstrated that during a mean follow-
up period of 2.7 years, high sensitivity C- reactive protein (hsCRP)
was a marker for relatively short-term risk of ischemic stroke in
prehypertension subjects [98]. Furthermore, CRP levels predicted
future ischemic stroke and mortality in general population, inde-
pendently from traditional cardiovascular risk factors [99]. This
potentially could be explained given recent advances suggesting
that hypertension promotes and accelerates the atherosclerotic proc-
ess via inflammatory mechanisms [100, 101]. Data have also indi-
cated that Ang II stimulates and enhances the CD40/CD40 ligand
(CD40L)-induced inflammatory process, thus, soluble CD40L
(sCD40L) levels could be used to discriminate hypertensive pa-
tients at a high risk of cardiovascular events [102, 103]. Notably,
there is evidence that the determination of CRP levels, may con-
tribute to the management of hypertension during the first hours
after stroke onset [104]. Moreover, elevated CRP levels have been
associated with a greater incidence of left ventricular hypertrophy,
diastolic dysfunction and arterial stiffness in essential hypertensives
[105, 106].
INFLAMMATION AS A TARGET OF THERAPY IN ES-
SENTIAL HYPERTENSION
Upon examining all the aforementioned data, inflammatory
biomarkers could be potential therapeutic targets, in the aim of
Hypertension and Inflammation Current Pharmaceutical Design, 2011, Vol. 17, No. 37 4125

Table 1. Association of Essential Hypertension with Inflammatory Markers

Investigators Markers Associations P- value Patients Methods

Parissis et al [96] GM-CSF + p=0.099 Hypertensives ELISA

MCP-1 + p=0.0093 Vs
MIP-1a + p=0.0089 Controls
ICAM-1 + p=0.0041
VCAM-1 + p=0.0045

Parissis et al [95] GM-CSF + p<0 .01 Hypertensives ELISA

MCP-1 + p <0.001 Vs
MIP-1a + p <0.005 controls

Peeters et al [87] TNF-a - p=NS Hypetensives ELISA

IL-1 + p <0.01 (ex vivo) Vs Ex vivo cytokine
IL-6 + p <0.01 (ex vivo) Controls production with lipopoly-
Il-1ra + p<0.001 saccharide

Madej et al [94] ICAM-1 + p <0.001 Hypetensives ELISA

MCP-1 + p <0.0001 Vs
Controls

Bautista et al [73] CRP + OR (hypertension): 1.56 General population Nephelometric assays

(95% CI, 1.14, 2.13; P =
0.005, 4th quartiles of CRP)

Bautista et al [82] CRP - p=NS Healthy ELISA

IL-6 + p<0.05 subjects
TNF-a + p<0.05

Kim et al [90] TNF-a + p=0.011 Hypertensives ELISA

IL-6 - p=NS
(BP)
GM-CSF : granulocyte macrophage colony stimulating factor; MCP-1 : Macrophage chemotactic protein-1; MIP-1: macrophage. inflammatory proteins-1; TNF-a : tumor necrosis
factor-a; IL-6, IL-12: interleukin-6, interleukin-12; CRP : C-reactive protein; ICAM-1 : intercellular adhesion molecule 1; VCAM-1: vascular cell adhesion molecule-1; BP: Blood
pressure.
+ : Significant association, - : Absence of association

