Cardiovascular Research 48 (2000) 194–210
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Review
Kinin B 1 receptors and the cardiovascular system: regulation of expression
and function
Peter G. McLean
a,b ,
*, Mauro Perretti b , Amrita Ahluwalia a
a
Center for Clinical Pharmacology, Department of Medicine, The Rayne Institute, University College London, 5 University Street,
London WC1 E6 JJ, UK
b
Department of Biochemical Pharmacology, The William Harvey Research Institute, St. Bartholomew’ s and the Royal London School of Medicine
and Dentistry, London EC1 M6 BQ , UK
Received 24 March 2000; accepted 7 July 2000
Abstract
Kinins are important peptide mediators of a diverse range of physiological and pathological functions of the cardiovascular system. The
kinin peptides exert their effects by selective activation of two distinct G-protein coupled receptors termed B 1 and B 2 . The principal kinin
peptides involved in the acute regulation of cardiovascular function during normal physiology are bradykinin (BK) and Lys-BK which
produce their effects via activation of B 2 receptors. The B 1 receptor is activated by the des-Arg 9 kinin metabolites namely des-Arg 9 BK
and Lys-des-Arg 9 BK, the synthesis of which are increased during inflammation. The B 1 receptor, which is not constitutively expressed, is
induced in various pathologies relating to inflammation. Recent investigations into the molecular mechanisms of B 1 receptor induction
and their distribution and function in the cardiovascular system have shown that following an inflammatory stimulus the B 1 receptor is
induced and may play an important role in modulation of cardiovascular function. This review summarises recent studies on B 1 receptor
expression and function in the cardiovascular system and discusses the role of these receptors in regulation of circulatory homeostasis and
their potential as therapeutic targets.  2000 Elsevier Science B.V. All rights reserved.
Keywords: G-proteins; Infection / inflammation; Receptors; Signal transduction
1. Introduction
The kinin peptides, particularly bradykinin (BK), LysBK (kallidin) and their biologically active des-Arg 9 metabolites are the functional components of the kallikrein–kinin
system. Kinins are important mediators of a diverse range
of physiological and pathological responses of the cardiovascular system. The physiological actions of this
system are produced by two endogenous kinins, BK and
Lys-BK, formed by proteolytic cleavage of high- and
low-molecular-weight kininogens (HMWK and LMWK)
by plasma or tissue kallikrein (PK or TK), respectively.
*Corresponding author. Tel.: 144-207-679-6619; fax: 144-207-6912838.
E-mail address: [email protected] (P.G. McLean).
BK and Lys-BK are metabolised and deactivated by
kininase I or kininase II (also known as angiotensin
converting enzyme). The activity of kininase I is of
particular relevance to this review in that it produces kinin
metabolites without the C-terminal arginine residue, desArg 9 BK (DABK) and Lys-des-Arg 9 BK (Lys-DABK) from
BK and Lys-BK, respectively. Whilst these des-Arg 9
metabolites are largely inactive in normal conditions, in
certain immuno-pathological situations they produce responses characteristic of inflammation including vasodilation, oedema and leukocyte recruitment within the microcirculation.
The kinins mediate their effects via the selective activation of kinin receptors of which there are two types, B 1
Time for primary review 32 days.
0008-6363 / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved.
PII: S0008-6363( 00 )00184-X
P.G. McLean et al. / Cardiovascular Research 48 (2000) 194 – 210
and B 2 . The B 2 receptor is constitutively expressed and
mediates the majority of the acute vascular actions of BK
[1]. In contrast, the B 1 receptor is generally absent from
normal tissue but following an inflammatory insult, receptor expression is induced in a variety of cell types
including vascular smooth muscle cells (VSMC), endothelial cells (EC) and fibroblasts (see below). The activity
of the kinins suggests that they may be involved in
inflammatory cardiovascular disease, and the inducibility
of the kinin B 1 receptor makes it an exciting potential
therapeutic target in such pathological conditions. This
review will address the role of B 1 receptors in the
physiology and pathophysiology of the cardiovascular
system and will highlight the therapeutic potential of
agents that interact with this system.
2. The kinin B 1 receptor: an inducible G-proteincoupled receptor (GPCR)
The B 1 receptor was first defined as mediating the
contractile effect of kinins in the rabbit isolated aorta [2].
Regoli and Barabe´ [3] later suggested the existence of two
types of kinin receptor in 1980 based on differential in
vitro tissue reactivity to the endogenous agonists DABK
and BK. The order of agonist potency at B 1 receptors was
shown to be DABK.Tyr(Me)8 BK.BK, with a reverse
order at the B 2 receptor (i.e. BK.Tyr(Me)8 BK.DABK)
[3]. This profile is determined by the discriminating nature
of the C-terminal arginine of B 2 receptor selective agents,
that is absent in B 1 receptor selective compounds. The
selectivity of the kinin peptides is further determined at the
receptor by differences in a single position in the third
transmembrane domain of the human B 1 and B 2 receptors
[4]. The reader is referred to recent excellent reviews
discussing kinin receptor ligands in greater detail [5,6]
In 1992, Phillips et al. [7] demonstrated the expression
of both B 1 and B 2 receptors in Xenopus oocytes injected
with mRNA from NG108-15, rat uterus, and human
fibroblast cell line WI38. Structural analysis revealed that
the receptors are encoded by distinct mRNA [8]. The
human B 1 receptor gene was subsequently cloned from
human embryonic lung fibroblasts [9] and was shown to be
a member of the 7-transmembrane domain GPCR family.
The mouse [10], rat [11] and rabbit [12] B 1 receptors
display functional and structural homology with the human
receptor. The rabbit receptor shows greatest homology
with the human receptor whilst homology with the rodent
receptors is relatively low. Interestingly this difference in
homology is demonstrated by differences in preferred
agonists; Lys-DABK in humans and rabbits and DABK in
rodents [5]. This selectivity of Lys-DABK for the human
B 1 receptor depends on interaction between the peptide
N-terminal L-lysine and the fourth extracellular domain of
the human B 1 receptor [13].
195
3. B 1 receptor regulation: mechanisms of induction
The low homology (36%) between the B 1 and B 2
receptors suggests that both receptors may be components
of very different regulatory systems [14]. One important
example of this is the differential regulation of their
expression. The inducibility of the B 1 receptor was first
reported by Regoli et al., [2] who described a time- and
protein synthesis-dependent appearance of contractile reactivity to DABK in rabbit isolated aorta following 2–3 h of
tissue incubation in physiological buffer [15]. This is due
to de novo synthesis of B 1 receptor since the response is
absent in tissues treated with inhibitors of RNA transcription, translation or of protein maturation [5].
