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From the
Mice that are homozygous for the targeted disruption of the gene
encoding the B
The nonapeptide hormone bradykinin (BK)
The physiological
actions of the kinins are a consequence of their interaction with
transmembrane receptors. Two distinct bradykinin receptor subtypes,
B
Pharmacological studies of
bradykinin receptors have led to the proposal that additional
bradykinin receptor subtypes
exist
(23, 24, 25, 26, 27, 28, 29, 30) .
Several of these studies are complicated by the fact that they compared
the action of synthetic peptide antagonists on bradykinin receptors in
tissues isolated from different species
(23, 26) .
However, other studies describe differences in the pharmacological
properties of bradykinin receptors from different tissues within the
same species (24, 25, 27-30). From these analyses, separate
smooth muscle and neuronal subtypes of the B
Much has been learned about the
physiological role of these receptors from the development and use of
potent B
Generation of Bk2r
Genomic DNA was prepared from a tail biopsy collected by snipping
approximately 1.5 cm from the end of the tail of the mouse. Tails were
digested overnight at 55 °C by 0.3 µg of Proteinase K in 0.7 ml
of buffer containing 50 mM Tris, pH 8.0, 100 mM EDTA,
and 0.5% SDS. The DNA was extracted twice with 0.5 ml of
phenol/chloroform and once with chloroform. Genomic DNA was
precipitated with an equal volume of ethanol, and the DNA clump was
transferred using a pipette tip to a 70% ethanol wash and then
transferred to and resuspended in TE (10 mM Tris, pH 7.4, 1
mM EDTA).
Genomic Southern blots were performed by
modifications of established procedures. Approximately 10 µg of
genomic DNA was digested overnight with the appropriate restriction
enzyme. The digest was extracted with phenol/chloroform, and
chloroform, then ethanol-precipitated. The pellet was resuspended in
TE, and the DNA was separated by electrophoresis on an 0.8% agarose
gel. DNA on the gel was transferred to a Zeta-Probe GT membrane
(Bio-Rad) with a PosiBlot apparatus (Stratagene) and then
UV-cross-linked with a Stratalinker (Stratagene). The DNA on the
membrane was incubated overnight at 65 °C with >1
Embryonic stem (ES) cells (AB 2.1) derived from mouse strain
J129 Sv/Ev were transfected with a targeting vector designed to disrupt
the Bk2r gene encoding the B
The proposed role of BK receptors in reproduction was
examined by establishing five mating pairs of
Bk2r
Previous studies have
indicated that a high level of B
We have generated a mouse in which the B
A role of
kinins in reproduction has been proposed due to the presence of the
components of the kallikrein-kinin system in the uterus and in semen.
The uterus contains a relatively high density of B
Previously, several pharmacological
studies have proposed the existence of multiple B
The demonstration
that the Bk2r
We wish to thank Drs. John Mudgett and Lex Van der
Ploeg for helpful advice. We thank Dr. Karla Stevens for clinical
pathology, Frank Shen for statistical analyses, and B. Bowery for
excellent technical assistance.
Volume 270,
Number 23,
Issue of June 9, pp. 13706-13710, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
Bradykinin Receptor Gene in Mice
Eliminates Bradykinin Action in Smooth Muscle and Neurons (*)
ABSTRACT
INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
bradykinin receptor have been generated. The
gene disruption results in a deletion of the entire coding sequence for
the B receptor. The disruption of the B receptor gene has been confirmed by genetic, biochemical, and
pharmacological analyses. Mice that are homozygous for the disruption
of the B receptor gene are fertile and indistinguishable
from their littermates by visual inspection. Bradykinin fails to
produce responses in pharmacological preparations from ileum, uterus,
and the superior cervical ganglia from these mice. Therefore,
expression of a single gene appears to be responsible for conferring
responsiveness to bradykinin in these tissues.
()
and the decapeptide kallidin
([Lys
]BK) are generated by the action of a family
of serine proteases, kallikreins, on a large protein precursor,
kininogen, present in plasma and
tissue
(1, 2, 3, 4) . The removal of the
C-terminal arginine residue from these ligands by a carboxypeptidase
generates a second set of active hormones
(5, 6) .
Collectively, these kinins are generated at sites of tissue damage and
are rapidly degraded by the angiotensin converting enzyme and other
proteases. BK and kallidin are algesic and inflammatory agents. BK acts
on afferent sensory neurons to elicit pain and to release additional
mediators of pain and inflammation. BK is also a very potent vasoactive
hormone that appears to act in a paracrine rather than a systemic
fashion. Vasodilation mediated by BK in the airways may contribute to
the pathogenesis of asthma
(7) . In contrast to this potentially
deleterious effect, the vasodilatory properties of BK may be beneficial
following an ischemic event
(8, 9) .
and B, have been proposed by pharmacological
analyses
(5) and shown to exist by the molecular cloning of
cDNAs encoding G-protein-coupled receptors with the appropriate
pharmacological profiles
(10, 11) . Whereas the B bradykinin receptor subtype is found in healthy smooth muscle and
neurons, the B receptor subtype is only detected following
tissue injury
(12, 13, 14) . The actions of
bradykinin and kallidin reside with the B receptor which
possesses a high affinity for these ligands but has a dramatically
reduced affinity for their carboxypeptidase-generated
metabolites
(11, 15) . By contrast, the B bradykinin receptor is preferentially activated by
[des-Arg]kallidin and possesses a low affinity
for bradykinin
(5, 10, 16) . The potential for
transformation of the selectivity of a peptide ligand from the B
to the B receptor by carboxypeptidase action has been
observed with both agonists and antagonists
(17, 18) .