reducing cardiovascular risk of hypertensive patients. Current anti-
hypertensive strategies using ACE inhibitors, ARBs and calcium
antagonists, as well as several other agents, seem to exert additive
anti-inflammatory effects in hypertension, according to clinical and
experimental data [107] (Table 2).
Classical Antihypertensive Agents
ngiotensin II receptor antagonists (AT1 antagonists) are re-
ported to affect parameters of the inflammation both in vitro and in
vivo. Specifically, 80 mg/day administration telmisartan caused
significant reduction in the IL-6 levels and a considerable decrease
in hs-CRP in essential hypertension [108]. Moreover, a randomized,
double-blind study demonstrated that candesartan improved endo-
thelial function, fibrinolysis, oxidant stress and reduced MCP-1 and
TNF-a [109]. Later, the same investigators showed that this agent
also increased adiponectin levels and improved insulin sensitivity in
hypertensive patients [110]. Also, Ang II receptor blockade by
olmesartan seems to decrease several inflammatory mediators in
essential hypertension effectively during 12 weeks of therapy [111,
112].
In addition, a growing body of evidence has suggested the po-
tential anti-inflammatory effects of ACE inhibitors. For example,
enalapril have showed similar effects on BP and on circulating
adhesion molecules with candesartan [113]. Moreover, treatment
with enalapril but not losartan, significantly decreased plasma lev-
els of cAMs and MCP-1 in hypertensive patients [114]. Antihyper-
tensive treatment with candesartan (8 mg/day) and lisinopril (10
mg/day) decreased serum MMP-9 levels (p<0.001) and TIMP-1
levels were increased (p=0.022) [115]. Also, in a randomized, dou-
ble blind, clinical trial including 288 hypertensive, treatment with
losartan improved several metabolic parameters (adiponectin, vis-
fatin) and decreased vascular remodeling biomarkers, whereas
ramipril did not [116]. Concerning calcium antagonists, in a ran-
domized, multicentre trial treatment with both nifedipine and enala-
pril tended to reduce ICAM-1 and E-selectin levels [117]. Further-
more, lacidipine treatment for 3 weeks significantly prevented the
collar-induced intimal thickening and accompanying vascular dys-
function in early atherosclerosis [118]. According to experimental
data, chronic mineralocorticoid receptor antagonism (spironolac-
tone), reduced the expression of ICAM-1 and improved cerebral
vessel structure after remodeling had developed in a model of hu-
man essential hypertension [119]. These additional to lowering BP
properties, may have implications for atherogenesis and the reduc-
tion of cardiovascular events.
4126 Current Pharmaceutical Design, 2011, Vol. 17, No. 37 Androulakis et al.

Table 2. Anti-inflammatory Effects in States of Hypertension

Investigators Setting Markers Effects on Inflammation P-Value

De Ciuceis et al [134] Male Sprague-Dawley rats VCAM-1 ng/ml  p< 0.05

(Fenofibrate 30 mg/kg)
 p=NS
(Rosiglitazone 1 mg/kg)
 p< 0.05
(Rosiglitazone 2 mg/kg)
Han et al [123] Hypertensive- sCD40L ng/ml  p=NS
hypercholesterolemic (Simvastatin 20 mg)
p=0.001

(Losartan 100 mg) p=0.001


(Combination)
Rajagopalan et al [121] Hypertensive CRP mg/dL 
(V) p<0.05
(VS20) p=0.045
(VS80) p=0.0001
MCP-1 ng/L

(V) p=0.0329
(VS20) p=0.001
(VS80) p=0.0167
Koh et al [109] Hypertensive MCP-1 (pg/ml)  p=0.003

CRP (mg/dL)  p=NS

TNF-a (pg/ml)  p=0.026

MMP-9 (ng/ml)  p=NS


MDA (μM) (Candesartan 16 mg) p=0.009
h et al [132] Hypertensive – hs-CRP 
hypertriglyceridemic (C-F) p<0.001
(C-P) p< 0.03
CD40

