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ME Moreau et al

26

the formation of compensatory vasculature in a rodent
ischemia model after occlusion of the femoral artery
(281). FR190997 is a nonpeptide B2R agonist (or
partial agonist) derived chemically from a series of B2R
antagonists (282). Speculatively, it has been proposed
that this drug could be exploited as an antihypertensive
or cardioprotective agent, but clinical testing remains to
be performed (283). Much experimental and some
clinical works on the effect of ACEi naturally suggests
that kinin receptor agonists could be used as vasoactive
agents, but the inflammatory properties of these
compounds probably cannot be dissociated from their
vasodilator

/

angiogenic effects (273). One B2R agonist

that has been developed up to a certain point, labradimil
(RMP-7), was a peptidase-resistant BK analog used
to transiently open the blood-brain barrier, thus
deliberately exploiting an inflammatory effect (284).

B1R may not be responsible for the cardiovascular

effect of kinins in healthy humans but in the case of
tissue injury, the receptor expression is induced, as in
the cardiac endothelium of patients with heart failure
(285), and B2R expression remains usually unchanged.
However infusion of a pharmacologic concentration of
the BK agonist des-Arg

9

-BK does not cause vasodilation

in the forearm of congestive heart failure patients treated
chronically with ACEi.

2.2 Inflammation

Injections of substances known to activate the contact

system, such as carrageenan, induce a swelling that
reaches a maximal response at 3 h post-injection (286).
BK release is related to the intensity of an acute inflam-
mation reaction, based on the inhibitory effect of a B2R
antagonist, but repeated injections of the irritant pro-
duced a reaction that becomes responsive to a B1R
antagonist (Fig. 5). This type of observation was also
made using an antigen-induced model of chronic inflam-
mation where the B1R antagonist [Leu

8

]des-Arg

9

-BK

was shown to become more potent to inhibit plasma
extravasation of joint inflammation as the model pro-
gressed (287).

BK administration reproduces two of the cardinal

signs of inflammation (

rubor

, 

calor

) through the

activation of B2R that causes vasodilatation due to
NOS and PLA

2

 stimulation leading to NO and PGI

2

production by vascular endothelial cells. The ensuing
exudation of protein-rich fluid from the circulation,
facilitated by kinins, is largely determined by the rise of
vascular permeability, particularly at the level of post-
capillary venules via endothelial cells contraction. This
is the essentially vasogenic mechanism of a third
cardinal sign of inflammation, swelling (

tumor

).

Models of chronic inflammation provide the involve-

ment of the B1R (151). The role of infiltrating leuko-
cytes is relevant in these models as they may supply
cytokines (IL-1

β

, TNF-

α

) levels required to induce B1R

expression. Conversely, B1R seems to be of importance
in neutrophil accumulation in inflamed tissues, as the
ablation of the corresponding gene in mice is associated
with a significant defect of this process (mechanism not
fully elucidated) (288).

2.3 Pain and neurological applications

The specific role of B1R and B2R in inflammatory

pain perception (

dolor

, the 4th cardinal sign of inflam-

mation) is correlated to the amplitude and the kinetics
of their expression. B2R are generally constitutively
expressed on primary non-myelinated sensory neurons
and BK activates these nociceptors to contribute to the
acute pain response (289) through the release of DAG
(173) and the protein kinase C activation (290).

One of the most promising applications of kinin

receptor antagonists is analgesia. A number of animal
models of inflammatory pain have been exploited to
show that B1R or B2R antagonists exert analgesia (151).
Although the interest for a B1R antagonist is currently

Fig. 5.

Effects of kinin receptor antagonists on carrageenan-

induced paw edema. Effects of a B

1

 (Lys[Leu

8

]des-Arg

9

-BK,

32.5 nmol

/

paw) and B

2

 (HOE 140, 3.25 nmol

/

paw) receptor

antagonist on carrageenan-induced paw edema. The anti-edema
potential of the B1R antagonist is evidenced only at the second
challenge, consistent with B1R absence in the uninflamed tissue.
Carrageenan was injected twice, at 24-h intervals. Carrageenan 0.5%
(black circle), carrageenan 0.5% with B1R antagonist (grey square),
or with B1R and B2R antagonists (white triangle). (Reproduced with
permission from A. Décarie, PhD Thesis, p. 156, Université de
Montréal, 1997)

The Kallikrein-Kinin System

27

strong, due to their efficacy in the later of persistent
phases of inflammatory pain, the analgesic effect of
recent nonpeptide antagonists of the B2R is surprisingly
good (LF 16-0687, bradyzide) (291, 292). However, the
fact that peptide antagonists of either receptor subtype
are analgesic may support a peripheral mode of action,
as these agents are likely to be excluded from the CNS.
A peripheral site of action is further supported by the
localized expression of the B1R mRNA in a zymosan-
induced inflammatory pain model applied to the rat
(291).