The stimulus for post-isolation B 1 receptor induction in
these in vitro studies is unclear but may be related to the
trauma of isolating vessels ex vivo. B 1 receptor upregulation occurs, in vitro and in vivo, under the control of
specific cytokines released in situations of trauma and
stress, including interleukin (IL)-1b and tumour necrosis
factor (TNF)-a [16–18]. Additionally, studies in vitro
show that certain cytokines and growth factors (e.g. IL-1b,
IL-2, interferon-g, epidermal growth factor and oncostatin)
increase the rate at which a B 1 receptor-mediated response
develops as a consequence of tissue isolation and incubation [15,17–21]. This upregulation is again due to de novo
protein synthesis and is sensitive to glucocorticoids
[17,22]. Of all the cytokines IL-1b has been shown to be
the optimal inducer of B 1 receptor expression in various
cell types of several species in vitro [18,23] including
human embryo lung fibroblasts. In these cells IL-1b
upregulates B 1 receptor mRNA expression at both a
transcriptional and post-transcriptional level [24,25]. In
addition, agents that stimulate the synthesis of these
cytokines, in particular bacterial lipopolysaccharide (LPS)
also lead to functional B 1 receptor expression when
administered either in vitro or in vivo [16,18,26]. B 1
receptor induction also occurs following heat stress,
another immunopathological stimulus [27].
The induction of functional B 1 receptor-mediated responses is associated with B 1 receptor mRNA and protein
expression. This was first shown in the rat isolated heart
where in vitro perfusion with IL-1b promoted B 1 receptor
induction at both the molecular (mRNA expression) and
functional level (coronary vasodilation) [18]. This inducibility to IL-1b has also been demonstrated in vivo for
the first time in our laboratory [28] (see below).
Studies attempting to identify the molecular mechanisms
involved in B 1 receptor induction implicate the inflammatory transcription factor, nuclear factor kB (NF-kB).
Interestingly NF-kB is not only involved in mediating
certain B 1 receptor effects but also receptor induction
[24,29,30]. Accordingly, NF-kB binding domains [24,29]
have been identified in the promoter region of the B 1
receptor gene and IL-1b and TNFa-induced B 1 receptor
expression is directly related to NF-kB activation [5].
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P.G. McLean et al. / Cardiovascular Research 48 (2000) 194 – 210
Additionally, it has been proposed that B 2 receptor activation and consequent desensitisation may be a direct
stimulus for B 1 receptor induction since B 2 receptor
agonists also cause NF-kB activation [31,32].
Apart from differential expression profiles, kinin receptors also display important differences in their susceptibility to desensitisation. When activated by an agonist, B 2
receptors undergo desensitisation and internalisation [33–
35] a characteristic accounting for the rapid reversibility of
its biological effects in vitro. Conversely, B 1 receptors,
once induced, are not internalised or desensitised [20,33–
35]. This difference may be explained by the presence of a
large C-terminal loop in the B 2 receptor containing Ser and
Tyr residues, typical phosphorylation sites [36,37]. In
addition, Cys324 in the cytoplasmic carboxyl terminus of
the B 2 receptor appears to play an integral role in agonistinduced internalisation. Replacement of the cytoplasmic
carboxyl terminus of the B 2 receptor starting from Cys324,
with that of the B 1 receptor (beginning at Cys330) greatly
reduced ligand internalisation without significantly altering
ligand binding affinity or coupling efficiency. In contrast,
the corresponding replacement in the B 1 receptor led to an
increase of ligand internalisation without altering affinity
or coupling. These results indicate that the cytoplasmic
carboxyl terminus of the human B 2 receptor contains
sequences that are necessary and sufficient to permit rapid
ligand-induced sequestration of human kinin receptors and
internalisation of their agonists [34]. This differential
susceptibility to desensitisation would support the hypothesis that an integrated system develops from B 2 receptormediated acute inflammation to a sustained B 1 receptormediated chronic, or at least prolonged, inflammatory
response. Thus one could speculate that B 2 receptors are
unlikely to be involved in sub-acute and chronic inflammatory conditions, whereas B 1 receptors are better equipped
to mediate the development and progression of a chronic
inflammatory response.
4. Synthesis of B 1 receptor endogenous ligands: the
kallikrein–kinin system
The synthesis of kinins is determined by the activity of
the kallikrein–kinin system that is comprised of two
separate pathways differentiated by their location: the
plasma and tissue systems [5]. The various elements of the
kallikrein–kinin system have been reviewed in detail
elsewhere (see Bhoola et al. [1]; Kaplan et al. [38]). In
brief, the substrates for kinin synthesis are the multidomain proteins known as kininogens of which there are
three types; high molecular weight kininogen (HMWK),
low molecular weight kininogen (LMWK) and Tkininogen. The kininogens contain the nine amino acid
peptide sequence for BK (Arg-Pro-Pro-Gly-Phe-Ser-ProPhe-Arg). HMWK, the precursor of BK, is a circulating
protein in the plasma system, whereas LMWK, the pre-
cursor for Lys-BK, is distributed in tissues, fibroblasts and
other structural cells within connective tissue [1]. Tkininogen is the rodent equivalent of human HMWK [1].
The human kininogen gene has been mapped to chromosome 3 (3q26-3qter) [39] that codes, via alternative
splicing, for the expression of both HMWK and LMWK.
Kallikreins are the enzymes that cleave kininogens and
liberate kinins. Plasma kallikrein (PK) releases BK from
HMWK [40]; a process that is upregulated during an
inflammatory insult such as ischaemia–reperfusion (I / R)
injury [41]. There is also evidence that HMWK adsorbed
on extracellular proteins of Streptococcus pyrogenes, an
important pathogen in ‘sepsis’ can release BK in the
presence of prekallikrein [42] thus implicating kinin
generation in the pathophysiology of this disease. Tissue
kallikreins (TK) are a family of serine proteases closely
related to PK and are highly effective in the generation of
biologically active kinins. Human TK preferentially releases the decapeptide Lys-BK from kininogens, as found
in the nasal secretions of subjects with allergic or viral
rhinitis [43]. Human TK is widely expressed in many
tissue types including glandular and duct cells, as well as
in neutrophils [44], cultured VSMCs, colonic goblet cells,
and renal distal tubules and collecting ducts [45–48].
4.1. Kinin metabolism
The kinins are metabolised by several different enzymes, but the two most relevant with regard to the
deactivation of BK are kininase I and kininase II. BK
exhibits a very short half-life (10–50 s) in blood plasma in
vitro and in vivo [49]. Kininase II, otherwise known as
angiotensin I converting enzyme (ACE), is the most
efficient and the major mechanism for BK inactivation
[50], removing the C-terminal dipeptide from BK or LysBK and generating biologically inactive fragments. Assays
for BK-like peptides have shown that kininase II accounts
for between 40 and 75% of the hydrolysis of exogenous
synthetic BK by serum or cardiac membrane preparations
of humans, rabbits or rats [49,51]. Kininase II is predominantly located on the surface of the luminal membrane of ECs and is therefore in a prime location for the
inactivation of circulating BK.