(C-F) p< 0.001
(C-P) p= 0.05
Chujo et al [108] Hypertensive IL-6 (pg/mL)  p<0.01

TNF-a (pg/mL)  p=NS

hs-CRP (mg/dL)  p=NS

(Telmisartan 40 mg)
MCP-1: Macrophage chemotactic protein-1; TNF-a: tumor necrosis factor-a; IL: interleukin; hsCRP: high sensitivity C-reactive protein; VCAM-1: vascular cell adhesion molecule-1;
MMP-9: M-phase phosphoprotein 9; CCR2: cell chemoattractant receptor 2; MDA: malondialdehyde; V: valsartan 160 mg; VS20: valsartan 160 mg + simvastatin 20 mg; VS80:
valsartan 160 mg + simvastatin 80 mg; C: candesartan 16 mg; F: fenofibrate 200 mg; P: placebo.
: Significant reduction,  : Absence of significant reduction
Hypertension and Inflammation
Other Pharmacological Strategies Targeting Inflammation in
Hypertension
a. Statins
Statins have been shown to possess beneficial effects which
may occur not only due to their cholesterol lowering effects, but
also, to their cholesterol-independent or pleiotropic effects [120].
Regarding the combination of anti-hypertensive treatment with
statins, in a double-blind trial, 404 patients were randomized to 12
weeks valsartan, or valsartan plus simvastatin at different dosages.
The combination of valsartan with simvastatin 80 mg was superior
in reducing hs-CRP and plasma MCP-1 levels [121]. Furthermore,
pharmacological treatment with rosuvastatin led to reductions in IL-
6, TNF-a, glutathione reductase and superoxide dismutase levels
and an increase in the superoxide dismutase level, beyond the lipid-
lowering effects [122]. In a randomized, double-blind study, sim-
vastatin, losartan and combined therapy significantly reduced
sCD40L to the greatest extent in patients with high baseline
sCD40L levels, a proinflammatory mediator which plays an impor-
tant role in atherogenesis [123].
b. Selective and Non-selective COX-inhibitors
A number of studies have focused on the role of selective and
non-selective COX-2 (Cyclooxygenase-2)-inhibitors (coxibs and
nonsteroidal anti-inflammatory drugs (NSAIDs)), as specific anti-
inflammatory drugs, in hypertension. Firstly, these drugs seem to
exert substantial effect on BP, as shown by several studies have
revealed differences within the group of selective COX-2 inhibitors.
For instance, rofecoxib has been associated with a greater increase
in blood pressure while celecoxib’s effect was comparable to other
NSAIDs [124, 125]. In accordance, data obtained from a recent
meta-analysis involving coxibs and non-selective NSAIDs have
suggested that COX-2 inhibitors were associated with BP elevation
compared with placebo and nonselective NSAIDs [126]. Concern-
ing the potential mechanisms involved, they might include a distur-
bance of sodium and water retention and a potential interference
within the anti-hypertensive effects of ACE-inhibitors and beta-
blockers, but not of calcium channel blockers [127, 128].
These agents have been associated with beneficial effects on
vascular function. Treatment with celecoxib reduced low-grade
chronic inflammation, oxidative stress and endothelial function
[129]. Similar results have been observed in endothelial function of
patients with arterial hypertension treated with celecoxib within 3 h
after the first dose [130].
c. Peroxisome Proliferator-activated Receptors Agonists
The newly appreciated anti-inflammatory actions of peroxisome
proliferator-activated receptors (PPAR) agonists (fibrates, thia-
zolidinediones or glitazones), which seem to antagonize Ang II
effects, may allow novel therapies for the inflammatory component
of hypertension [131]. More specifically, fenofibrate combined with
candesartan significantly decreased plasma malondialdehyde,
hsCRP, and sCD40L levels relative to baseline measurements
[132]. Importantly, pioglitazone reduced CRP, ICAM-1 and
VCAM-1 levels within 1 month, whereas CRP levels were de-
creased after 6 months of treatment with either pioglitazone or vo-
glibose [133]. In accordance with clinical studies, low doses of
fenofibrate and roziglitazone corrected vascular structural abnor-
malities, improved endothelial function, oxidative stress, and vascu-
lar inflammation in an Ang II-induced model of hypertension [134].
d. Cannabinoid Receptor Antagonist
Targeting the endocannabinoid system offers novel therapeutic
opportunities with regards to the treatment of hypertension. More
specifically, a new class of drugs interacting with the cannabinoid-1