When activated, both receptor subtypes interact with G-proteins to
initiate a signal transduction cascade that stimulates phospholipid
metabolism. The B receptor subtype activates both
phospholipase C and phospholipase A, resulting in the
mobilization of Ca and prostaglandin
synthesis
(19, 20, 21) . Similarly, activation of
the B
receptor subtype has been recently shown to stimulate
phosphatidylinositol metabolism and arachidonic acid
release
(16, 22) .
bradykinin
receptor have been proposed
(24, 25) . In addition, a
B
bradykinin receptor subtype has been proposed based on
the differential activity of peptide and non-peptide antagonists in
blocking BK-induced contraction of the guinea pig
trachea
(27, 28) .
and B bradykinin receptor
antagonists
(18, 31, 32, 33) , but these
reagents are limited by their pharmacokinetic properties. Disruption of
a gene by homologous recombination has become a valuable tool in
discerning the physiological roles of gene products
(34) . We
describe here the generation and initial characterization of mice in
which the gene encoding the B bradykinin receptor is
disrupted by gene targeting. Smooth muscle and neuronal preparations
from Bk2r mice have been examined
for their ability to respond to BK. The genetic ablation of the B
bradykinin receptor will complement pharmacological analyses to
define the physiological role of this receptor. In addition, the
Bk2r mouse will allow the question
of additional genes encoding B
bradykinin receptor subtypes
to be answered unambiguously.
Mice-Gene targeting was done in the embryonic stem (ES)
cell line AB 2.1
(35) derived from J129 Sv mice. The mouse
genomic DNA utilized to construct the targeting vector was obtained
from a cosmid clone isolated from a library constructed by Dr. John
Mudgett (Merck Research Laboratory, Rahway, NJ) from an ES cell line,
J1, derived from J129 Sv/Ev mice. ES cell clones containing the
targeted disruption of the Bk2r gene were separated from SNL
feeder cells by treating the cell culture with trypsin, allowing the
feeder cells to reattach for 30-45 min, and removing the
unattached ES cells. Two Bk2r-targeted ES clones, KO-5 and
KO-24, were injected into C57Bl/6J recipient 3
-day-old
blastocysts in separate experiments using established
techniques
(36) . The injected C57Bl/6J recipient blastocysts
were reimplanted into day 3 pseudopregnant Tac:SW(fBR) mice and allowed
to develop to term. Progeny were screened initially by coat color
chimerism, the agouti color being an indicator of ES cell contribution.
10
cpm/ml radiolabeled probe in a solution containing 0.25
M NaHPO
, pH 7.2, 6.5% SDS, and 10%
dextran sulfate. Probes were radiolabeled with
[
-P]dCTP (3000 Ci/mmol, Amersham) using a
random priming kit (Boehringer Mannheim). Hybridized filters were
washed at 60 °C with 0.1
SSC, 0.1% SDS twice for 30 min and
then subjected to autoradiography.
Membrane Binding Assay
Mice were sacrificed by cervical
dislocation. The uterus and ileum were removed and the wet weight was
determined. The tissues were homogenized, using a Polytron, in
approximately 20 volumes of ice-cold 20 mM HEPES, pH 7.4.
Membranes were prepared, and binding assays were performed as described
previously
(37) .
Uterine Contraction Assay
The entire uterus was
removed, and the two horns were separated. The uterus horns were placed
in buffer (154 mM NaCl, 5.6 mM KCl, 0.45 mM
CaCl, 5.9 mM NaHCO, 2.6 mM
glucose) bubbled with 95% O/5% CO, and
connective tissue and fat were removed. A 2-cm portion was removed from
each horn and attached to a glass tissue holder with 3-0 surgical
silk and placed in a tissue bath containing buffer maintained at 30
°C and bubbled with O/CO as above. One gram
of tension was applied to the tissue, and tension was measured by a
Gould Statham force transducer and recorded on a HP 7758B system.
Tissues were washed four times over a 1-h equilibration period prior to
the addition of pharmacological agents. The tension was then readjusted
and compounds were added; following the addition of each compound, the
preparation was washed for 30-45 min before the addition of the
subsequent compound.
Superior Cervical Ganglia Assay
Superior cervical
ganglia were removed and dissected as described previously
(38) .
Ganglia from control and Bk2r mice
were desheathed and placed in a grease-gap recording chamber. The
chamber was perfused with buffer (125 mM NaCl, 5 mM
KCl, 1 mM KH
PO, 2.5 mM
CaCl, 1 mM MgSO, 25 mM
NaHCO, 10 mM glucose, and 0.1 µM
tetrodotoxin) maintained at 25 °C and bubbled with gas as described
above. The potential difference between the ganglion cell body and the
postganglionic trunk was measured using Ag/AgCl electrode connected by
a DC amplifier to a chart recorder. Between the addition of each
pharmacological agent, the preparation was washed for 40-60 min.
bradykinin receptor.
