PHYSIOLOGICAL RESEARCH • ISSN 0862-8408 (print) • ISSN 1802-9973 (online)
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Physiol. Res. 62: 511-517, 2013
Antioxidant/Oxidant Status and Cardiac Function in Bradykinin
B1- and B2-Receptor Null Mice
S. DELEMASURE1, N. BLAES4, C. RICHARD2,3, R. COUTURE5, M. BADER6,
P. DUTARTRE1,2, J.-P. GIROLAMI4, J.-L. CONNAT1,2, L. ROCHETTE1,2
1COHIRO Biotechnology, Faculty of Medicine, Dijon, France, 2Laboratory of Cardio-Metabolic
Pathophysiology and Pharmacology (LPPCM), INSERM, U866, Université de Bourgogne, Dijon,
France, 3Department of Cardiology, University Hospital, Dijon, France, 4Institute of Metabolic and
Cardiovascular Diseases (I2MC), INSERM, U1048, Université Paul Sabatier, Toulouse, France,
5Department of Physiology, Faculty of Medicine, Université de Montréal, Montréal, Qc, Canada,
6Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
Received December 13, 2012
Accepted June 17, 2013
On-line September 10, 2013
Kinin-vasoactive peptides activate two G-protein-coupled
receptors (R), B1R (inducible) and B2R (constitutive). Their
complex role in cardiovascular diseases could be related to
differential actions on oxidative stress. This study investigated
impacts of B1R or B2R gene deletion in mice on the cardiac
Echocardiography-Doppler was performed in B1R (B1R-/-) and B2R
(B2R-/-) deficient and wild type (WT) adult male mice. No
functional alteration was observed in B2R-/- hearts. B1R-/- mice had
significantly lowered fractional shortening and increased
and plasma antioxidant and oxidant status.
isovolumetric contraction time. The diastolic E and A waves
velocity ratio was similar in all mice groups. Thus B1R-/- mice
provide a model of moderate systolic dysfunction, whereas B2R-/-
mice displayed a normal cardiac phenotype. Plasma antioxidant
capacity (ORAC) was significantly decreased in both B1R-/- and
B2R-/- mice whereas the vitamin C levels were decreased in B2R-/-
mice only. Plasma ascorbyl free radical was significantly higher in
B1R-/- compared to WT and B2R-/- mice. Therefore, the oxidative
stress index, ascorbyl free radical to vitamin C ratio, was
increased in both B1R-/- and B2R-/- mice. Hence, B1R and B2R
deficiency are associated with increased oxidative stress, but
there is a differential imbalance between free radical production
and antioxidant defense. The interrelationship between the
differential B1R and B2R roles in oxidative stress and
cardiovascular diseases remain to be investigated.
Doppler • Echocardiography • Kinin receptor • Knockout •
S. Delemasure, COHIRO Biotechnology, 7 Bvd Jeanne-d’Arc,
Faculty of Medicine, 21000 Dijon, France. Fax: +33(0)
380393273. E-mail: firstname.lastname@example.org
Kinins are vasoactive peptides that play
important roles in cardiovascular homeostasis and
pathology (Regoli et al. 2012). They cause vasodilation,
vascular permeability, and also inflammation. Kinin
peptides, namely bradykinin (BK) and Lys-BK, are
generated by cleavage of kininogens by plasma or tissue
kallikreins. They are rapidly metabolized by kininase I
and angiotensin 1-converting enzyme (Bhoola et al.
1992). Kinins and their C-terminal metabolites (des-Arg9-
BK and Lys-des-Arg9-BK) activate G protein-coupled
receptors (R), B2R and B1R, respectively (Regoli et al.
2001, Leeb-Lundberg et al. 2005). B2R is constitutively
expressed on endothelial cells and leads to prostacyclin
and nitric oxide release through endothelial nitric oxide
synthase. Kinins also induce a direct negative
chronotropic effect mediated by the B2R (Ribuot et al.
1993). B1R is weakly expressed under physiological
512 Delemasure et al.
conditions but plays a fundamental role in the cardiac
function (Lauton-Santos et al. 2007). This receptor is
strongly up-regulated by pro-inflammatory cytokines and
oxygen free radicals (Couture and Girolami 2004).
Oxidative stress, defined as imbalance between free
radicals production and antioxidant defenses, is of great
importance in the function of the kallikrein-kinin system
(Dias et al. 2010, Kayashima et al. 2012). The main
objective of this study was to investigate the impact of
B1R or B2R deletion in mice on left ventricular (LV)
function and plasma oxidative stress markers in
Materials and Methods
B1R-/- mice (n=9) on a 129/SvjxC57/J6
background (Pesquero et al. 2000) were obtained from
Dr. Michael Bader’s Laboratory (Max-Delbrück Center
for Molecular Medicine, Berlin-Buch, Germany) and
backcrossed 10 times to C57BL/6J as previously reported
(Mori et al. 2008). B2R-/- mice (n=9) on a C57BL/6J
background were used (Blaes et al. 2012). Age-matched
six-month-old male C57BL/6J wild type mice (WT,
n=10) (Jackson Laboratories, Bar Harbor, Me) were used
as control animals. The experimental study was approved
by the local ethics committee and the investigators
complied with authorization 21CAE057 from the French
government, which agrees with the Directive 2010/63/EU
of the European Parliament.
carried out as previously described (Delemasure et al.
