Endothelium-dependent contractions and endothelial dysfunction in human hypertension

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DOI: 10.1111/j.1476-5381.2009.00240.x · Source: PubMed
Abstract
The endothelium is a crucial regulator of vascular physiology, producing in healthy conditions several substances with a potent antiatherosclerotic properties. Accordingly, the presence of endothelial dysfunction is associated with subclinical atherosclerosis and with an increased future risk of cardiovascular events. A large body of evidence supports the fundamental role of nitric oxide (NO) as the main endothelium-derived relaxing factor. However, in the presence of pathological conditions, such as hypertension, endothelial cells, in response to a number of agents and physical stimuli, become also a source of endothelium-derived contracting factors (EDCFs), including endothelins and angiotensin II and particularly cyclooxygenase-derived prostanoids and superoxide anions. These latter were at first identified as responsible for impaired endothelium-dependent vasodilation in patients with essential hypertension. However, cyclooxygenase-dependent EDCFs production is characteristic of the aging process, and essential hypertension seems to only anticipate the phenomenon. It is worth noting that both in aging and hypertension EDCF production is associated with a parallel decrease in NO availability, suggesting that this substance could be oxygen free radicals themselves. Accordingly, in hypertension both indomethacin, a cyclooxygenase inhibitor, and vitamin C, an antioxidant, increase the vasodilation to acetylcholine by restoring NO availability. In conclusion, hypertension is characterized by a decline in endothelial function, associated with a progressive decrease in NO bioavailability and increase in the production of EDCF. The mechanisms that regulate the balance between NO and EDCF, and the processes transforming the endothelium from a protective organ to a source of vasoconstrictor, proaggregatory and promitogenic mediators remain to be determined.
THEMED SECTION: ENDOTHELIUM IN PHARMACOLOGY
REVIEW
Endothelium-dependent contractions and
endothelial dysfunction in human hypertension
Daniele Versari, Elena Daghini, Agostino Virdis, Lorenzo Ghiadoni and Stefano Taddei
Department of Internal Medicine, University of Pisa, Pisa, Italy
The endothelium is a crucial regulator of vascular physiology, producing in healthy conditions several substances with a potent
antiatherosclerotic properties. Accordingly, the presence of endothelial dysfunction is associated with subclinical atherosclerosis
and with an increased future risk of cardiovascular events. A large body of evidence supports the fundamental role of nitric oxide
(NO) as the main endothelium-derived relaxing factor. However, in the presence of pathological conditions, such as hyperten-
sion, endothelial cells, in response to a number of agents and physical stimuli, become also a source of endothelium-derived
contracting factors (EDCFs), including endothelins and angiotensin II and particularly cyclooxygenase-derived prostanoids and
superoxide anions. These latter were at first identified as responsible for impaired endothelium-dependent vasodilation in patients
with essential hypertension. However, cyclooxygenase-dependent EDCFs production is characteristic of the aging process, and
essential hypertension seems to only anticipate the phenomenon. It is worth noting that both in aging and hypertension EDCF
production is associated with a parallel decrease in NO availability, suggesting that this substance could be oxygen free radicals
themselves. Accordingly, in hypertension both indomethacin, a cyclooxygenase inhibitor, and vitamin C, an antioxidant, increase
the vasodilation to acetylcholine by restoring NO availability. In conclusion, hypertension is characterized by a decline in
endothelial function, associated with a progressive decrease in NO bioavailability and increase in the production of EDCF. The
mechanisms that regulate the balance between NO and EDCF, and the processes transforming the endothelium from a protective
organ to a source of vasoconstrictor, proaggregatory and promitogenic mediators remain to be determined.
British Journal of Pharmacology (2009) 157, 527–536; doi:10.1111/j.1476-5381.2009.00240.x
This article is part of a themed section on Endothelium in Pharmacology. For a list of all articles in this section see
the end of this paper, or visit: http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009
Keywords: endothelium; hypertension; vasodilation; endothelium-derived contractions; EDCF; cyclooxygenase; oxidative stress
Abbreviations: COX, cyclooxygenase; EDCF, endothelium-derived contracting factor; EDHF, endothelium-derived hyperpo-
larizing factor; eNOS, nitric oxide synthase; ET, endothelin; FBF, forearm blood flow; L-NMMA, monomethyl-
L-arginine; NO, nitric oxide; ROS, reactive oxygen species
Introduction
The endothelium, considered for years a mere selectively
permeable barrier between the bloodstream and the vascular
wall, is now recognized to be a fundamental homeostatic
organ for the regulation of the vascular tone and structure.