On the other hand, the role of the CNS expression of

kinin receptors in pain perception is of great interest.
The occurrence of “wind up” (facilitation) to repeated
dorsal root stimulation in vitro is reduced by about 50%
in the B1R gene knockout mice (288), suggesting the
presence of a constitutive B1R population in the pain
neurosensory pathways in this species. B1R mRNA is
expressed in rat and human dorsal spinal cords (293,
294) and throughout the rostral-caudal portion of
monkey brain (295). However, whether the presence of a
background mRNA concentration predicts the presence
of mature receptors is not clear: there is published
evidence showing that the B1R mRNA is detectable in
the control rat spinal dorsal cord, but not the correspond-
ing binding sites; however, both increase as a function of
the pathology (streptozotocin-induced diabetes) (296).

Abundant preclinical evidence shows that post-

traumatic brain edema is reduced by B2R pharmaco-
logical blockade (297, 298); this is likely to be a
vasogenic response. The nonpeptide drug LF 16-0687 is
currently being evaluated for this indication in humans.
Cultured human brain microvascular endothelial cells
express the B1R (299). The biological significance of
B1R activation during inflammation can be considered
in the context of both blood-brain barrier permeability
and chemoattraction. The activation of B1R reduces
IL-8 secretion by these cells, suggesting dissociation
between permeability of fluids and leukocyte traffick-
ing. By this mechanism, activation of B1R would
produce a perivascular infiltrate enriched for high
molecular weight molecules with a relative paucity of
immune cells. Moreover, a correlation has been ob-
served between B1R activity and its expression on
peripheral T lymphocytes in multiple sclerosis patients
(300). Nevertheless, B1R activation prevents the infiltra-
tion of T lymphocytes through an artificial blood-brain
barrier, suggesting a protective role of B1Rs in this
disease via an inhibition of IL-8 secretion.

B2R is widely distributed in the rat brain, but follow-

ing kindling-induced epilepsy, the relatively low levels
of B1R expression, in normal rodents, are functionally
detectable in several brain areas (potentiation of electri-

cally evoked glutamate overflow) (301).

Local inflammation of viscera, such as small intestine

or bladder, and related pain are mediated by endogenous
kinins via a viscero-visceral hyper-reflexia. Kinin
receptor antagonists were shown to inhibit this hyper-
reflexia, but a temporal shift of mediation is seen from
B2Rs to B1Rs (302). BK-receptor expression in inflam-
matory bowel disease, namely, ulcerative colitis and
Crohn’s disease, may be altered in intestinal inflam-
mation. Increased B1R gene and protein expression in
active inflammatory bowel disease provides a structural
basis for the important role of kinins in chronic inflam-
mation (303).

Clinical trials for the analgesic effects of B1R antago-

nists are currently being conducted.

2.4 Diabetes

Some experimental data suggest that diabetes is

another pathological condition that could induce B1R
expression. Insulino-dependent diabetes (type I diabetes)
derives from an auto-immune response (insulitis)
implicating an overproduction of cytokines such as IL-
1

β

 and TNF-

α

. Moreover, hyperglycemia and oxidative

stress can also activate NF-

κ

B. The addition of cytokines

overproduction and hyperglycemia could then induce
B1R expression through NF-

κ

B (304, 305). The peptide

B1R antagonist [Leu

8

]des-Arg

9

-BK prevents the pro-

gression of steptozotocin-induced insulin-dependent
diabetes in rodents (306), but not treatment with
Icatibant, suggesting that the B1R has a selective role
in the insulitis that precedes diabetes in this model.

Furthermore, established streptozotocin-induced dia-

betes in rodents is associated with prominent B1R
expression (307, 308) and the associated hyperalgesia
(309). However, these observations were made on
insulin-dependent diabetes without insulin treatment, a
wasting disease with high blood cytokine levels, and
have an uncertain significance for the complications of
diabetes in present day human patients. Another line of
investigation suggests that kinins exert protective effects
in diabetes models in rodents as inhibitors of kininases
improved the sensitivity to insulin and as Icatibant
significantly reduced the effect of these kininases
inhibitors. These observations support that these meta-
bolic effects are mediated by endogenous BK and B2R
(310, 311).

2.5 Renal disease

Malignant hypertension is observed when B2R

knockout mice are overloaded with dietary sodium
(312). This confirmed the long time suspected role of
the renal kallikrein-kinin system in handling sodium
and water metabolism, in parallel to the renin-angio-

ME Moreau et al

28

tensin-aldosterone endocrinal axis (313).