Other peptidases including aminopeptidase P and neutral
endopeptidase (NEP) also play an important role in kinin
metabolism in vivo. Aminopeptidase P is responsible for
up to 30% of total BK metabolism in rat lung and coronary
circulation [52,53]. NEP, also a membrane-bound peptidase, located in high concentration on leukocyte membranes
[50,54] cleaves two bonds in BK [55] and is responsible
for 10–20% of BK inactivation [1]. The NEP homologue
endothelin converting enzyme, located at the surface of EC
and SMCs can also metabolise BK as efficiently as it
metabolises big endothelin [56,57].
Kininase I enzymes (otherwise known as Arg carboxypeptidases) play a lesser role in the deactivation of BK
P.G. McLean et al. / Cardiovascular Research 48 (2000) 194 – 210
being responsible for less than 10% of total BK metabolism [49]. However, kininase I activity is of particular
importance, since this enzyme is responsible for the
generation of the des-Arg 9 kinins. Under normal conditions
B 1 receptors are absent and these fragments remain
functionally ‘silent’ and it is only following situations
where these receptors have been induced (see above) that
des-Arg 9 metabolites show activity. Kininase I is composed of the arginine carboxypeptidases, carboxypeptidase
N in the plasma and carboxypeptidase M in tissues
(predominantly membrane-bound and widely distributed,
including in the microvasculature [50,54]). The half-life of
DABK is 4- to 12-fold higher than that of BK under
comparable experimental conditions [49,51] and this may
explain why the in vivo concentration of DABK is
consistently higher than that of BK. Therefore, it appears
that, whilst the synthesis of DABK is not considerable its
half life endows it with a much greater capacity to
accumulate than BK. Interestingly, blocking the competing
kininase II pathway with enalaprilat improves the conversion of BK to DABK [49,51]. The techniques used to
determine the above kinetics are limited by the fact that
they only measured kinin metabolism in normal, noninflammatory tissue / cells. It is possible that the formation
of des-Arg 9 kinins is greater at inflammatory sites than in
plasma or normal tissue (see below).
4.2. Kallikrein–kinin system during injury and
inflammation
All the necessary components required for kinin synthesis are not only present but elevated at sites of inflammation. In models of sepsis and myocardial I / R injury, the
levels of detectable des-Arg 9 kinins are increased 2 to
4-fold [41,58]. This elevation may be due to several factors
including the possibility that plasma protein extravasation,
at sites of inflammation, will provide substrate (HMWK)
and enzyme (PK) for enhanced BK synthesis [59]. Additionally, during an inflammatory response the activity of
the kallikrein–kinin system is enhanced by activation of
the tissue kallikrein–kinin pathway [14]. Firstly, levels of
LMWK are elevated by inflammatory cytokines [60].
Secondly, not only is TK present in and secreted from
infiltrating leukocytes [5,44] but the synthesis of this
protease is enhanced after trauma or inflammation [61].
Other enzymes that may also catalyse kinin formation are
neutrophil elastase and mast cell tryptase, also present at
sites of inflammation [62]. Additionally, in experimental
models of sepsis, there is evidence demonstrating that
elevated levels of endogenous B 1 receptor ligands (i.e.
des-Arg 9 kinins) are associated with increased expression
of the tissue bound carboxypeptidase M (kininase I)
[58,63]. This elevation of des-Arg 9 kinins can be further
enhanced by pre-treatment of animals with the kininase II
inhibitor captopril [58]. Given the central role played by
LPS in sepsis, these experimental data suggest that DABK
197
may be involved in the pathology of this syndrome (see
Section 6.1). Furthermore, fibrin degradation products that
are released during sepsis will inhibit kininase II [64] thus
further shifting the balance in favour of increased DABK
production.
5. Kinin B 1 receptor distribution and function in the
cardiovascular system
B 1 receptor expression has been demonstrated in a
variety of blood vessels, both veins and arteries, in several
species. Expression has also been described in cardiac
tissue and in the central nervous system. Thus, the major
systems involved in the regulation of cardiovascular
homeostasis have the capacity to express these receptors.
Table 1 summarises the distribution of this receptor, with
expression in ECs and VSMCs of several vessels ranging
from large elastic arteries and veins to small muscular
arteries. B 1 receptors are present on the ECs and VSMCs
of the tunica media in the renal, femoral, carotid, coronary,
vertebral, basilar and pericallosal arteries. The ECs of the
large elastic pulmonary artery contain both B 1 and B 2
receptors. In the ECs and VSMCs of arterioles, B 2 receptor
immunolabelling is more intense than that observed for B 1
receptors. Only B 2 receptor immunoreactivity was detected
on the ECs of the large veins and in the aorta [65] (see
Table 1 for further details).
Studies attempting to identify the cell signalling pathways involved in B 1 receptor activity show some heterogeneity. Bovine pulmonary artery ECs synthesise prostaglandins in response to B 1 receptor activation [66,67]. In
bovine aortic (BA) and rat microvascular coronary (RMC)
ECs B 1 receptor activation results in intracellular accumulation of guanosine-39,59-cyclic monophosphate (cGMP)
[68,69] and is associated with B 1 receptor mRNA expression in RMCECs, human umbilical vein (HUV) ECs but
paradoxically not in BAECs [70]. B 1 receptor-mediated
vascular effects generally involve protein kinase C activation and calcium release [20,71] leading to the promotion
of phosphoinositide hydrolysis by phospholipase C or
arachidonic acid release by phospholipase A 2 [72].
5.1. Vascular reactivity: mechanisms and mediators
As mentioned earlier, the first described response to B 1
receptor activation was the contraction of rabbit aorta
[2,3]. Since this initial observation the vasoactivity of B 1
receptor ligands has been described in several blood
vessels, both arteries and veins, in a variety of species
(Table 1). In general, vascular reactivity to B 1 receptor
ligands is not present constitutively, but is acquired
following incubation or application of an inflammatory
insult.