Under physiologic conditions, endothelial cells are able to
synthesize and secrete a large spectrum of antiatheroscle-
rotic substances, the most characterized of which is nitric
oxide (NO), a gas generated from the metabolism of
L-arginine by constitutive endothelial NO synthase (eNOS)
(Vanhoutte, 1989). In normal conditions, endothelial
stimulation induces the production and release of NO,
which diffusing to surrounding tissues and cells, exerts its
cardiovascular protective role by relaxing media-smooth
muscle cells, preventing leukocyte adhesion and migration
into the arterial wall, muscle cell proliferation, platelet adhe-
sion and aggregation, and adhesion molecule expression
(Vanhoutte, 1989; Taddei et al., 2003). In disease conditions,
including the presence of cardiovascular risk factors, the
endothelium undergoes functional and structural alterations
and loses its protective role, becoming a pro-atherosclerotic
structure (Vanhoutte, 1989). The loss of the normal endot-
helial function is referred to as ‘endothelial dysfunction’,
which is characterized by impaired NO bioavailability. This
can follow either a reduced production of NO by eNOS, or,
more frequently, an increased breakdown by reactive oxygen
species (ROS) (Vanhoutte, 1989; Taddei et al., 2003). When
NO availability is significantly reduced, the endothelium
Correspondence: Stefano Taddei, Department of Internal Medicine, University
of Pisa, Via Roma 67, Pisa 56100, Italy. E-mail: s.taddei@med.unipi.it
Received 8 September 2008; revised 20 January 2009; accepted 5 February
2009
British Journal of Pharmacology (2009), 157, 527–536
© 2009 The Authors
Journal compilation © 2009 The British Pharmacological Society All rights reserved 0007-1188/09
www.brjpharmacol.org
activates various compensatory physiological pathways. In
this setting, the endothelium-dependent vasodilation is
partly maintained, although impaired, by the production
and release of endothelium-derived vasodilators other
than NO, such as prostanoids (prostacyclin) and other
endothelium-derived hyperpolarizing factors (EDHFs). Of
importance, a dysfunctioning endothelium also becomes a
source of other substances and mediators which are detri-
mental to the arterial wall, including endothelin-1 (ET-1),
thromboxane A
2
, prostaglandin H
2
and ROS (Taddei et al.,
2003), with various pro-atherosclerotic features, including a
vasoconstricting action. Accordingly, the presence of endot-
helial dysfunction, characterized by both NO deficiency and
activation of endothelium-dependent vasoconstriction, has
been implicated in the pathogenesis of atherosclerosis and
thrombosis (Taddei et al., 2003; Brunner et al., 2005).
How to evaluate endothelial function
The regulation of the endothelial physiology is largely district-
specific and differs in various organs and tissues, and within
the same vascular district it largely varies in relation to vessel
size – that is, large arteries (macrocirculation) versus arterioles
(microcirculation). It is therefore conceivable that the use of
systemic circulating markers of endothelial function is unreli-
able. In addition, NO is a gas with a very short half-life and its
moment-by-moment quantification in a specific vascular dis-
trict is almost impossible. For these reason, NO bioavailability
in humans is indirectly estimated from its local vasodilating
effect after endothelia stimulation with specific external
mechanical and pharmacological stimuli, that is, through
vascular reactivity tests (Deanfield et al., 2005). Specifically,
endothelium-dependent vasodilation can be evaluated by the
use of either receptor-operated (acetylcholine, bradykinin,
substance P), mechanical (increase in shear stress) or mixed
(dynamic exercise and cold pressor test) stimuli and in differ-
ent vascular beds (John and Schmieder, 2000; Deanfield et al.,
2005). In the heart, endothelial function can be assessed in the
macrocirculation by quantitative angiography, evaluating the
change in coronary artery diameter after local infusion of
agonists (e.g. acetylcholine), and in the microcirculation as
changes in flow by intravascular ultrasound (Deanfield et al.,
2005). This central coronary approach has conceivably the
highest clinical value, as it explores the vascular bed more
often involved by atherosclerosis and responsible for cardiac
events. However, its invasiveness highly limits its applicability
(Deanfield et al., 2005). For this reason, several other techni-
ques have been developed to assess peripheral circulation en-
dothelial function. In particular, peripheral microcirculation
can be thoughtfully studied by venous plethysmography to
evaluate forearm blood flow (FBF) changes to intraarterial in-
fusion of various substances. This approach is very useful as it
allows to study the mechanisms underlying endothelial dys-
function by administering endothelial agonist and antagonist
(Deanfield et al., 2005). However, again FBF is still invasive and
requires brachial artery cannulation. Therefore, in recent years
flow-mediated dilation of the brachial artery has been widely
used among researchers; indeed, although its reproducibility is
limited, it has the advantage of being non-invasive as it uses
ultrasound analysis of brachial artery diameter after local
increase in shear stress, induced by 5 min of forearm ischemia
(Deanfield et al., 2005) and additionally the stimulus used (in-
crease in flow) is more physiological than the local infusion of
endothelial agonists at pharmacological concentrations (e.g.
muscarinic agents). Finally, it is noteworthy that vascular
responses obtained in different vascular districts and using dif-
ferent stimuli and techniques are poorly related and give there-
fore different information (Anderson et al., 1995). Considering
this aspect and the autocrine-paracrine nature of endothelial
physiology, high caution should be paid in the interpretation
of experimental studies and mostly in considering data
obtained in a vascular district as completely indicative endot-
helial function in other district (e.g. coronary circulation).