The coding sequence for the mouse B bradykinin receptor
lies on a single exon
(39, 40) which corresponds to exon
4 in the structure of the rat B bradykinin receptor
gene
(41) . The pharmacological profile of this mouse bradykinin
receptor expressed in mammalian cells is consistent with the B subtype classification
(40) . The positive-negative
selection
(34) targeting vector constructed contains 1 kb of
mouse genomic DNA immediately upstream of the coding sequence of the
mouse B bradykinin receptor, a neomycin resistance
gene which replaces the coding sequence of the B bradykinin
receptor, 5.4 kb of mouse genomic DNA downstream of the B receptor coding sequence, and a tk gene
(Fig. 1A). Homologous recombination of this vector with
the mouse chromosome should result in the replacement of the entire
coding sequence of the mouse B bradykinin receptor with the
neomycin resistance gene. The drug (1-(2-deoxy
2-fluoro-B-D-arabinofluranosyl)-5-iodouracil) (FIAU) was
utilized to enrich for ES cell clones containing a homologous
recombination event by selecting against the presence of the tk gene
(34) . Genomic Southern analysis was utilized to
identify three positive ES cell clones
(42) . Two of these clones
were injected into mouse blastocysts isolated from C57Bl/6 mice; one
produced four highly chimeric male mice. Each of these four chimeric
mice was bred to C57Bl/6 wild type mice; three of the mice were found
to transmit the agouti coat color marker associated with the embryonic
stem cells to offspring, indicating germ line transmission. Genomic DNA
was isolated from the agouti offspring, digested with DraI,
and probed with a 1.6-kb fragment that lies downstream of the DNA
contained in the targeting vector. The presence of the disrupted allele
was monitored by the shift of the DraI fragment from 9.0 kb in
wild type to 7.5 kb (Fig. 1). Approximately 50% of these F mice were found to be Bk2r.
Bk2r
siblings were interbred to
obtain mice homozygous for the disruption. The progeny of these matings
generated the expected genotypes: homozygous wild type, heterozygotes,
and homozygous knockouts (Fig. 1B).
Figure 1:
A, schematic of the targeted
disruption of the Bk2r gene. The targeting vector
(top), the endogenous Bk2r gene (middle)
with the restriction sites, and probes were utilized to detect
restriction fragments indicative of the wild type chromosome.
Restriction sites are BamHI (B), DraI
(D), EcoRI (R), and NsiI
(N). The initiation of the putative coding sequence for the
B bradykinin receptor is indicated by ATG and the stop by
TGA. The targeted Bk2r allele (bottom) with the
restriction sites and probes were utilized to discern restriction
fragments diagnostic of the disrupted chromosome. B, genomic
Southern blot of DNA isolated from the progeny of mating heterozygous
Bk2r mice. The genomic DNA was
digested with DraI and probed with the 1.6-kb 3` probe.
Representatives of the three genotypes are shown. Lane 1,
Bk2r
; lane 2,
Bk2r
; lane 3,
Bk2r
.
The deletion of
the coding sequence for the B bradykinin receptor in the
Bk2r mice was confirmed by genomic
Southern analysis. The single band of 9 kb that was detected in both
genomic DNA from Bk2r
and
Bk2r
mice by an 818-bp probe
containing the DNA encoding the putative seven transmembrane helices of
the receptor was absent in Bk2r
mice
(Fig. 2). To confirm that the expected gene targeting occurred
upstream of the B
receptor coding sequence genomic DNA
extracted from 26 Bk2r mice was
digested with EcoRI and probed with a 600-bp fragment upstream
of the DNA contained in the targeting vector. A single band of 4 kb
indicative of the disrupted allele was detected in each of the
Bk2r
mice, whereas the wild type
band of 6 kb was detected in controls (data not shown). Taken together,
these results indicate that the desired gene targeting event disrupted
the B
bradykinin receptor gene in the expected manner which
resulted in the deletion of the coding sequence for the receptor.
Figure 2:
Genomic Southern blot of DNA extracted
from Bk2r (1),
Bk2r
(2),
Bk2r
(3), and
Bk2r
(4). The genomic DNA was
digested with DraI and probed with the 3` probe (A).
The blot was stripped and reprobed (B) with an 818-bp probe
generated by polymerase chain reaction using the primers
5`-TTCCTCTGGGTGCTGTTCGT-3` and 5`-CACGATCACGTACACCAGTG-3` using the
cloned mouse B
bradykinin receptor as a template. These
polymerase chain reaction primers are based on the human B bradykinin receptor DNA sequence and correspond to sequences
encoding putative transmembrane domain 1 and transmembrane domain 7 of
the B bradykinin receptor.
A
total of 158 F progeny were generated by breeding
Bk2r siblings. The genotype
distribution of the progeny was 34
Bk2r
, 76
Bk2r
, and 48
Bk2r
.
analysis
indicates that these results do not differ significantly from the
predicted 1:2:1 Mendelian ratio for the transmission of the disrupted
allele (p = 0.26). Thus, the disruption of the B receptor gene does not appear to have any gross effects on mouse
development and viability. Adult and juvenile
Bk2r mice are indistinguishable from
heterozygous or homozygous wild type littermates by visual inspection.