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P.G. McLean et al. / Cardiovascular Research 48 (2000) 194 – 210
Table 1
Kinin B 1 receptor distribution and function in the cardiovascular system a
Species / vessel /
effect in vivo
Location of
receptor expression
Functional
effect
Mechanism
of action
Human
Aorta
Pulmonary artery
Femoral artery
Renal artery
Carotid artery
Coronary artery
Vertebral artery
Basilar artery
Pericallosal artery
Femoral vein
Pulmonary vein
Renal vein
Muscular arteriole
Umbilical artery
Umbilical vein
–
EC
EC / VSM b
EC / VSM
EC / VSM
EC / VSM b
EC / VSM b
EC / VSM
EC / VSM
–
–
–
EC / VSM
nd
EC
nd
nd
nd
nd
nd
Vasodilation
nd
nd
nd
nd
nd
nd
nd
Vasoconstriction
Vasoconstriction
Rabbit
Aorta
Mesenteric vein
Mesenteric artery
Mesenteric artery
Carotid artery
Coeliac artery
Blood pressure
VSM
nd
VSM
nd
nd
nd
nd
Vasoconstriction
Vasoconstriction
nd
Vasodilation
Vasodilation
Vasodilation
Hypotension
Endo2, IP, AA
nd
IP, AA
Endo1 / 2, PG
Endo1, NO
Endo2, PG
PG
Pig
Renal vein
Coronary artery
Blood pressure
nd
nd
nd
Vasoconstriction
Vasodilation
Hypotension
nd
Endo1, NO
nd
Rat
Portal vein
Perfused kidney
coronary circulation
Blood pressure
coronary circulation
nd
nd
nd
nd
EC
Vasoconstriction
Vasoconstriction
Vasodilation
Hypotension
nd
PG
nd
Endo1, PG
nd
cGMP
Cat
Pulmonary bed
Pulmonary bed
Hindlimb bed
nd
nd
nd
Vasoconstriction
Vasodilation
Vasodilation
Catecholamines
NO
NO
Dog
Renal artery
Blood pressure
nd
nd
Vasodilation
Hypotension
Endo2, PG
nd
Cow
Coronary artery
Pulmonary artery
Aorta
nd
EC
EC
Vasodilation
nd
nd
Endo1, NO
IP, AA, NO, PG
PG, cGMP
Endo1 / NO
nd
nd
a
EC, endothelial cell; VSM, vascular smooth muscle; 2, absence of immunoreactive labelling; nd, not determined; Endo1, endothelium-dependent;
Endo2, endothelium-independent; NO, nitric oxide; PG, prostaglandin; IP, inositol phosphate; AA, arachadonic acid; cGMP, cyclic guanosine-39,59-cyclic
monophosphate. See text for references.
b
Blood vessels with atheromatous disease.
5.1.1. B1 receptor-mediated vasoconstriction
B 1 receptor ligands cause vasoconstriction of a range of
blood vessels including rabbit aorta [2,71,73] rabbit
mesenteric vein [74], pig renal vein [75] and human
umbilical artery [76] and vein [22,77,78] (see Table 1).
More recently vascular B 1 receptors have been identified
in the rat isolated perfused kidney, activation of which lead
to vasoconstriction [79]. B 1 receptor-mediated contraction
P.G. McLean et al. / Cardiovascular Research 48 (2000) 194 – 210
of vascular smooth muscle is generally not dependent on
an intact endothelium and involves a direct co-operation
between protein kinase C and calcium release
[20,35,71,80]. However, in the feline pulmonary vascular
bed the vasoconstrictor response to DABK is mediated by
the release of catecholamines and subsequent activation of
a-adrenergic receptors [81] whereas prostaglandin-dependent constriction is observed in rat portal vein [82].
5.1.2. B1 receptor-mediated vasodilation
B 1 receptor-mediated vasodilator responses are usually
an endothelium-dependent phenomenon as is the case in
the rat coronary circulation [18], bovine [83], porcine [84]
and human coronary arteries [85] and in rabbit mesenteric
[86] and carotid arteries [87]. In the large part this
endothelium-dependency can be attributed to activation of
eNOS and subsequent release of vasodilator NO as demonstrated using NOS inhibitors in a wide range of blood
vessels including the rabbit carotid [87], bovine [83]
porcine [84] and human [85] coronary arteries [81] (see
Table 1). B 1 receptor-mediated vasorelaxation in these
latter studies [81,84,87,88] was not sensitive to cyclooxygenase inhibition and hence is unlikely to involve
prostaglandin release. In contrast, B 1 receptor-mediated
vasodilation of the rat coronary circulation [18] and rabbit
mesenteric artery [86,89] involves the release of
eicosanoids, in particular prostacyclin [18].
In some vessels, B 1 receptor-meditated vasodilation is
endothelium-independent and this has been attributed to
prostaglandin activity, e.g. in rabbit coeliac and mesenteric
artery [90,91]. This functional and mechanistic diversity of
B 1 receptor-mediated vascular reactivity may be related to
species and / or regional variation and / or due to differences
in local sensitivity to vasodilator mediators. B 1 receptors
are positively coupled to phospholipase A 2 and thereby
cause arachidonic acid release [35,72,80]. Despite this
ability to elevate prostaglandin synthesis it is clear that
functional responses depend entirely upon local prostaglandin sensitivity. For example, B 1 receptor stimulation
causes prostaglandin synthesis and contraction of RASMC
however the latter response is not blocked by indomethacin
[71] a scenario repeated in bovine vascular tissue
[92,93,67,83]. Indeed, the rabbit aorta does not relax in
response to PGI 2 or PGE 2 [94]. In contrast, these prostaglandins produce potent vasodilation in rabbit mesenteric
and coeliac arteries and rat coronary circulation [94–97],
tissues in which B 1 receptor activation induces PGI 2
secretion [98,18] and a prostaglandin synthesis-dependent
relaxant response. Taken together, not all endotheliumindependent B 1 receptor-mediated relaxant responses are
mediated by prostaglandins, despite the observations that
prostaglandins are consistently released in response to B 1
receptor activation. This is possibly linked to the absence
of specific prostaglandin receptors.
With few exceptions, it would seem that B 1 receptor
activation consistently produces constrictor responses in
199
veins and dilator responses in arteries. This pattern of
reactivity is in line with a pro-inflammatory role of the B 1
receptor; i.e. arterial / arteriolar dilation associated with
venoconstriction would lead to increased hydrostatic pressure thus enhancing plasma protein extravasation and the
associated inflammatory events. Whilst this is an attractive
hypothesis the observation that B 1 receptor activation does
cause contraction of some arteries suggests that B 1 receptor-mediated control of vascular tone is a complex and
still unresolved process.
5.2. Myocardial effects
The expression of kinin receptors by cardiomyocytes
and cardiac conduction tissue has been demonstrated
[99,100]. B 1 receptors are also expressed on sympathetic
fibres in myocardial tissue the activation of which enhances noradrenaline outflow [101–103]. In contrast, other
studies have shown that B 1 receptor activation reduces
sympathetic outflow and this effect has been linked to the
proposed protective activity of des-Arg 9 kinins in I / R
injury [101]. B 2 receptor activation results in a prostaglandin-independent negative chronotropic effect in the
canine sinus node [99]. Both B 1 and B 2 receptor stimulation can prolong the action potential duration in rat
ventricular muscle [100] and this has been suggested to be
a possible explanation for the anti-arrhythmic activity of
the kinins.