2012) using a Vevo 770® (Visualsonics; Toronto, Canada)
equipped with a 30-MHz high-frequency linear
transducer. Briefly, cardiac parameters were measured in
anesthetized mice (with isoflurane) in parasternal short
and long axis views, and then the values were averaged.
Heart rate was measured from the cardiac cycles using
three consecutive beats. Left ventricular internal
diameters and LV wall thickness determined by the inter-
ventricular septum, posterior wall and anterior wall were
measured at end diastole and systole. Systolic function
was evaluated by the fractional shortening. LV mass was
Pulsed wave Doppler of the mitral valve was
recorded from the apical four-chamber view in order to
assess the diastolic function. Mitral Doppler flow spectra
showed a higher early ventricular filling wave (E) and a
lower late filling wave caused by atrial contraction (A).
We measured the E and A wave velocities ratio (E/A), the
isovolumetric relaxation time defined as the time interval
between end of aortic outflow and onset of the mitral
inflow, the isovolumetric contraction time defined as the
time interval between end of mitral inflow and onset of
the aortic outflow and informing on the dynamics of LV
Measurement of peroxyl radical scavenging activity in
The antioxidant scavenging activity in plasma
was evaluated by Oxygen Radical Absorbance Capacity
(ORAC) miniaturized assay adapted from Cao et al.
(1993). Fluorescence decay of allophycocyanin (APC,
Sigma) due to a peroxyl radical generator (AAPH,
was measured over time using a Victor3V fluorimeter
(PerkinElmer), with excitation and emission filters
P620/8 and D665, respectively. Trolox (6-Hydroxy-
2,5,7,8-tetramethylchroman-2-carboxylic acid, Sigma), a
soluble vitamin E analog, was used as antioxidant
reference. ORAC was calculated using the net area under
the decay curve and was expressed as µmol/l of trolox
equivalent (TE). For each sample, the plasma antioxidant
capacity was measured in quadruplicate.
Measurement of plasma vitamin C
After mixing the plasma with metaphosphoric
acid (5 %), the concentrations of ascorbate and
dehydroascorbic acid (total vitamin C) were measured by
high performance liquid chromatography equipped with
fluorescence detection (exc. = 360 nm; em. = 440 nm)
(Tessier et al. 1996).
Detection of ascorbyl free radical in plasma and
estimation of oxidative stress
Ascorbyl free radical was detected by Electron
Spin Resonance (ESR) spectroscopy as previously
reported (Vergely et al. 1998). Plasma was analyzed into
a quartz capillary tube using a Bruker EMX X-band
spectrometer. The formation of ascorbyl free radical was
evaluated by the height of the signal and expressed in
arbitrary units (AU). The plasma oxidative stress was
estimated by the ascorbyl free radical to vitamin C ratio.
Cardiac Function and Oxidative Stress in Kinin Receptor Knockout Mice 513
Data are expressed as mean ± SE. Differences
between groups were evaluated by one-way ANOVA
followed by pairwise comparisons by Student-Newman-
Keuls test using SigmaPlot 11.0 (Systat software; San
Jose, CA). A value of P<0.05 was considered statistically
Echocardiographic measurements of LV
The body weights were similar for B2R-/- and
WT mice but significantly lower for B1R-/- mice (minus
13 %, P<0.05) (Fig. 1A). LV weights, measured by
echocardiography, were similar for the three groups
(mean of 128 mg). The heart to body weight ratio was
thus significantly higher in B1R-/- (5.0±0.1) compared to
B2R-/- (4.5±0.2) and WT (4.4±0.1) mice. The heart rates
were stable and did not significantly differ between
B1R-/-, B2R-/- and WT mice, with a mean of 430 beats/min
under anesthetized conditions (Fig. 1A). LV wall
thickness measurements were similar for the knockout
and WT mice. An upward trend, however not statistically
significant, was noted for left ventricular internal
diameter in B1R-/- mice compared to B2R-/- and WT mice.
Consequently, B1R-/- mice had a significant decline in
fractional shortening compared to B2R-/- and WT (–18 %,
P<0.05) mice (Fig. 1B).
Doppler measurements of transmitral LV inflow
B1R-/- and B2R-/- mice had E and A wave velocities
ratio and isovolumetric relaxation time similar to WT mice
(Fig. 1C). The mitral ejection time was unchanged. An
increased isovolumetric contraction time was observed in
B1R-/- compared to B2R-/- and WT mice (+27 %, P<0.05).