Clinical pathology was performed on six
Bk2r
mice (three male and three
female) and four control mice (two Bk2r
and two Bk2r
mice; one of each
sex). There were no differences in serum sodium, potassium, calcium,
chloride, or phosphorus between control and knockout animals. In
addition, no abnormalities were detected in either the gross pathology
or the histopathology of the Bk2r
mice.
mice. All five of the mating
pairs generated offspring. Four of the mating pairs produced offspring
approximately 3 weeks after mating, with an average litter size of nine
pups. The fifth mating pair produced offspring after a delay of 3
months. These results indicate that the B
bradykinin
receptor is not critical for fertility.
receptor expression is
found in the ileum and uterus
(11, 40) , tissues that
have been used extensively in characterizing BK receptor pharmacology
and function. Membranes were prepared from ileum and uterus from six
control (either Bk2r or
Bk2r
) and six
Bk2r
mice and tested for their
ability to bind 1 nM [
H]BK
(Fig. 3). The ilea from individual control animals exhibited 5.9
± 1.1 pmol/g of tissue (wet weight) of specific BK binding
sites. By contrast, no BK binding sites were detected in membranes
prepared from the ilea of Bk2r mice.
Similarly, specific BK binding sites were detected in uterine membranes
from control mice but not from Bk2r
mice. Therefore, the disruption of the gene encoding the B
bradykinin receptor eliminates the [H]BK
binding site in these two smooth muscle preparations.
Figure 3:
Binding of 1 nM [H]BK to membranes from smooth muscle
tissues of control and Bk2r mice.
Membranes were prepared from the ileum and uterus of
Bk2r
and
Bk2r
control (CON) mice and
Bk2r
``knockout''
(KO) mice. The ileum membranes were prepared from ilea removed
from individual animals and assayed separately. Whereas uterine tissue
was removed from the six control animals and pooled prior to preparing
membranes, likewise the uterine tissue removed from six
Bk2r
mice was pooled. Binding assays
were performed as described under ``Materials and
Methods.''
The action of
bradykinin on the uterus is to elicit a smooth muscle
contraction
(5) . In control mice, 1 uM BK contracted
uterine muscle strips as did 1 µM oxytocin and 50
mM KCl (Fig. 4). By contrast, 1 µM BK was
unable to produce a contraction in Bk2r mice (n = 11). The uterine muscle from the
Bk2r
mice was capable of contracting
as demonstrated by the ability of oxytocin or KCl to stimulate a
contraction to the same degree as the controls. Thus, the disruption of
the gene encoding the B
bradykinin receptor destroys not
only the BK binding site in the uterus but also the functional response
to BK. The B receptor agonist
[des-Arg]kallidin was inactive on the uteri from
control and Bk2r
mice (data not
shown). Taken together, these results strongly indicate that the
actions of BK in these smooth muscle preparations are mediated through
a single B
bradykinin receptor subtype.
Figure 4:
Uterine contraction assay. The individual
uteri were removed from the mice and prepared as described under
``Materials and Methods.'' The tension of the uterine
contraction elicited by the addition, in order, of 1 µM
bradykinin (BK), 1 µM oxytocin (OT), and
50 mM KCl was analyzed in Bk2r and Bk2r
control (C)
mice and Bk2r
``knockout''
(KO) mice. Between the addition of each agent, the preparation
was washed for 30-40 min.
Previous studies
have suggested the existence of smooth muscle and neuronal subtypes of
the B bradykinin receptor
(24, 25) . To
address this issue, the effect of the disruption of the B bradykinin receptor gene on a BK response in a neuronal
preparation was analyzed. BK caused a dose-dependent depolarization of
the isolated superior cervical ganglia from
Bk2r control mice with a maximum
response at 3 µM of 168 ± 21% relative to 1
µM muscarine (n = 6) (data not shown). In
contrast, BK was totally inactive on the superior cervical ganglia from
Bk2r
mice (n = 8),
whereas the ability of either muscarine or substance P methyl ester (23
± 8%, n = 4) to depolarize the ganglia was
unaltered (Fig. 5). Thus, disruption of the B
receptor gene eliminates BK-mediated actions in both neuronal and
smooth muscle preparations, supporting the idea that a single gene
encodes the B bradykinin receptor subtype in mammals.
Figure 5:
Depolarization of the superior cervical
ganglia from control and Bk2r mice.
The superior cervical ganglia was isolated and prepared as described
under ``Materials and Methods.'' Depolarizations to agents
administered at the time indicated by the arrow were analyzed
in Bk2r
mice (A) and
Bk2r
mice (B). The
depolarization was elicited by 1 µM muscarine, 3
µM bradykinin, and 1 µM substance P methyl
ester (SP-O-Me). The agents were added in the order indicated,
and the preparation was washed 40-60 min between each agent. The
time and voltage scale is indicated by the
inset.
bradykinin receptor is disrupted by gene targeting, resulting in
a deletion of the entire coding sequence for this receptor. Molecular
genetic analysis indicates that the disruption occurred in the
predicted manner. The disruption of the B receptor has no
visible phenotype. However, the loss of B receptor function
can be readily demonstrated in several tissues, indicating that the
gene encoding the receptor has indeed been disrupted.
bradykinin receptors. BK has been demonstrated to be a
proinflammatory agent, and the implantation of the embryo has been
likened to an inflammatory response
(43) . This information,
coupled with recent work showing an increase in kallikrein levels in
the implantation node in rats, has led to the proposal that kinins
participate in the implantation of the embryo by regulating local blood
flow
(43) . The results of other studies indicate that BK may be
an important factor in promoting sperm motility
(44) . Our
results demonstrate that the Bk2r mice are fertile and that they have normal litter sizes. Although
these data do not rule out a role for kinins in reproduction, they
demonstrate that the B
receptor does not play an essential
role in this process. It remains possible that the kinin pathway is
involved in reproduction by acting through the B bradykinin
receptor, which responds to the carboxypeptidase metabolites of
kallidin and bradykinin. However, it remains to be determined whether
the expression of the B bradykinin receptor is induced
during reproductive processes.
bradykinin subtypes, possibly encoded by different
genes
(23, 24, 25, 26, 29, 30) .