Clinical significance of endothelial dysfunction
Endothelial dysfunction, defined as reduced vasodilating
response to endothelial stimuli, is observed in the presence of
major cardiovascular risk factors, including aging (Brunner
et al., 2005), menopause (Brunner et al., 2005), smoking
(Brunner et al., 2005), diabetes mellitus (Brunner et al., 2005),
hypercholesterolemia (Brunner et al., 2005) and hypertension
(Brunner et al., 2005). Notably, the presence of multiple risk
factors is able to determine a progressive worsening of endot-
helial function (Vita et al., 1990; Benjamin et al., 2004). Con-
versely, the presence of endothelial dysfunction is also
suggested to increase the susceptibility to develop hyperten-
sion (Rossi et al., 2004) and diabetes (Rossi et al., 2005), thus
being not only a collateral feature of established risk factors,
but also a possible pathogenetic mechanism for their onset.
The hypothesis that endothelial dysfunction is clinically
relevant in the progression of the atherosclerotic process is
supported by several evidences. Thus, the presence of sub-
clinical and clinical target organ damage, an intermediate
stage in the continuum of vascular disease, is associated to the
presence of endothelial dysfunction. In particular, increased
intima-media thickness of the common carotid artery, a non-
invasive marker of atherosclerosis is directly related to the
impairment of endothelial dysfunction in the peripheral cir-
culation (Ghiadoni et al., 1998; Juonala et al., 2004). More-
over, in patients with coronary artery stenosis, an impairment
of endothelium-dependent vasodilation in coronary arteries
is present, not only in a diseased vessel but also in a non-
diseased pre-stenotic arterial segments (Ludmer et al., 1986) or
vessels (Quyyumi et al., 1997), and in the coronary microcir-
culation (Egashira et al., 1993; Quyyumi et al., 1997). Interest-
ingly, an inverse relation between the presence of intramural
plaques as detected by intravascular ultrasound and vasodila-
tion to intracoronary acetylcholine is present in patients
without angiographic evidence of coronary atherosclerosis
(Zeiher et al., 1994). These data are supported also by
longitudinal studies, showing a significant augmented risk of
developing arteriolosclerosis and plaques in heart trans-
planted patients with coronary endothelial dysfunction
(Davis et al., 1996; Hollenberg et al., 2001). Overall, these data
support the presence of a link between endothelial dysfunc-
tion and the probability of developing or worsening structural
changes in the coronary and carotid circulation.
Endothelium and hypertension
528
D Versari et al
British Journal of Pharmacology (2009) 157 527–536
In recent years a large number prospective of studies has
been conducted in several groups of patients to prove the
prognostic significance of the association between endothe-
lial dysfunction and cardiovascular disease (Taddei and Sal-
vetti, 2002; Lerman and Zeiher, 2005). As previously noted,
the endothelium-dependent vasodilating responses in differ-
ent vascular districts of the same subject are poorly related
(Anderson et al., 1995; Eskurza et al., 2001; Park et al., 2001),
both because of the different techniques and stimuli used and
because of the highly region-specific regulation of endothelial
physiology. Despite this district specificity, the presence of
endothelial dysfunction almost invariably results to be an
independent predictor of future clinical events wherever
detected. Accordingly, this prognostic role has been demon-
strated in peripheral (Neunteufl et al., 2000; Heitzer et al.,
2001; Gokce et al., 2002; Brevetti et al., 2003) and central
circulation (Schachinger et al., 2000; Suwaidi et al., 2000;
Halcox et al., 2002; Schindler et al., 2003; Targonski et al.,
2003), in microcirculation (Heitzer et al., 2000; Suwaidi et al.,
2000; Targonski et al., 2003) and large arteries (Neunteufl
et al., 2000; Schachinger et al., 2000; Suwaidi et al., 2000;
Gokce et al., 2002; Halcox et al., 2002; Brevetti et al., 2003;
Schindler et al., 2003; Targonski et al., 2003) and indepen-
dently from the used endothelial stimulus. Caution must,
however, be paid in interpreting the data, as so far the total
number of clinical events investigated is limited and not
conclusive to define the presence of endothelial dysfunction
as an independent risk factor for cardiovascular events or as
an integrated marker for the global risk.
Endothelial dysfunction in essential hypertension
Most of studies investigating endothelium-derived contract-
ing factors (EDCFs) and relaxing factors in humans have been
performed in the peripheral microcirculation using the per-
fused forearm technique, which providing the possibility of
local intra-arterial infusion of vascular active agents, allows to
investigate fine biochemical mechanisms (Figure 1). With this
technique, the detection of increase or decrease in FBF by
venous plethysmography is a highly reliable index of local
vasodilation or vasoconstriction respectively.
A large body of evidence invariably demonstrates that the
presence of endothelial dysfunction is a hallmark of the
hypertensive patient (Panza et al., 1994; 1995; Taddei et al.,
1998b; John and Schmieder, 2000). A reduction in the net
production of NO does not seem to be importantly implicated
in impairing NO bioavailability in hypertension, although a
lack of the enzyme substrate L-arginine by enhanced activity
of vascular arginase has been recently suggested in some
forms of experimental hypertension (Zhang et al., 2004).