5.3. Control of blood pressure
B 1 receptor-mediated hypotensive responses have been
demonstrated and characterised in the rabbit [16], rat [18]
pig [104], and dog [105]. The mechanism of this effect
may be explained by the profile of reactivity within the
vasculature, i.e. arterial dilation and venoconstriction.
However, a reduction in heart rate was also observed in
conjunction with the hypotensive effect of intravenously
administered B 1 receptor agonists in the rabbit [106]. The
authors suggest that early decreases in mean arterial
pressure induced following B 1 receptor activation are due
to the acute decreases in peripheral vascular resistance,
presumably as a consequence of arterial dilation. However,
the sustained hypotensive response was associated with a
decrease in cardiac output attributed to decreases in cardiac
contractility and heart rate. The B 1 receptor-mediated
hypotensive response is generally only observed following
an inflammatory stimulus e.g. endotoxin treatment, however some studies suggest that the hypotensive response
occurs in ‘normal’ animals [105]. This may be an example
of species variation, but is more likely to be associated
with pre-existing infection [107].
A role for B 1 receptors in the central control of blood
pressure (BP) has recently been reported. Caligiorne et al.
[108] showed that DALBK microinjection into the nucleus
tractus solitarii of Wistar Kyoto (WKY) rats prevented the
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P.G. McLean et al. / Cardiovascular Research 48 (2000) 194 – 210
cardiovascular effects of exogenous BK. Additionally it
has been reported that central B 1 receptor blockade lowers
BP in spontaneously hypertensive rats (SHR) but not in
normotensive rats [109]. Support for a central rather than
peripheral role of B 1 receptors in hypertension is provided
by the fact that in a transgenic rat (mREN2)27 model of
hypertension no expression of the B 1 receptor was detected
in aorta, heart and kidneys [110]. However, it is possible
that B 1 receptor expression is localised to other vascular
beds, not tested, that contribute significantly to peripheral
resistance, e.g. the mesenteric vasculature. A role for B 1
receptors in the central control of BP was confirmed by
Emanueli et al. [111] who demonstrated that intracerebroventricular administration of B 1 receptor agonists increases BP in both WKY and SHR. Accordingly, B 1
receptor blockade or ‘knock-down’ with antisense oligonucleotides reduced BP in SHR, but not in WKY rats
[111]. Furthermore, BP was elevated following central
administration of a kininase II inhibitor and this effect was
attenuated by central B 1 receptor blockade [111]. Together
these results suggest that central B 1 receptors may play a
role in the pathology of essential hypertension. In contrast
however, Martins et al. [112] reported that neither DABK
nor the B 1 receptor antagonist DALBK injected into the
fourth cerebral ventricle altered the BP of WKY or SHR
[113,114]. Normal regulation of BP however does not
appear to involve B 1 receptors since B 1 receptor KO mice
do not display a hyper- or hypotensive phenotype [115]. In
contrast, B 2 receptor knockouts are predisposed to hypertension [116,117].
5.4. Inflammation and the microcirculation
Many of the effects of peripheral B 1 receptor activation
are proinflammatory; vasodilation, increased blood flow
[106,118], plasma protein extravasation [113,119], activation of leukocyte-endothelial cell interactions [28] and
subsequent leukocyte accumulation [120]. B 1 receptormediated leukocyte recruitment was first demonstrated in
our laboratory in 1996 [120]. In this study we showed that
neutrophils accumulate in dorsal air pouches of mice when
treated locally with IL-1b (4 h). This leukocyte accumulation was partially inhibited by B 1 receptor blockade with
DALBK, but not by B 2 receptor blockade with HOE140.
DABK itself also caused leukocyte migration in this
model, but only in mice that had been previously treated
(24 h) with IL-1b. DABK-induced leukocyte recruitment
was inhibited by selective antagonists of the receptors for
the neuropeptides substance P and calcitonin gene-related
peptide (CGRP) [120] indicating that DABK, directly or
indirectly, activates sensory C-fibres to release neuropeptides that, in turn, stimulate leukocyte recruitment. Support
for a role for B 1 receptors in the cellular component of an
inflammatory response was provided in a recent study in
which a less specific inflammatory stimulus was used, i.e.
sephadex bead-induced pulmonary leukocyte accumulation
in guinea pigs was inhibited by B 1 receptor antagonism
[114]. B 1 receptor-mediated leukocyte recruitment has also
been demonstrated in a separate study by Vianna and
Calixto [113]. In this study intrathoracic injection of
DABK produced an inflammatory response characterized
by plasma protein extravasation and leukocyte accumulation. In contrast to our study, these effects were observed
in ‘normal’ animals suggesting that, in this model, B 1
receptors are either constitutively expressed or were already induced. This discrepancy is hard to explain, but
may be an example of regional and / or species variation.
However, it is more likely associated with a pre-existing
inflammatory state (e.g. infection) that would lead to the
appearance of pre-formed B 1 receptors. Similar to our
study, the DABK-induced leukocyte recruitment was inhibited by B 1 receptor blockade and by neurokinin and
CGRP receptor antagonists [113].
Since our 1996 study we have confirmed our findings
and extended them to the microvasculature of mouse
mesentery [28]. This investigation has been performed at
the level of the leukocyte-endothelial cell interaction in
post-capillary venules using the intravital microscopy
technique. We demonstrated that B 1 receptor activation
induces all three phases of the leukocyte recruitment
process: cell rolling, adhesion and emigration (Fig. 1).
This is in contrast to other agents which display specificity
in their action, e.g. histamine which preferentially enhances leukocyte rolling [121]. Additionally, this functional activity was temporally associated with receptor
mRNA and protein expression. Modest basal expression of
the B 1 receptor mRNA was detected in saline injected
animals, however, this was not associated with protein
expression [28]. It is possible that B 1 receptor mRNA is
constitutively expressed but an appropriate inflammatory
stimulus is required to achieve optimal translation. In this
model, DABK-induced effects were independent of B 2
receptor activation since experiments using HOE 140 or B 2
receptor knockout mice had no effect on the magnitude of
the cellular response. As illustrated in Fig. 2, we showed
that the DABK-induced leukocyte trafficking responses
involved the release of neuropeptides from C fibers, since
capsaicin treatment inhibited the responses. Furthermore,
mast cells were involved in the response since DABKinduced leukocyte trafficking was reduced following mast
cell depletion with compound 48 / 80 and DABK treatment
was shown histologically to induce mast cell degranulation. These findings provide clear evidence that B 1 receptors play an important role in the initiation of leukocyte
recruitment during an inflammatory response and this
effect appears to involve the activation of sensory C fibres
and / or mast cells. The exact relationship and sequence of
events between the C-fibre- and mast cell-dependent
pathways is less clear but certain possibilities are addressed in Fig. 2.