A number of these studies were based on pharmacological differences in
tissue preparations isolated from different species. More recent
studies using the potent B receptor antagonist HOE-140 have
clarified some of the previous results and led to the proposal that
much of the pharmacological diversity observed was due to differences
in the species from which the receptor was derived
(45) . This
proposal was supported by the demonstration that cloned species
homologs of the B bradykinin receptor are pharmacologically
distinct
(39, 40) . However, pharmacological differences
have also been observed in different tissues from the same species. For
example, in rat vas deferens
[Thi,D-Phe
]BK acts as a
full agonist in stimulating sympathetic nerves to elicit muscle twitch
and as a weak partial agonist in directly stimulating smooth muscle
contraction
(25) . These observations, coupled with differences
in the ability of
[D-Arg,Hyp,Thi,D-Phe
]BK
to antagonize the neurogenic and musculotropic effects of
BK
(24) , led to the proposal of different smooth muscle and
neuronal B bradykinin receptor
subtypes
(24, 25) . The finding of the present study that
BK receptor function is totally eliminated in both the uterus and the
sympathetic superior cervical ganglia of
Bk2r mice clearly demonstrates that
a single gene is responsible for sensitivity to BK in both of these
tissues. This observation suggests that the pharmacological differences
previously reported between neuronal and smooth muscle preparations are
not a consequence of genetic diversity. The cloning of identical
B
bradykinin receptor cDNAs from cultured neuronal cells
and smooth muscle is also consistent with a single B bradykinin receptor gene encoding BK receptors in both smooth
muscle and neurons
(39, 46, 47) . A recent report
has suggested that two different subtypes of B receptors,
termed B and B
and characterized by differing
affinities for BK analogues (K
for BK of
2 pM and 910 pM, respectively), are present in guinea
pig ileum membranes
(30) ; similar findings were previously
reported in rat myometrial membranes
(29) . The total loss of all
specific [
H]BK binding sites in membranes
prepared from the ileum of Bk2r mice
and loss of BK action in the uterus argues that these high and low
affinity sites are not due to genetically distinct receptor subtypes.
Our results are consistent with a single gene encoding the B
bradykinin receptor subtype; however, an exhaustive survey of the
effects of BK on intact animals and on tissues isolated from control
and Bk2r mice will be necessary to
determine whether other genes might encode additional B
bradykinin receptor subtypes or the proposed tracheal B receptor subtype
(27, 28) .
mice have the
phenotype of BK insensitivity in several different tissues indicates
that we have produced an animal devoid of the B
bradykinin
receptor. The Bk2r mice will provide
an animal model for the evaluation of the diverse roles of the B
bradykinin receptor in the inflammatory response, the
cardiovascular system, renal function, and reproduction. The
Bk2r mice will also provide an
animal model for the exploration of the role of the B
receptor in the absence of the B receptor.
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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H. Fan, J. Stefkova, and S. S. El-Dahr Susceptibility to metanephric apoptosis in bradykinin B2 receptor null mice via the p53-Bax pathway Am J Physiol Renal Physiol, September 1, 2006; 291(3): F670 - F682. [Abstract] [Full Text] [PDF]
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 A. Duka, I. Duka, G. Gao, S. Shenouda, I. Gavras, and H. Gavras Role of bradykinin B1 and B2 receptors in normal blood pressure regulation Am J Physiol Endocrinol Metab, August 1, 2006; 291(2): E268 - E274. [Abstract] [Full Text] [PDF]
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 Z. Shariat-Madar, F. Mahdi, M. Warnock, J. W. Homeister, S. Srikanth, Y. Krijanovski, L. J. Murphey, A. A. Jaffa, and A. H. Schmaier Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin Blood, July 1, 2006; 108(1): 192 - 199. [Abstract] [Full Text] [PDF]
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 N. Picard, M. Van Abel, C. Campone, M. Seiler, M. Bloch-Faure, J. G.J. Hoenderop, J. Loffing, P. Meneton, R. J.M. Bindels, M. Paillard, et al. Tissue Kallikrein-Deficient Mice Display a Defect in Renal Tubular Calcium Absorption J. Am. Soc. Nephrol., December 1, 2005; 16(12): 3602 - 3610. [Abstract] [Full Text] [PDF]
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B. Maul, W. Krause, K. Pankow, M. Becker, F. Gembardt, N. Alenina, T. Walther, M. Bader, and W.-E. Siems Central angiotensin II controls alcohol consumption via its AT1 receptor FASEB J, September 1, 2005; 19(11): 1474 - 1481. [Abstract] [Full Text] [PDF]