Nonetheless, so far the main cause of hypertension-related
endothelial dysfunction in humans has been identified with
an increased NO breakdown. In particular, hpertension-
related endothelial dysfunction has been demonstrated to be
the consequence of increased oxidative stress production
(Taddei et al., 1998a). ROS, mainly superoxide anions, are
highly reactive and destroy NO, thus reducing its bioavailabil-
ity and producing peroxynitrites (Vanhoutte, 1989), which
have several negative effects on vascular function and struc-
ture (Szabo et al., 2007). Supporting this hypothesis, the intra-
arterial administration of high doses of the antioxidant
vitamin C in the forearm of essential hypertensive patients, is
able to acutely restore a normal endothelium-dependent
vasodilation and to restore NO bioavailability (Taddei et al.,
1998a). Various enzymatic and non-enzymatic sources of ROS
have been described to be activated in endothelial cells,
smooth muscle cells and inflammatory cells within the arte-
rial wall of hypertensive patients, including NAD(P)H-
oxidase, xanthine oxidase, cyclooxygenase (COX) and
Figure 1 Schematic representation of the perfused forearm technique to evaluate endothelial function in human peripheral microcirculation.
The brachial artery of the non-dominant forearm is cannulated for drug infusion at systemically ineffective rates, intra-arterial blood pressure
(BP) and heart rate (HR) monitoring. Forearm blood flow is measured by strain-gauge venous plethysmography.
Endothelium and hypertension
D Versari et al
529
British Journal of Pharmacology (2009) 157 527–536
uncoupled eNOS (John and Schmieder, 2000). In the presence
of hypertension, the reduced NO availability is partially com-
pensated by the activation of alternative pathways, including
the production and release of EDHFs which contribute to
maintain endothelium-dependent vasodilation (Taddei et al.,
1999a). In this condition, a complex interplay between NO
and ET-1 can contribute to the establishment of endothelial
dysfunction. Indeed, despite having normal circulating levels
of ET-1, hypertensive patients show an augmented vasocon-
strictor activity of the peptide in the peripheral circulation
which parallels the diminished NO availability (Schiffrin,
1999). At the vascular level, ET-1 binds to and exerts its effects
through its specific receptors ET
B
and ET
A.
In particular, ET
A
are mainly localized in the smooth muscle cell and stimulate
vascular contraction and hypertrophy (Penna et al., 2006). On
the contrary, ET
B
are scantly represented on smooth muscle
cells but they are abundant on endothelial cells and mediate
NO release thus inhibiting vasoconstriction and cell prolifera-
tion (Penna et al., 2006). In the presence of endothelial dys-
function, activation of endothelial ETB receptors is not able to
increase NO-mediated vasodilation and the resulting con-
tracting effect of ET-1 is enhanced (Penna et al., 2006). This
phenomenon is further fostered by the reduced inhibitory
effect of NO on ET-1 production and activity (Taddei et al.,
1999b). The overall altered equilibrium between the two
systems can lead to an increased vasoconstricting and prolif-
erative activity of endotelin-1.
It is worth noting that hypertension-related endothelial
dysfunction does not seem to represent a pathogenetic
mechanism for the increased blood pressure values, as there is
no association between the degree of endothelial dysfunction
and blood pressure values (John and Schmieder, 2000). The
condition seems rather to be partly genetically determined
and accordingly offspring of hypertensive patients, although
normotensive, show impaired endothelial function (Taddei
et al., 1996b). Finally, endothelial dysfunction is not a specific
feature of hypertension, but it is common to the majority of
cardiovascular risk factors (Deanfield et al., 2005).
EDCFs
In the years following the discovery of the obligatory role of
endothelial cells to induce a vasodilating response to acetyl-
choline in rabbit isolated arteries (Furchgott and Zawadzki,
1980), De Mey and Vanhoutte (De Mey and Vanhoutte, 1982;
1983) also observed that the endothelium can induce con-
tractions of isolated canine arteries and veins. Since then, the
pathophysiology of endothelium-dependent contraction has
been deeply investigated. Several agents and physical stimuli
induce such contractions through the activation of various
biochemical pathways leading to the production and secre-
tion of different EDCFs in different animal species and vascu-
lar districts. Although relaxing factors play a crucial role in the
regulation of circulatory vasomotion, experimental evidence
support the concept that also contracting factors have a sig-
nificant role, which becomes particularly important in aging,
in the hypertensive process or under other pathological con-
ditions such as diabetes, vasospasm and reperfusion injury
(Katusic and Shepherd, 1991; Luscher et al., 1992).
Among proteic mediators, ET represent a potent vasocon-
stricting agent released by the endothelium, particularly in
pathological conditions (Vanhoutte, 1989). Additionally,
also angiotensin II, beyond being produced systemically, can
be released by endothelial cell and induce local vascular
constriction (Vanhoutte, 1989). However, COX-dependent
EDCFs are at the moment considered to play a primary role
(Figure 2). It was demonstrated that arachidonic acid, a pre-
cursor of COX-derived products, is able to induce
endothelium-dependent contractions in arteries and veins
and that this phenomenon is inhibited by COX blockers
(Miller and Vanhoutte, 1985; Katusic et al., 1988). Under
pathological conditions, such as experimental diabetes and
hypertension, COX-dependent EDCFs can be released fol-
lowing endothelial stimulation with acetylcholine or the
calcium ionophore A23187 (Konishi and Su, 1983; Luscher
and Vanhoutte, 1986; Katusic et al., 1988), as well as physi-
cal stimuli such as shear stress (Huang et al., 2000). Experi-
mental studies have identified two main COX-derived
products which can behave as EDCFs, namely thromboxane
A2 or prostaglandin H2 (Vanhoutte, 1989; Luscher et al.,
1992). However, although considered a vasodilator, also
derived prostacyclin is able to behave like an EDCF under
disease conditions, such as hypertension (Rapoport and Wil-
liams, 1996; Gluais et al., 2005). These substances, once pro-
duced diffuse to the underlying vascular smooth muscle
cells and through the activation of specific receptors (TP
receptors) (Vanhoutte et al., 2005) induce contraction.