The site of B 1 receptor expression is unclear from these
studies. There are some in vitro observations suggesting B 1
P.G. McLean et al. / Cardiovascular Research 48 (2000) 194 – 210
201
Fig. 1. Intravital video-microscopy images of leukocyte trafficking responses in mouse mesenteric post-capillary venules in vivo in response to (A) saline
(0.25 ml, i.p., 2 h), (B) des-Arg 9 bradykinin (30 nmol, i.p., 2 h), (C) des-Arg 9 bradykinin (30 nmol, i.p., 4 h). Mice were anesthetized with diazepam (60
mg / kg s.c.) and Hypnorm  (0.7 mg / kg fentanyl cirate and 20 mg / kg fluanisone i.m). A Zeiss Axioskop ‘FS’ with a water-immersion objective lens
(magnification of 340; Zeiss) and an eyepiece (310 magnification; Zeiss) was used to observe the microcirculation. The acquired images were displayed
onto a colour video monitor and recorded for subsequent off-line analysis. Mesenteries were superfused with bicarbonate-buffered solution at 378C. Images
reprinted with permission from the Journal of Experimental Medicine.
202
P.G. McLean et al. / Cardiovascular Research 48 (2000) 194 – 210
Fig. 2. Possible sites of action of des-Arg 9 bradykinin (DABK) in the initiation of leukocyte trafficking. DABK and Lys-DABK act on B 1 receptors
possibly expressed on sensory neurones and mast cells to activate the process of leukocyte trafficking. Kinin-mediated leukocyte recruitment may involve,
as intermediaries, release of substance P (SP) from sensory neurons and histamine (hist) from mast cells, which will active NK 1 or H 1 receptors,
respectively, on either the endothelium, mast cell or sensory neurone.
receptor expression on phagocytic cells and lymphocytes.
For instance, human neutrophils secrete elastase in response to BK or Lys-DABK mediated by B 2 and B 1
receptors, respectively [122]. In addition, Lys-DABK
causes increased permeability of an endothelial layer
maintained in vitro only in the presence of neutrophils
¨
[122]. These neutrophils were naıve,
non-activated cells
hence suggesting that B 1 receptors are constitutively
expressed on these cells. Circulating lymphocytes also
appear to exhibit a chemokinetic response to kinins via the
stimulation of B 1 receptors in vitro [123]. Furthermore, B 1
receptor induction has been shown to occur on T lymphocytes during the course of multiple sclerosis, and when
activated mediate a reduction in T-cell migration in vitro
[124]. However, in a recent study we showed that DABK
had no effect on various parameters of neutrophil function
in vitro [120]. At the present time it remains unclear as to
whether B 1 receptors are present on leukocytes.
In contrast to the above studies of B 1 receptor-mediated
inflammation, B 2 receptors appear to play little role in the
cellular component of a vascular inflammatory response.
Whilst B 2 receptor-mediated effects such as plasma protein
extravasation and adhesion molecule expression have been
reported, BK produces no cellular response when injected
into the skin [1]. This is confirmed by the observation that
very high doses of BK are required to promote leukocyte–
endothelial cell interactions in rat mesenteric post-capillary
venules; doses 100–500 times higher than that required to
promote changes in blood flow [125]. Therefore it appears
that B 2 receptors may only have a small role to play in the
cellular component of the inflammatory response.
6. Role played by B 1 receptors in pathophysiology of
the cardiovascular system
Pathological activation of the kallikrein–kinin system
generally occurs during situations of stress such as inflammation or shock (e.g. following a pathogenic or chemical
insult). This acute response consists of the activation of
PK, leading to BK generation. Release of BK and subsequent activation of B 2 receptors has been suggested to
play an important role in acute inflammation and the
immediate hypotensive response to endotoxin [1]. However, it now appears that the subsequent formation of
des-Arg 9 kinins and induction and activation of B 1 receptors may also play an important role in the pathology of
human disease, particularly those diseases in which a
vascular inflammatory component exists.
P.G. McLean et al. / Cardiovascular Research 48 (2000) 194 – 210
6.1. Sepsis and the kallikrein–kinin system
Sepsis is defined as the systemic inflammatory response
syndrome (SIRS) that results from infection and is referred
to as ‘septic shock’ when accompanied by hypotension that
is unresponsive to fluid therapy [126]. Endotoxins, released
from gram-negative bacteria, are thought to play an
integral role in the pathogenesis of sepsis. Exposure to
gram-negative or gram-positive bacteria, fungi or proteoglycan polysaccharides can trigger the release of inflammatory substances including kallikrein from infiltrating
leukocytes, platelets and ECs, as well as directly activating
the kallikrein–kinin system leading to increased kinin
synthesis [126]. Kinins appear to be particularly important
in the pathogenesis of SIRS and sepsis when endotoxin is
the critical pathogen [127]. The early peripheral vascular
changes accompanying endotoxic shock include a fall in
blood pressure. A key feature of endotoxemia is a hypodynamic state which alters the distribution of blood to
exchange vessels in tissues and organs throughout the
body. One such example of this disordered autoregulation
in sepsis is the coronary microcirculation [128,129]. This
phenomenon is thought to be due partly to the release of
NO from iNOS expressed in vascular smooth muscle
[128], an important mediator of sepsis-induced hypotension [130], however NO-independent mechanisms exist but
remain to be elucidated [131,132]. Several studies support
a role for the B 1 receptor which has been implicated in the
regulation of the coronary circulation in rat and rabbit
models of endotoxemia [18,16,133]. Infusion of BK or
DABK results in cardiovascular changes, particularly
hypotension, similar to those occurring in endotoxic shock
[18,134]. In animal models, endotoxin causes rapid activation of the kallikrein–kinin system increasing kinin levels
[135,136]. This effect appears to be specific to LPS as the
monophosphoryl lipid A derivative of bacterial LPS fails
to induce B 1 receptor-dependent responses to DABK in the
rabbit in vivo [137]. Similarly, the pathological response to
intravenous endotoxin in healthy human volunteers [138]
is associated with activation of the kallikrein–kinin systems. In addition, consumption of pre-kallikrein and
HMWK is also increased in patients with endotoxemia,
and this is particularly true for patients with septic shock
(or hypotensive sepsis) compared to those with uncomplicated sepsis [139–142].