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 Z Dlamini and K D Bhoola Upregulation of tissue kallikrein, kinin B1 receptor, and kinin B2 receptor in mast and giant cells infiltrating oesophageal squamous cell carcinoma J. Clin. Pathol., September 1, 2005; 58(9): 915 - 922. [Abstract] [Full Text] [PDF]
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 J. Ferreira, A. Beirith, M. A. S. Mori, R. C. Araujo, M. Bader, J. B. Pesquero, and J. B. Calixto Reduced Nerve Injury-Induced Neuropathic Pain in Kinin B1 Receptor Knock-Out Mice J. Neurosci., March 2, 2005; 25(9): 2405 - 2412. [Abstract] [Full Text] [PDF]
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 L. M. F. Leeb-Lundberg, F. Marceau, W. Muller-Esterl, D. J. Pettibone, and B. L. Zuraw International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences Pharmacol. Rev., March 1, 2005; 57(1): 27 - 77. [Abstract] [Full Text] [PDF]
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H. Fan, J. R. Harrell, S. Dipp, Z. Saifudeen, and S. S. El-Dahr A novel pathological role of p53 in kidney development revealed by gene-environment interactions Am J Physiol Renal Physiol, January 1, 2005; 288(1): F98 - F107. [Abstract] [Full Text] [PDF]
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 V. Vellani, O. Zachrisson, and P. A McNaughton Functional bradykinin B1 receptors are expressed in nociceptive neurones and are upregulated by the neurotrophin GDNF J. Physiol., October 15, 2004; 560(2): 391 - 401. [Abstract] [Full Text] [PDF]
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M. Kakoki, N. Takahashi, J. C. Jennette, and O. Smithies Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor PNAS, September 7, 2004; 101(36): 13302 - 13305. [Abstract] [Full Text] [PDF]
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 Y. Ikeda, I. Hayashi, E. Kamoshita, A. Yamazaki, H. Endo, K. Ishihara, S. Yamashina, Y. Tsutsumi, H. Matsubara, and M. Majima Host Stromal Bradykinin B2 Receptor Signaling Facilitates Tumor-Associated Angiogenesis and Tumor Growth Cancer Res., August 1, 2004; 64(15): 5178 - 5185. [Abstract] [Full Text] [PDF]
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 H.-Z. Hu, N. Gao, S. Liu, J. Ren, X. Wang, Y. Xia, and J. D. Wood Action of Bradykinin in the Submucosal Plexus of Guinea Pig Small Intestine J. Pharmacol. Exp. Ther., April 1, 2004; 309(1): 320 - 327. [Abstract] [Full Text]
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I. Duka, A. Duka, E. Kintsurashvili, C. Johns, I. Gavras, and H. Gavras Mechanisms Mediating the Vasoactive Effects of the B1 Receptors of Bradykinin Hypertension, November 1, 2003; 42(5): 1021 - 1025. [Abstract] [Full Text] [PDF]
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P. M. Abadir, R. M. Carey, and H. M. Siragy Angiotensin AT2 Receptors Directly Stimulate Renal Nitric Oxide in Bradykinin B2-Receptor-Null Mice Hypertension, October 1, 2003; 42(4): 600 - 604. [Abstract] [Full Text] [PDF]
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 J.-P. Fortin, F. Gobeil Jr, A. Adam, D. Regoli, and F. Marceau Do angiotensin-converting enzyme inhibitors directly stimulate the kinin B1 receptor? Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H277 - H282. [Abstract] [Full Text] [PDF]
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R. A. Skidgel, F. Alhenc-Gelas, and W. B. Campbell Regulation of Cardiovascular Signaling by Kinins and Products of Similar Converting Enzyme Systems: Prologue: Kinins and related systems. New life for old discoveries Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H1886 - H1891. [Full Text] [PDF]
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J. P. Schanstra, J. Duchene, F. Praddaude, P. Bruneval, I. Tack, J. Chevalier, J.-P. Girolami, and J.-L. Bascands Regulation of Cardiovascular Signaling by Kinins and Products of Similar Converting Enzyme Systems: Decreased renal NO excretion and reduced glomerular tuft area in mice lacking the bradykinin B2 receptor Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H1904 - H1908. [Abstract] [Full Text] [PDF]
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H. D. Xiao, S. Fuchs, J. M. Cole, K. M. Disher, R. L. Sutliff, and K. E. Bernstein Regulation of Cardiovascular Signaling by Kinins and Products of Similar Converting-Enzyme Systems: Role of bradykinin in angiotensin-converting enzyme knockout mice Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H1969 - H1977. [Abstract] [Full Text] [PDF]
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A. Ni, H. Yin, J. Agata, Z. Yang, L. Chao, and J. Chao Overexpression of Kinin B1 Receptors Induces Hypertensive Response to Des-Arg9-bradykinin and Susceptibility to Inflammation J. Biol. Chem., January 3, 2003; 278(1): 219 - 225. [Abstract] [Full Text] [PDF]