Accordingly, most COX-mediated endothelium-dependent
contractions are inhibited by smooth muscle cell
TP-receptor antagonists (Tesfamariam et al., 1989; Yang et al.,
2002; Virdis et al., 2007). Interestingly, in the setting of
hypertension a hyperresponsiveness of vessels to
TP-mediated contraction is present despite the lack of TP
gene overexpression (Tang et al., 2008).
Initial data showed that in the aorta of spontaneously
hypertensive rats, preferential inhibitors of COX-1 rather
than those of COX-2 prevented the endothelium-dependent
contractions to acetylcholine (Ge et al., 1995; Yang et al.,
2002). Similarly, in vessels from angiotensin II-infused mice
selective, COX-1 but not COX-2 inhibition is able to improve
endothelium-dependent vasodilation, and this phenomenon
is accompanied by increased expression of COX-1 and
decreased expression of COX-2 gene (Virdis et al., 2007). It is
to note that also the activation of COX, and particularly of
membrane-bound COX-1, is able to produce superoxide
anions. It was demonstrated that increased vascular levels
of oxidative stress, either COX-derived or produced by
other sources, in both spontaneously hypertensive rats and
angiotensin-II-infused mice is able enhance membrane-
bound COX transformation of arachidonic acids into endop-
eroxides (Ge et al., 1995; Vanhoutte et al., 2005; Virdis et al.,
2007). The increased activity of COX-1 is related to both an
enhanced gene expression and to a direct activation of
the enzyme. However, interestingly, the angiotensin-II-
dependent COX-1enzymatic activation but not expression
seems to be ROS-mediated (Virdis et al., 2007).
Finally, it is to note that beside the role of COX-1 in modu-
lating endothelium-dependent contractions, COX-2 is also
able to produce EDCFs, particularly in those vascular district
Endothelium and hypertension
530
D Versari et al
British Journal of Pharmacology (2009) 157 527–536
in which it is expressed at a higher level (Camacho et al.,
1998; Shi and Vanhoutte, 2008).
COX-dependent contractions in human
hypertension
As already underscored, hypertension is associated to a
reduced vasodilating response to acetylcholine (Panza et al.,
1990; Taddei et al., 1993); interestingly in hypertensive
patients, but not in healthy controls, intraarteial administra-
tion of the COX inhibitor indomethacin at high doses is able
to improve the vasodilation to acetylcholine (Taddei et al.,
1993), suggesting the possible production of COX-dependent
EDCFs contributing to the onset endothelial dysfunction in
human hypertension (Figure 3). Notably, COX-inhibition
does not influence endothelial function in secondary forms of
hypertension, indicating that COX-derived EDCFs conceiv-
ably do not play a significant role in determining endothelial
dysfunction in these conditions (Taddei et al., 1993)
(Figure 3). Taken together, these results suggest that EDCF
production is not a consequence of the simple increase in
blood pressure values, but is likely genetically related to essen-
tial hypertension. At this regard, the possibility that EDCFs
could be related to the pathogenesis of essential hypertension
is excluded by data derived from young normotensive off-
spring of essential hypertensive patients. These subjects show
an impaired response to acetylcholine as compared with
matched offspring of normotensive subjects, but not to the
endothelium-independent vasodilator sodium nitroprusside
(Taddei et al., 1996b), suggesting the presence of endothelial
dysfunction. However, in contrast to frank hypertensive
patients, this alteration is not improved by indomethacin
infusion; on the contrary, the administration of the eNOS
substrate L-arginine is effective in enhancing the vasodilating
response to acetylcholine indicating that a primary defect in
the L-arginine-NO pathway, rather than the production of
COX-derived EDCFs, is responsible for the endothelial dys-
function in subjects with a familial predisposition to develop
hypertension (Taddei et al., 1996b).
A strong cross-relation is present between the hypertensive
progress and ageing in terms of endothelium-dependent
vasodilation and contraction. It is well-known that the ageing
process is accompanied by a progressive worsening of NO
availability and of endothelium-dependent vasodilation,
both in large arteries and in small vessels of the peripheral and
coronary circulation (Vita et al., 1990; Egashira et al., 1993;
Zeiher et al., 1993; Taddei et al., 1995a; 1997a,b), and increas-
ing age is therefore one of the main determinants of endot-
helial dysfunction. The main mechanism responsible for age-
related endothelial dysfunction in the adults, at least in the
peripheral microcirculation, seems to be a primary defect in
the L-arginine-NO pathway, as the administration of
L-arginine is able to restore the forearm vasodilation to intra-
brachial acetylcholine. In contrast, after the age of 60 years,
along with a further impairment of the L-arginine-NO-
Figure 2 Schematic representation of the interplay between endothelium-derived relaxing (nitric oxide NO) and contracting factors. Under
endothelial stimulation nitric oxide synthase (eNOS) is stimulated to generate NO from L-arginine and NO, diffusing to the underlying smooth
muscle cells, induces relaxation by increasing the production of cyclic-GMP. In pathologic conditions, such as hypertension, endothelial
stimulation also leads to an increased production of superoxide anions (O
2
) by NADPH-oxidase (NADPH-ox) and cyclooxygenase (COX).