receptor seems to have favorable effects on body weight, waist
circumference, insulin resistance and dyslipidaemia [135]. Interest-
ingly, rimonabant normalized BP and reduced cardiac contractility
Current Pharmaceutical Design, 2011, Vol. 17, No. 37 4127
in a model of SHR [136]. Furthermore, several experimental studies
suggest that rimonabant has potent anti-inflammatory activity,
however scarce data exist from large-scale human studies, which
could confirm or reject these primary results [137, 138].
e. Benefits of Physical Activity in Hypertension
It is widely accepted that physical activity is an effective anti-
hypertensive treatment, recommended for all patients diagnosed
with hypertension. Recently, it has become increasingly evident
that it may also have beneficial effects in inflammatory status in
that state. Notably, markers of inflammation have been inversely
associated with exercise in a dose-dependent manner, as well
documented by cross-sectional epidemiological studies [139, 140].
In addition, Adamopoulos et al. demonstrated that physical training
induced a significant reduction in circulating inflammatory cytoki-
nes IL-6 and TNF-a and soluble adhesion molecules sICAM-1 and
sVCAM-1 [141, 142]. Several other studies reported significant
reductions in CRP and IL-6 level for treated hypertensive patients,
mixed hypertensive and normotensive patients. However, there is a
need for more studies examining the inflammation-lowering effects
of exercise alone in untreated hypertension, as it is expected that in
that case a more robust anti-inflammatory response to physical
activity might be observed compared with treated hypertensive
[143].
Novel Experimental Data
Regarding novel experimental data, relaxin has emerged as an
important vasodilator of pregnancy, however the mechanisms un-
derlying relaxin-induced vasodilation are not fully elucidated. In an
experimental study, McGuane et al. demonstrated that incubation of
renal arteries with recombinant human H2 relaxin for 3 hours in
vitro attenuated myogenic constriction. A new in vitro model for
relaxin-induced vasodilation may has been established and angio-
genic growth factors seem to b important mediators [144]. Further-
more, cardiotrophin-1 (CT-1) may affect vascular smooth muscle
cells in states of hypertension. According to data derived from a
SHR model, CT-1 enhanced VSMCs proliferation and hypertrophy,
with an enhanced stimulation in SHRs. Accordingly, CT-1 expres-
sion in VSMCs was upregulated by aldosterone and hypertension,
with a greater magnitude in SHRs thus, CT-1 may represent a new
target of vascular damage in hypertension. [145]. Interestingly,
MMPs have been shown to participate in the pathophysiology of
vascular damage. Thus, MMP modulators, which are currently be-
ing developed, could potentially play important role as therapeutic
target however, clinical studies are currently lacking [146].
CONCLUSIONS
Recent studies have consistently supported the hypothesis that
inflammation plays a key role in the pathophysiology of hyperten-
sion. Also, inflammatory markers are associated with the prognosis
and clinical outcome in that state. Many studies have demonstrated
that Ang II and other components of renin-angiotensin-aldosterone
system, such as aldosterone contribute to the inflammatory re-
sponse. Moreover, it has been the established relationship between
oxidative stress, blood pressure and inflammation, a process which
also involves pro-inflammatory transcription factors and other im-
portant mediators of chronic inflammation. Importantly, these data
reviewed here provide evidence that identification of clinically
useful indices and development of novel therapeutic approaches to
interfere with inflammation and oxidative stress may ameliorate
cardiovascular outcomes in hypertensives. Common anti-
hypertensive drugs and other agents seem to exert beneficial effects
in hypertensive patients by preventing vascular inflammation and
consequently vascular damage. However, further large scale ran-
domized studies are required to determine the potential favorable
effects of suppression of inflammatory process on the management
and treatment of arterial hypertension.
4128 Current Pharmaceutical Design, 2011, Vol. 17, No. 37 Androulakis et al.

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