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 H. A. Baptista, M. C. W. Avellar, R. C. Araujo, J. L. Pesquero, J. P. Schanstra, J. L. Bascands, J. P. Esteve, A. C. M. Paiva, M. Bader, and J. B. Pesquero Transcriptional Regulation of the Rat Bradykinin B2 Receptor Gene: Identification of a Silencer Element Mol. Pharmacol., December 1, 2002; 62(6): 1344 - 1355. [Abstract] [Full Text] [PDF]
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 T. K. Monsees, S. Blocher, F. Heidorn, A. Winkler, W.-E. Siems, W. Muller-Esterl, J. Hayatpour, W. Miska, and W.-B. Schill Expression and Location of the Bradykinin B2 Receptor in Rat Testis Biol Reprod, December 1, 2002; 67(6): 1832 - 1839. [Abstract] [Full Text] [PDF]
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F. Trabold, S. Pons, A. A. Hagege, M. Bloch-Faure, F. Alhenc-Gelas, J.-F. Giudicelli, C. Richer-Giudicelli, and P. Meneton Cardiovascular Phenotypes of Kinin B2 Receptor- and Tissue Kallikrein-Deficient Mice Hypertension, July 1, 2002; 40(1): 90 - 95. [Abstract] [Full Text] [PDF]
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 M. E. Marin-Castano, J. P. Schanstra, E. Neau, F. Praddaude, C. Pecher, J.-L. Ader, J.-P. Girolami, and J.-L. Bascands Induction of Functional Bradykinin B1-Receptors in Normotensive Rats and Mice Under Chronic Angiotensin-Converting Enzyme Inhibitor Treatment Circulation, February 5, 2002; 105(5): 627 - 632. [Abstract] [Full Text] [PDF]
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Y.-H. Liu, J. Xu, X.-P. Yang, F. Yang, E. Shesely, and O. A. Carretero Effect of ACE Inhibitors and Angiotensin II Type 1 Receptor Antagonists on Endothelial NO Synthase Knockout Mice With Heart Failure Hypertension, February 1, 2002; 39(2): 375 - 381. [Abstract] [Full Text] [PDF]
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 M. J. Ryan, S. P. Didion, D. R. Davis, F. M. Faraci, and C. D. Sigmund Endothelial Dysfunction and Blood Pressure Variability in Selected Inbred Mouse Strains Arterioscler. Thromb. Vasc. Biol., January 1, 2002; 22(1): 42 - 48. [Abstract] [Full Text] [PDF]
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I. Duka, S. Shenouda, C. Johns, E. Kintsurashvili, I. Gavras, and H. Gavras Role of the B2 Receptor of Bradykinin in Insulin Sensitivity Hypertension, December 1, 2001; 38(6): 1355 - 1360. [Abstract] [Full Text] [PDF]
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S. Metayer, F. Dacheux, Y. Guerin, J.-L. Dacheux, and J.-L. Gatti Physiological and Enzymatic Properties of the Ram Epididymal Soluble Form of Germinal Angiotensin I-Converting Enzyme Biol Reprod, November 1, 2001; 65(5): 1332 - 1339. [Abstract] [Full Text] [PDF]
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I. V. Yosipiv, S. Dipp, and S. S. El-Dahr Targeted disruption of the bradykinin B2 receptor gene in mice alters the ontogeny of the renin-angiotensin system Am J Physiol Renal Physiol, November 1, 2001; 281(5): F795 - F801. [Abstract] [Full Text] [PDF]
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E. Kintsurashvili, I. Duka, I. Gavras, C. Johns, D. Farmakiotis, and H. Gavras Effects of ANG II on bradykinin receptor gene expression in cardiomyocytes and vascular smooth muscle cells Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1778 - H1783. [Abstract] [Full Text] [PDF]
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 R. G. Hill Book Review: Molecular Basis for the Perception of Pain Neuroscientist, August 1, 2001; 7(4): 282 - 292. [Abstract] [PDF]
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 S. Bergaya, P. Meneton, M. Bloch-Faure, E. Mathieu, F. Alhenc-Gelas, B. I. Levy, and C. M. Boulanger Decreased Flow-Dependent Dilation in Carotid Arteries of Tissue Kallikrein-Knockout Mice Circ. Res., March 30, 2001; 88(6): 593 - 599. [Abstract] [Full Text] [PDF]
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J. Maly, L. Karasova, M. Simova, S. Vitko, and S. S. El-Dahr Angiotensin II-Induced Hypertension in Bradykinin B2 Receptor Knockout Mice Hypertension, March 1, 2001; 37(3): 967 - 973. [Abstract] [Full Text] [PDF]
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I. Duka, E. Kintsurashvili, I. Gavras, C. Johns, M. Bresnahan, and H. Gavras Vasoactive Potential of the B1 Bradykinin Receptor in Normotension and Hypertension Circ. Res., February 16, 2001; 88(3): 275 - 281. [Abstract] [Full Text] [PDF]
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N. Berthiaume, M. Yanagisawa, J. Labonte, and P. D'Orleans-Juste Heterozygous Knock-Out of ETB Receptors Induces BQ-123-Sensitive Hypertension in the Mouse Hypertension, December 1, 2000; 36(6): 1002 - 1007. [Abstract] [Full Text] [PDF]
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 S. S. EL-DAHR, L. M. HARRISON-BERNARD, S. DIPP, I. V. YOSIPIV, and S. MELEG-SMITH Bradykinin B2 null mice are prone to renal dysplasia: gene-environment interactions in kidney development Physiol Genomics, September 8, 2000; 3(3): 121 - 131. [Abstract] [Full Text] [PDF]