Released superoxide is able to scavenge NO, thus reducing its bioavailability and impairing endothelium-dependent vasodilation. Additionally,
stimulated COX also produces endoperoxides and consequently thromboxane-A
2
, prostaglandin-E
2
, prostaglandin-F
2a
prostaglandin-D
2
and
prostacyclin, which binding to a specific receptor (TP) on smooth muscle cells, cause vasoconstriction.
Endothelium and hypertension
D Versari et al
531
British Journal of Pharmacology (2009) 157 527–536
pathway, COX-dependent EDCF production becomes evident
and significant (Taddei et al., 1997b) (Figure 4). This natural
alteration of the equilibrium in the vascular reactivity is
anticipated by essential hypertension, which therefore repre-
sents a condition of premature vascular ageing. Indeed, in
hypertensive patients, the production of COX-dependent
EDCFs starts in the age range of 31–45 years and in patients
older than 45 years the potentiating effect of indomethacin is
increased in parallel with increasing age (Taddei et al., 1997b)
(Figure 4). The overall data indicate that COX-dependent
EDCFs production is a phenomenon naturally occurring in
the vascular ageing process and can be anticipated in the
presence of hypertension.
It is worth noting that COX-derived EDCFs do not seem
to play a significant role in the regulation of basal vascular
tone of essential hypertensive patients, as intrabrachial
indomethacin infusion does not influence forearm basal flow
(Taddei et al., 1993). Indeed, COX-derived vasoconstricting
factors are not produced in baseline conditions and therefore
do not modulate tonic NO release. Indeed, intrabrachial
monomethyl-L-arginine (L-NMMA) infusion causes a dose-
dependent vasoconstriction, which is related to basal NO
production (Vallance et al., 1989). Conversely, in essential
hypertension the vascular response to L-NMMA is reduced,
indicating a decrease in basal NO release (Calver et al., 1992;
Taddei et al., 1995b). Interestingly, when L-NMMA is co-
infused with indomethacin in the brachial artery of essential
hypertensive patients, COX inhibition does not improve the
blunted vasoconstrictor response to the eNOS inhibitor, sug-
gesting that COX-derived EDCFs production is not respon-
Figure 3 Change in forearm blood flow (FBF%) in the forearm microcirculation in response to increasing doses of the endothelium-
dependent vasodilator acetylcholine in healthy subjects and hypertensive patients. (A) Both essential and secondary hypertensive patients
clearly show a reduced maximal vasodilation to acetylcholine. Moreover, only in healthy subjects this response is inhibited by the
co-administration of the eNOS inhibitor L-NMMA, demonstrating the presence of endothelial dysfunction in hypertensive patients (role of NO).
(B) The vasodilation to acetylcholine is not influenced by the co-administration of the COX-inhibitor indomethacin in healthy subjects and in
secondary hypertension, while it is improved in essential hypertensives, demonstrating the significant role of COX-derived contracting factors
in this patients. Reproduced using data from Taddei et al. (1997b). COX, cyclooxygenase; eNOS, nitric oxide synthase; L-NMMA, monomethyl-
L-arginine.
Endothelium and hypertension
532
D Versari et al
British Journal of Pharmacology (2009) 157 527–536
sible for the impaired basal release of NO (Taddei et al.,
1997a). Similarly, antioxidant vitamin C infusion is also
devoid of effect on vasoconstriction to L-NMMA in essential
hypertension, ruling out a possible role for oxidative stress
in determining this impairment (Taddei et al., 1998a). These
data suggest that although essential hypertensive patients
show impaired NO availability, involving both basal and
agonist-stimulated release, the mechanisms responsible for
these two specific defects are different and COX activity seems
to be implicated only in the pathophysiology of the latter.
COX-derived EDCFs in other clinical conditions
Estrogens are known to protect the vessel wall both indirectly,
by improving metabolic profile (Bush et al., 1987), and by a
direct beneficial action on endothelial cells as demonstrated
by the negative effects of acute endogenous estrogen depriva-
tion following ovariectomy (Gisclard et al., 1988; Williams
et al., 1990). The progressive estrogen levels decrease, as
occurring in menopausal women is characterized by endot-
helial dysfunction, in both normotensive and hypertensive
females (Celermajer et al., 1994; Taddei et al., 1996a).
Ovariectomy/hysterectomy for uterine leiomyoma repre-
sents a useful model to investigate the role of acute estrogen
deprivation on vascular reactivity. In these patients acute
estrogen deprivation induces a decrease in the forearm
vasodilation to acetylcholine, but not to the endothelium-
independent vasodilator within 1 month after surgery (Pinto
et al., 1997), and this alteration is corrected by estrogen
replacement therapy (Pinto et al., 1997). As expected, in
normal adult women the vasodilatory response to acetylcho-
line is blunted by the co-administration of an eNOS inhibitor,
while COX-inhibitors have no effect. However, after ovariec-
tomy, indomethacin becomes able to enhance the response to
acetylcholine, with no effect of the eNOS inhibitor, suggest-
ing that acute endogenous estrogen deprivation fosters
COX-derived EDCFs production and blunts NO availability.