6.1.1. Kinin receptors and sepsis
Support for a role of kinin receptors in the hypotensive
response in sepsis is provided by several studies demonstrating a partial restoration of blood pressure following
treatment with kinin receptor antagonists. Endotoxin treatment produces a profound biphasic hypotensive response,
a brief early phase followed by a prolonged late phase. The
first phase is sensitive to B 2 receptor blockade [136,143],
but not affected by B 1 receptor antagonists (McLean,
Perretti and Ahluwalia, unpublished observation). The
203
prolonged phase, which is the stage at which patients
present in the clinic, has been extensively studied and is
known to be partially dependent on enhanced NO production from the induction of iNOS [130]. In a recent
study [18] we showed that B 1 receptor antagonists produced a partial reversal of the prolonged phase of endotoxin-induced hypotension. The inhibition of ACE / kininase II
with captopril did not appear to markedly affect the role of
B 1 receptors in hypotension in this model [18]. Mice
lacking the gene for the B 1 receptor have been developed
[115] and a full characterization of the responses to
bacterial infection and endotoxic shock in these animals is
needed. It was suggested that the immediate hypotensive
response to endotoxin is markedly blunted in these animals
[115]. This finding contrasts the observation made in the
rat, and requires confirmation in a full study, but certainly
suggests that the B 1 receptor is involved in the hypotensive
response to endotoxin.
6.1.2. Kinin receptor antagonists in the treatment of
sepsis
A role for kinin receptors in endotoxic shock, while an
attractive target, is not yet certain because specific
metabolically stable kinin receptor antagonists have only
recently been made available. The following sections
describe some of the findings arising from studies of kinin
receptor antagonists in animal models of endotoxic shock
and human sepsis.
6.1.2.1. B2 receptor antagonists Given the evidence
implicating kinins in the pathogenesis of sepsis it is not
surprising that pre-formed B 2 receptors have been suggested to play a role in certain aspects of the septic
syndrome. However, reports investigating the effects of B 2
receptor antagonism in models of endotoxemia are conflicting showing both beneficial effects and negative
efficacy. One of the first studies to investigate the effect of
kinin receptor blockade in endotoxic shock was that of
Wilson et al. [136] who tested the B 2 receptor antagonist
3
7
D-Arg-Hyp -D-Phe -bradykinin (NPC 567). In this study
administration of LPS to rats resulted in an increase in
circulating bradykinin and prostaglandin levels and a
profound hypotensive response. NPC 567 infusion
dramatically reduced mortality from 100 to 50% at 24 h
which was accompanied by a significant reduction in
6-keto-PGF 1a levels and partial reversal of the hypotensive
effects. Other studies confirm beneficial effects of B 2
receptor blockade in sepsis [144,145]. However, there are
also contrary reports indicating no benefit of B 2 receptor
antagonism. In particular, the study by Feletou et al. [146]
demonstrated that LPS-induced hypotension, metabolic
acidosis and leukopenia in rabbits was unaffected by the
B 2 receptor antagonist S 16118. Furthermore, in mice, LPS
administration induced over 90% mortality at 96 h which
was not reduced by S 16118 [146]. Other studies in rodents
204
P.G. McLean et al. / Cardiovascular Research 48 (2000) 194 – 210
report a negative efficacy for B 2 receptor blockade alone in
experimental endotoxic shock [147,148] although a beneficial effect was observed when used in combination with
leukocyte recruitment inhibitors (NPC 15669) [148].
6.1.2.2. B1 receptor antagonists B 1 receptor-mediated
hypotensive responses have been demonstrated and characterised in rabbit [16], rat [18] and pig [104] models of
endotoxemia indicating a potential role for this receptor in
the hypotensive response to endotoxin. Administration of
B 1 receptor antagonists blocks the hypotensive effect of
exogenously administered B 1 receptor agonists [16,18].
The only report investigating the effect of B 1 receptor
blockade on the endotoxic shock-associated hypotension
was performed recently in our laboratory [18]. We showed
that B 1 receptor blockade with DALBK or des-arg 10 HOE140 produced a modest reversal (5–9%) of endotoxin-induced hypotension. Therefore activation of B 1
receptors may have a modest role to play in the vascular
changes associated with endotoxemia, however the possibility of synergism with other therapies has not been
tested. The effect of selective B 1 receptor antagonists on
mortality associated with endotoxemia is unclear. Siebeck
et al. [145] showed that B 2 receptor blockade attenuates
endotoxin-induced mortality in pigs, whereas additional B 1
receptor blockade seemed to reverse these beneficial
effects [145]. However, the effect of B 1 receptor blockers
alone was not tested. The reasons for this apparent
contradiction regarding the role of B 1 receptors is unclear
but may be related to species differences. The pattern of B 1
receptor expression in endotoxic pigs is reportedly confined to the smooth muscle with no endothelial expression
[63]. In contrast, endotoxin-induced, B 1 receptor-mediated
vasodilation in rat vessels is endothelium-dependent [18]
similar to human coronary arteries [85]. However, it is
possible that B 1 receptor activation is protective, at least in
the porcine model of endotoxic shock, which may or may
not be relevant in other species. Alternatively, the level of
B 1 receptor blockade may be important; partial inhibition
may be beneficial whereas complete blockade is detrimental. Further studies with selective metabolically stable
kinin receptor antagonists are required to address this
controversy.
6.1.2.3. Mixed kinin receptor antagonists It is possible
that the apparent contradictory findings with kinin receptor
antagonists lie in their receptor selectivity. Certain peptidic
B 2 receptor antagonists are non-selective and have some
efficacy at B 1 receptors in vivo. CP-0127 is a peptide
dimer of two single chain BK antagonists linked together
creating a compound with high potency in vitro [149] and
long duration of action in vivo [143]. The pharmacology of
this compound is unique in that it appears to be a specific
B 2 receptor antagonist in vitro [150]. However, in vivo it
behaves as a B 2 receptor antagonist with moderate B 1
receptor antagonist activity (Cheronis, J.C. 1999. Personal
communication). CP-0127 itself does not have B 1 receptor
antagonist activity but its two metabolites, the mono and
bis-des-Arg derivatives do. Their potency is relatively low
but they are more stable and consequently accumulate
(Cheronis, J.C. 1999. Personal communication). Administration of such compounds (e.g. CP-0127, NPC-567)
inhibit hypotension and improve survival in rats and
rabbits challenged with endotoxin [136,143]. This improvement over B 2 receptor blockade alone would imply
that compounds possessing affinity at both kinin receptors
may prove advantageous in the therapy of sepsis [151].
Indeed, CP-0127 marginally improves survival in patients
with gram-negative sepsis [152], and it is possible that this
beneficial effect is correlated with the efficacy of this
compound at B 1 receptors.