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 P. G. McLean, A. Ahluwalia, and M. Perretti Association between Kinin B1 Receptor Expression and Leukocyte Trafficking across Mouse Mesenteric Postcapillary Venules J. Exp. Med., July 31, 2000; 192(3): 367 - 380. [Abstract] [Full Text] [PDF]
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J. B. Pesquero, R. C. Araujo, P. A. Heppenstall, C. L. Stucky, J. A. Silva Jr., T. Walther, S. M. Oliveira, J. L. Pesquero, A. C. M. Paiva, J. B. Calixto, et al. Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors PNAS, June 14, 2000; (2000) 120035997. [Abstract] [Full Text]
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 J. Cole, D. Ertoy, and K. E Bernstein Insights derived from ACE knockout mice Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2): 137 - 141. [PDF]
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C. Emanueli, M. B. Salis, J. Chao, L. Chao, J. Agata, K.-F. Lin, A. Munao, S. Straino, A. Minasi, M. C. Capogrossi, et al. Adenovirus-Mediated Human Tissue Kallikrein Gene Delivery Inhibits Neointima Formation Induced by Interruption of Blood Flow in Mice Arterioscler. Thromb. Vasc. Biol., June 1, 2000; 20(6): 1459 - 1466. [Abstract] [Full Text] [PDF]
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P. Madeddu, C. Emanueli, N.-E. Rhaleb, E. G. Shesely, and O. A. Carretero Can Knockout Mice Help Dissect Relevant Genes in Hypertension? Evidence and Confounding Factors • Response Hypertension, December 1, 1999; 34 (6): e14 - e15. [Full Text] [PDF]
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K. E. Loke, C. M. L. Curran, E. J. Messina, S. K. Laycock, E. G. Shesely, O. A. Carretero, and T. H. Hintze Role of Nitric Oxide in the Control of Cardiac Oxygen Consumption in B2-Kinin Receptor Knockout Mice Hypertension, October 1, 1999; 34(4): 563 - 567. [Abstract] [Full Text] [PDF]
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L. Cervenka, L. M. Harrison-Bernard, S. Dipp, G. Primrose, J. D. Imig, and S. S. El-Dahr Early Onset Salt-Sensitive Hypertension in Bradykinin B2 Receptor Null Mice Hypertension, August 1, 1999; 34(2): 176 - 180. [Abstract] [Full Text] [PDF]
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M. E. Alfie, S. Alim, D. Mehta, E. G. Shesely, and O. A. Carretero An Enhanced Effect of Arginine Vasopressin in Bradykinin B2 Receptor Null Mutant Mice Hypertension, June 1, 1999; 33(6): 1436 - 1440. [Abstract] [Full Text] [PDF]
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N.-E. Rhaleb, H. Peng, M. E. Alfie, E. G. Shesely, and O. A. Carretero Effect of ACE Inhibitor on DOCA-Salt– and Aortic Coarctation–Induced Hypertension in Mice : Do Kinin B2 Receptors Play a Role? Hypertension, January 1, 1999; 33(1): 329 - 334. [Abstract] [Full Text] [PDF]
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F. Marceau, J. F. Hess, and D. R. Bachvarov The B1 Receptors for Kinins Pharmacol. Rev., September 1, 1998; 50(3): 357 - 386. [Abstract] [Full Text] [PDF]
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D. K. ROHRER and B. K. KOBILKA G Protein-Coupled Receptors: Functional and Mechanistic Insights Through Altered Gene Expression Physiol Rev, January 1, 1998; 78(1): 35 - 52. [Abstract] [Full Text] [PDF]
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X.-P. Yang, Y.-H. Liu, G. M. Scicli, C. R. Webb, and O. A. Carretero Role of Kinins in the Cardioprotective Effect of Preconditioning : Study of Myocardial Ischemia/Reperfusion Injury in B2 Kinin Receptor Knockout Mice and Kininogen-Deficient Rats Hypertension, September 1, 1997; 30(3): 735 - 740. [Abstract] [Full Text]
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M. E. Alfie, D. H. Sigmon, S. I. Pomposiello, and O. A. Carretero Effect of High Salt Intake in Mutant Mice Lacking Bradykinin-B2 Receptors Hypertension, January 1, 1997; 29(1): 483 - 487. [Abstract] [Full Text] [PDF]
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D.-z. Wang, L. Chao, and J. Chao Hypotension in Transgenic Mice Overexpressing Human Bradykinin B2 Receptor Hypertension, January 1, 1997; 29(1): 488 - 493. [Abstract] [Full Text] [PDF]
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J. B. Pesquero, R. C. Araujo, P. A. Heppenstall, C. L. Stucky, J. A. Silva Jr., T. Walther, S. M. Oliveira, J. L. Pesquero, A. C. M. Paiva, J. B. Calixto, et al. Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors PNAS, July 5, 2000; 97(14): 8140 - 8145. [Abstract] [Full Text] [PDF]
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X.-P. Yang, Y.-H. Liu, D. Mehta, M. A. Cavasin, E. Shesely, J. Xu, F. Liu, and O. A. Carretero Diminished Cardioprotective Response to Inhibition of Angiotensin-Converting Enzyme and Angiotensin II Type 1 Receptor in B2 Kinin Receptor Gene Knockout Mice Circ. Res., May 25, 2001; 88(10): 1072 - 1079. [Abstract] [Full Text] [PDF]
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