This scenario is completed reverted by estrogen replacement
therapy (Pinto et al., 1997). Taken together, these results
suggest that estrogen protects endothelial function by main-
taining a physiological NO availability and preventing the
formation of COX-derived EDCFs.
Also in patients with congestive heart failure, systemic COX
inhibition with oral indomethacin is able to partially enhance
the blunted vasodilating response to acetylcholine, although
the nature of the COX-derived vasoconstrictor is not eluci-
dated, yet (Katz et al., 1993).
Conclusions
Overall, available data clearly indicate that essential hyper-
tension is characterized by an impaired vascular NO bioavail-
ability and endothelium-dependent vasodilation in the
coronary and peripheral circulation. In parallel with this alter-
ation, an increased production of EDCFs is present and con-
tributes to the condition of endothelial dysfunction of these
patients. Among EDCFs, COX-derived prostanoids and super-
oxide anions seem to be the most important determinants for
the impaired agonist-stimulated vasodilation, but not for
basal vascular tone. These processes do not appear to be char-
acteristic of hypertension, but rather the acceleration by the
hypertensive process of the para-physiologic age-related vas-
cular changes. The mechanisms that regulate the balance
between endothelium-derived relaxing and contracting
factors and the processes transforming the endothelium from
a protective organ to a source of vasoconstrictor, proaggrega-
tory and promitogenic mediators, such as COX-dependent
EDCFs remain to be determined.
Conflict of interest
None.
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Themed Section: Endothelium in Pharmacology
Endothelium in pharmacology: 30 years on: J. C. McGrath
Role of nitroso radicals as drug targets in circulatory shock: E. Esposito & S. Cuzzocrea
Endothelial Ca
2+
-activated K
+
channels in normal and impaired EDHF–dilator responses relevance to cardiovascular
pathologies and drug discovery: I. Grgic, B. P. Kaistha, J. Hoyer & R. Köhler
Endothelium-dependent contractions and endothelial dysfunction in human hypertension: D. Versari, E. Daghini, A. Virdis,
L. Ghiadoni & S. Taddei
Nitroxyl anion the universal signalling partner of endogenously produced nitric oxide?: W. Martin
A role for nitroxyl (HNO) as an endothelium-derived relaxing and hyperpolarizing factor in resistance arteries: K. L. Andrews,
J. C. Irvine, M. Tare, J. Apostolopoulos, J. L. Favaloro, C. R. Triggle & B. K. Kemp-Harper
Vascular K
ATP
channels: dephosphorylation and deactivation: P. Tammaro
Ca
2+
/calcineurin regulation of cloned vascular K
ATP
channels: crosstalk with the protein kinase A pathway: N. N. Orie,
A. M. Thomas, B. A. Perrino, A. Tinker & L. H. Clapp
Understanding organic nitrates a vein hope?: M. R. Miller & R. M. Wadsworth
Increased endothelin-1 reactivity and endothelial dysfunction in carotid arteries from rats with hyperhomocysteinemia:
C. R. de Andrade, P. F. Leite, A. C. Montezano, D. A. Casolari, A. Yogi, R. C. Tostes, R. Haddad, M. N. Eberlin, F. R. M. Laurindo,
H. P. de Souza, F. M. A. Corrêa & A. M. de Oliveira
Mechanisms of U46619-induced contraction of rat pulmonary arteries in the presence and absence of the endothelium:
C. McKenzie, A. MacDonald & A. M. Shaw
This issue is available online at http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009
Endothelium and hypertension
536
D Versari et al
British Journal of Pharmacology (2009) 157 527–536
    • "The endothelium, the thin inner lining of vessels, can be activated by chemical and physical stimuli that lead to the formation and release of EDRF prostacyclin , bradykinin, and contracting (EDCF) factors such as endothelin-1 and angiotensin II (Versari, Daghini, Virdis, Ghiadoni, & Taddei, 2009). Endothelial cells produce a wide range of factors that control cellular adhesion, smooth muscle reactivity, proliferation, and vessel wall inflammation and atherogenesis. "
    [Show abstract] [Hide abstract] ABSTRACT: Nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling plays a critical role in physiological homeostatic processes, such as smooth muscle tone in vascular and non-vascular tissues, platelet activity, cardiac contractility, renal function and fluid balance, as well as cell growth. Studies of the 90’s established endothelium dysfunction as one of the major causes of cardiovascular diseases and therapeutic strategies that benefit NO bioavailability have been applied in clinical medicine extensively. Recently, the basic and clinical studies of cGMP regulation through activation of soluble guanylyl cyclase (sGC), or inhibition of cyclic nucleotide phosphodiesterase type 5 (PDE5) have resulted in effective therapies for pulmonary hypertension, erectile dysfunction and more recently for benign prostatic hyperplasia. This section reviews 1) how endothelial dysfunction and NO deficiency lead to cardiovascular diseases; 2) how soluble guanylate cyclase (sGC) regulation leads to beneficial effects on disorders of the circulation system and 3) the epigenetic regulation of NO-sGC pathway components in the cardiovascular system. In conclusion, the discovery of the NO-cGMP pathway revolutionized the comprehension of pathophysiological mechanisms involved in cardiovascular and many other diseases. However, considering the expression “from bench to bedside”, the therapeutic alternatives that target NO-cGMP did not immediately follow the marked biochemical and pathophysiological revolution. Some therapeutic options have been effective and released on the market for pulmonary hypertension and erectile dysfunction such as inhaled NO, PDE-5 inhibitors and more recently sGC stimulators. The therapeutic armamentarium for many other disorders is expected in the near future. There are currently numerous active basic and clinical research programs in universities and industries attempting to develop novel therapies for many diseases and medical applications.