6.2. I /R injury
I / R injury is an inflammatory state also associated with
B 1 receptor induction. In both in vitro and in vivo models
of myocardial I / R functional B 1 receptor expression is
induced [153]. In rat isolated hearts ischemia-induces B 1
receptors that upon activation modulate noradrenaline
release or preserve endothelium-dependent vasodilation
[101,103,154]. Further support for a role of kinins in I / R
injury is provided by the demonstration that the kallikrein–
kinin system in the heart is activated as demonstrated by
an increase in the levels of kinins in the effluent of isolated
perfused hearts [41,155]. Similarly kinin levels are elevated in in vivo myocardial I / R injury; an effect further
increased by kininase II inhibition [156,157].
Recent studies indicate that BK, acting via B 2 receptors,
has a protective effect in I / R injury of the rat mesenteric
microcirculation [158] and rabbit myocardium [159]. Additionally treatment with angiotensin-converting enzyme
inhibitors further attenuate the extent of I / R injury, an
effect associated with elevated levels of endogenous kinins
[159]. Indeed, intracoronary perfusion of exogenous BK is
protective against I / R-induced ventricular fibrillation
[160,161]. B 1 receptors have also been suggested to play a
protective role since B 1 receptor antagonism blocks
DABK- or BK-induced decreases of I / R-induced noradrenaline outflow and arrhythmia [101].
That kinins exert a protective effect in I / R is surprising
because of their well-known proinflammatory actions.
Especially since B 2 receptors have been implicated in the
pathogenesis of post ischemic pancreatitis [162] and the
fact that B 1 receptors play a role in initiation of the
leukocyte–endothelial interaction that occurs in global
ischemia of the brain [163]. However, in a rat model of
cerebral artery occlusion, opposing effects of B 2 and B 1
receptor antagonism have been described [164]. Antagonism of B 2 receptors reduced cerebral infarct whereas B 1
receptor blockade reversed the beneficial effect of the B 2
receptor antagonist [164]. In this model B 1 and B 2
receptors have differential effects on ischemic brain pathology.
Therefore, it appears that kinin receptor activation has
P.G. McLean et al. / Cardiovascular Research 48 (2000) 194 – 210
the potential to modulate I / R injury. Further studies are
required to fully understand the mechanisms and functional
relevance of these observed effects and to determine under
which conditions these effects are protective or contributory to the pathology of I / R injury.
6.2.1. Ischaemic preconditioning
Activation of the kallikrein–kinin system is necessary
for the cardioprotective effect of preconditioning and
involves activation of both B 2 [165] and B 1 [101,154]
receptors. The use of selective antagonists has shown that
B 2 receptor activation mediates the benefits of ischaemic
preconditioning on certain features of I / R injury; reduced
arrhythmias [166], reduced infarct size [167] and improvement of post-ischaemic ventricular recovery [168]. B 1
receptor activation appears to be important in the protection provided by ischaemic preconditioning on endothelial
function [154] as well as inhibiting noradrenaline overflow
and preventing ventricular fibrillation at reperfusion [101].
In contrast to their role in I / R injury, which is less clear,
B 1 receptors are clearly important in the protection afforded by ischaemic preconditioning.
6.3. Atheromatous disease
Immunoreactivity for the human B 1 receptor is markedly increased in atheromatous plaques of the coronary,
vertebral, femoral and pericallosal arteries [65]. Intense
labelling for B 1 receptors was shown to be most apparent
on the ECs, foamy macrophages, infiltrating leukocytes
and in proliferating SMCs. Immunoreactive B 2 receptors
were also expressed in these lesions, but with a consistently lower intensity relative to the B 1 receptor. Pilot
studies in the rabbit on the effects of high dietary cholesterol on B 1 receptor expression in cardiac tissue were
negative [14] whilst in the same study, endotoxin treatment
caused marked cardiac B 1 receptor expression. Taken
together these studies suggest that up-regulation of B 1
receptors expression may occur as a result of the inflammatory nature of atherosclerosis, but not simply as a
result of hypercholesterolemia. The precise role of B 1
receptors (contributory or protective) in the development of
ischaemic heart disease is difficult to predict and requires
further study.
205
demonstrated [169]. B 1 receptor stimulation has been
shown to cause contraction and DNA synthesis in cytokine
treated rabbit aortic SMCs, the latter effect being unique to
cytokine-treated cells [20]. As such, B 1 receptor induction
may play a role, in concert, in the altered reactivity and
hypertrophic medial responses to injury in arteries following angioplasty although further studies are required to
confirm this. In contrast, B 1 receptor activation also leads
to suppression of DNA synthesis in PDGF-stimulated rat
mesenteric artery SMCs [170], although the significance of
this finding remains to be determined.
6.5. Other diseases
The role played by B 1 receptors in other diseases of the
cardiovascular system such as hypertension, cardiac failure
and their associated complications is unknown. It is
interesting to note that increased production of inflammatory cytokines occurs in human cardiac failure [171] that
would be expected to stimulate wide spread B 1 receptor
induction.
Polymorphisms in the human B 1 receptor gene have
been identified and appear to be associated with the risk of
end-stage renal disease [172,173]. An allele in which a
single base substitution (G699→C) occurs in the putative
promoter region with significantly lower frequency in a
population of renal failure patients and determines an
increased activity of promoter function [173]. B 1 receptor
polymorphisms have been suggested to have a protective
effect in the development of end-stage renal disease [172].
Whether B 1 receptor polymorphisms exist for other cardiovascular diseases remains to be determined
7. Conclusions
B 1 receptors are involved in certain cardiovascular
inflammatory pathologies such as endotoxic shock,
atheromatous disease, and myocardial ischaemia. Furthermore, the inducibility of the receptor makes it an attractive
target for therapeutic interventions. Drug development
efforts, however, will need to be acutely aware of the
possibility that activation of B 1 receptors may be pathogenic or protective depending on the disease and tissue
affected.
6.4. Angioplasty
Evidence suggesting a role for B 1 receptors in the
pathogenesis of angioplasty-induced vascular injury was
provided in a recent study by Pruneau et al. [169]. In this
study balloon catheter injury to the rabbit carotid artery led
to the development of a contractile response to the B 1
receptor agonist DABK. This induction of reactivity to
DABK was associated with the proliferation of SMCs but a
causal relationship between the two findings was not
Acknowledgements
Dr McLean and some of the authors’ work herein is
supported by the British Heart Foundation (BHF,
PG[97013). Dr Ahluwalia is funded by a BHF Intermediate Fellowship and Dr Perretti is a Research Fellow of
the Arthritis Research Campaign.
206
P.G. McLean et al. / Cardiovascular Research 48 (2000) 194 – 210
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