Specific polymorphisms of the human kinin receptor

locus have been associated with end-stage renal failure
(mixed aetiology), hypertension, and nephropathy in
diabetics (259, 265, 266); all these findings are
perfectible efforts to link the transmission of this locus
to human pathology. The protective effect of kinins in
renal disease has been extended to the B1R, as various
aspects of the chronic inflammatory response seem to be
limited by endogenous ligands of this receptor subtypes
in animal models (314).

2.6 Airway disease

Icatibant (HOE 140), a widely used peptide B2R

antagonist, has been found to significantly improve the
ventilatory function in humans with asthma when
administered in an aerosol form (269). The mode of
action of this drug was not related to an acute bron-
chodilator action, but rather to a long-term anti-inflam-
matory effect.

Persistent dry cough is a side effect related to the

use of ACEi in a relatively large number of patients.
The cause and the mechanism of dry cough is not fully
understood but can be attributed to a possible local
accumulation of BK that may lead to activation of
proinflammatory peptides and a local release of hista-
mine, inducing a cough reflex hypersentivity (264).
Another explanation implicates a BK-mediated increase
in lung PGs which produce cough and sensitize
bronchial contractility (315, 316). Several poly-
morphisms of the human B2R gene may be involved in
ACEi-related cough. The genotypic and allelic frequen-
cies of the 

−

58 thymine

/

cytosine (

−

58T

/

C) poly-

morphism of patients with essential hypertension were
analyzed (264). The frequencies of the TT genotype and
the T allele of 

−

58T

/

C are higher in the subjects with

cough than in subjects without cough. Moreover, 

−

58T

was found to have a higher transcription rate than that
of 

−

58C. The higher expression of the B2R might be

involved in the occurrence of ACEi-related cough.

2.7 Angioedema (AE)

An exon 1 polymorphism in the human B2R gene, in

which alleles differ by a 9 bp deletion, appears to confer
a higher level of expression, probably due to more
stability against the action of RNases. The B2R(

−

) allele

was always present in the most symptomatic cases of
HAE in a small series of patients and thus is proposed
to modulate in a dominant manner the phenotype of the
basic genetic defect of this disorder (130). However,
this polymorphism did not predict the incidence of the
most common side effect of ACEi, the non-productive
cough (260). ACE-induced angioedema is correlated to

a decreased ability to degrade des-Arg

9

-BK in hyper-

tensive patients (248). This biological marker has been
later attributed to a largely transmissible variability of
the expression of membrane APP (250). Encouraging
results in the clinical trial of the B2R antagonist
Icatibant support that kinin receptor blockade is of
therapeutic interest in HAE (209). It remains to be seen
whether B1R blockade could be as or more effective in
this and other forms of AE.

Conclusion

In this review, we tried to show that the complexity of

the kallikrein-kinin system results from the interaction
of its multiple components. We have exposed both
faces of this system, where the 

ying

 is often the shadow

of the 

yang

. We have also stressed that pathophysio-

logical models and pharmacological approaches vali-
dated in animals (potentiation of the cardiovascular
effects of kinins, suppression of their proinflammatory
effects) are sometimes difficult to apply in humans.
Notwithstanding these difficulties, several groups of
drugs are now available or being developed in human
medicine for the treatment of either the side effects
resulting from the chaotic activation of the contact
system or the potentiation of the cardioprotective effects
of kinins.

Recent experimental works open new pharmaco-

logical venues, as is the case for the antiangiogenic
property of the heavy chain of HK. It is particularly true
for des-Arg

9

-kinins and their B1R, the molecular target

of many novel antagonists. The nonpeptide B1R antago-
nists are now in development. They look particularly
promising in the treatment of inflammatory pain where
the roles of the B1R and its agonists have been shown in
animals. A number of other applications are awaiting
clear clinical conclusions about the applicability of
kinin receptor antagonists: inflammation (e.g., inflam-
matory bowel disease), asthma and allergy, brain edema
and wasting states, sepsis, congenital, or drug-induced
angioedema.

Acknowledgements

The laboratory of FM is supported by the Canadian

Institutes for Health Research (grant MOP-14077). The
laboratory of AA is supported by the Canadian Institutes
for Health Research (grant MOP-14077), the Fonds de
Recherche en Santé du Québec, and the NIH (grant 1-
R01-HL079184). The laboratory of NJB is supported
by the NIH (grant 1-R01-HL079184). GM received a
Fellowship from the Canadian Institutes for Health
Research.

The Kallikrein-Kinin System

29

We dedicate this review to Dr. J. Damas, for his retire-

ment. Dr. Damas discovered the Brown Norway rat, the
prototype of transgenic animals in kinin research.

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