    Full-text · Chapter · Jul 2016 · BMC Complementary and Alternative Medicine
    • "Resistance artery vascular remodelling may also exacerbate hypertension through its effects on vascular function, such as magnifying normal vasoactive inputs (vascular amplifier effect) [14] and vasorelaxation dysfunction, which is a well-established phenomenon in hypertension, being described in the subcutaneous resistance arteries of patients with endstage renal disease [15]. Vasorelaxation in resistance arteries involves three components: nitric oxide (NO), prostanoids, and endothelium-dependent hyperpolarization (EDH) [15], with the contribution of each dependent upon the vascular bed under study, and the varying degrees of relative impairment depending on the disease state [16] [17] [18]. "
    [Show abstract] [Hide abstract] ABSTRACT: Chronic kidney disease (CKD) and hypertension are co-morbid conditions both associated with altered resistance artery structure, biomechanics and function. We examined these characteristics in mesenteric artery together with renal function and systolic blood pressure (SBP) changes in the Lewis polycystic kidney (LPK) rat model of CKD. Animals were studied at early (6-weeks), intermediate (12-weeks), and late (18-weeks) time-points (n = 21), relative to age-matched Lewis controls (n = 29). At 12 and 18-weeks, LPK arteries exhibited eutrophic and hypertrophic inward remodelling characterised by thickened medial smooth muscle, decreased lumen diameter, and unchanged or increased media cross-sectional area, respectively. At these later time points, endothelium-dependent vasorelaxation was also compromised, associated with impaired endothelium-dependent hyperpolarisation and reduced nitric oxide synthase activity. Stiffness, elastic-modulus/stress slopes and collagen/elastin ratios were increased in 6 and 18-week-old-LPK, in contrast to greater arterial compliance at 12 weeks. Multiple linear regression analysis highlighted SBP as the main predictor of wall–lumen ratio (r = 0.536, P < 0.001 n = 46 pairs). Concentration–response curves revealed increased sensitivity to phenylephrine but not potassium chloride in 18-week-LPK. Our results indicate that impairment in LPK resistance vasculature is evident at 6 weeks, and worsens with hypertension and progression of renal disease.
    Article · Jan 2016
    • "The vasorelaxant effect is usually classified as endothelium dependent or independent depending on endothelial function. The endothelium regulates vascular smooth muscle tone through the secretion of vasorelaxant substances such as nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor [29], as well as through endothelium-derived contracting factors such as endothelins, angiotensin II, cyclooxygenase-derived prostanoids, and superoxide anions [30]. In the present study, ADE evoked a concentration-dependent relaxation of aortic rings precontracted by the application of PE (1 μM) or KCl (60 mM). "
    [Show abstract] [Hide abstract] ABSTRACT: Background: The root of Angelica dahurica Bentham et Hooker (Umbelliferae) has been used as a traditional medicine for colds, headache, dizziness, toothache, supraorbital pain, nasal congestion, acne, ulcer, carbuncle, and rheumatism in China, Japan, and Korea. Interestingly, it has been used in the treatment of vascular diseases including hypertension. The aim of this study was to provide pharmacological evidence for the anti-hypertensive effect of A. dahurica by investigating the mechanism underlying its vasorelaxant effect. Methods: The vasorelaxant effects of a 70 % methanol extract of the A. dahurica root (ADE) on rat thoracic aorta and its underlying mechanisms were assessed. Isolated rat aortic rings were suspended in organ chambers containing 10 ml Krebs-Henseleit (K-H) solution and placed between 2 tungsten stirrups and connected to an isometric force transducer. Changes in tension were recorded via isometric transducers connected to a data acquisition system. Results: ADE causes concentration-dependent relaxation in both endothelium-intact and endothelium-denuded aortic rings precontracted with phenylephrine (PE; 1 μM) or potassium (KCl; 60 mM) in K-H solution. And pre-treatment with ADE (1 mg/ml) inhibited calcium-induced vasocontraction of aortic rings induced by PE or KCl. However, ADE pre-treatment did not affect the contraction induced by PE or caffeine in Ca(2+)-free K-H solution. Conclusions: These results suggested that the ADE has vasorelaxant effect and the vasorelaxant activity is mediated by endothelium-independent pathway that includes the blockade of extracellular calcium influx through the receptor-operated Ca(2+) channel and voltage-dependent calcium channel pathways.
    Full-text · Article · Nov 2015
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