Plasma Oxygen Radical Absorbance Capacity
The antioxidant status evaluated by ORAC was
significantly lower in both B1R-/- mice (1492±47 µmol/l
TE) and B2R-/- mice (1781±55 µmol/l TE) compared to
WT mice (2322±84 µmol/l TE) (P<0.05) (Fig. 2A). B1R-/-
and B2R-/- ORAC did not significantly differ.
Plasma vitamin C and ascorbyl free radical
Plasma total vitamin C levels did not significantly
differ between B1R-/- and WT mice (51±4 versus
60±4 µmol/l) (Fig. 2B). In contrast, it was significantly
lower in B2R-/- mice (36±5 µmol/l, P<0.05) compared to WT
mice. The height of the signal intensity of the characteristic
spectra of plasma ascorbyl free radical was similar in B2R-/-
and WT mice. In contrast, B1R-/- mice exhibited a markedly
higher signal intensity in comparison with WT or B2R-/-
mice (+41 %, P<0.05; Fig. 2C and 2D). The plasma
oxidative stress, as evaluated by the ascorbyl free radical to
vitamin C ratio, was increased in B1R-/- and B2R-/- mice as
compared to WT mice (P<0.05). The difference between
B1R-/- and B2R-/- mice did not reach statistical significance
Fig. 1. Echocardiographic analysis of wild-type (WT) and B1R or B2R knockout mice (B1R-/-, B2R-/-). A. Measures concerning body weight,
heart rate and left ventricle (LV). * P<0.05 versus WT. B. Analysis of fractional shortening in WT, B1R or B2R knockout mice. * P<0.05
versus WT. C. Doppler transmitral inflow in WT, B1R-/- and B2R-/- mice. * P<0.05 versus WT.
514 Delemasure et al.
Fig. 2. Plasma antioxidant status in WT and
B1R-/-, B2R-/- mice. A. Determination using
ORAC (Oxygen Radical
Capacity) measurements. B. Total plasma
vitamin C quantified using HPLC. *P<0.05
versus WT. C. Characteristic doublet of
ascorbyl free radical ESR signal. ESR
spectra were recorded with Bruker EMX
capillary tube at
D. Quantification of ascorbyl free radical
determined by the measure of the ESR
signal height. * P<0.05
E. Plasma oxidative stress evaluated by the
ascorbyl free radical to vitamin C ratio in
WT and B1R-/-, B2R-/- mice. *P<0.05 versus
Although we do not bring indications on
myocardial oxidative stress markers, this study extends
the knowledge of the phenotypes of B1R and B2R null
mice. A decrease in plasma antioxidant scavenging
activity (ORAC) was observed in both deficient strains.
However, other plasma oxidative stress markers were
differentially altered. Plasma
concentration was decreased in B2R-/- mice but not in
B1R-/- mice, suggesting that B2R deficiency impacted
synthesis and/or recycling of ascorbate. Total vitamin C
(L-ascorbic acid and its oxidized form, dehydroascorbic
acid) acts as essential water-soluble antioxidant in plasma
(Farbstein et al. 2010). In humans, vitamin C must be
provided in the diet while mice can synthesize ascorbate
from glucose in the liver by the L-gulonolactone oxidase.
Reduction of total vitamin C may result from increased
renal excretion or to decreased liver synthesis. At
physiological pH, L-ascorbic acid primarily exists as
total vitamin C
ascorbate anion which, in presence of oxygen free
radicals, results in ascorbyl free radical, stable enough to
be detected by ESR spectroscopy in plasma (Vergely et
al. 1998). The plasma ascorbyl free radical content was
only increased in B1R-/-. Nevertheless, the ascorbyl free
radical to vitamin C ratio, index of oxidative stress
(Courderot-Masuyer et al. 2000), was markedly increased
in both B1R-/- and B2R-/- mice. The alterations of the
antioxidant/oxidant status in B1R-/- and B2R-/- mice versus
WT mice indicate that both kinin receptors control the
oxidative balance under physiological conditions,
although by different routes. In pathology, the B1R and
B2R roles are distinct (Kayashima et al. 2012). B1R is
involved in insulin resistance and in early diabetes by
increasing oxidative stress
mediators and later vascular alterations (Dias et al. 2012,
Pouliot et al. 2012) while B2R is involved in
cardiovascular protection (Couture and Girolami 2004)
and is necessary for cardioprotective effects provided by
angiotensin-converting enzyme inhibitors, even if B1R
can contribute to protective effects (Duka et al. 2008).
Cardiac Function and Oxidative Stress in Kinin Receptor Knockout Mice 515
Left ventricular systolic and diastolic functions
Previous evaluations of in vivo cardiac function
in kinin receptor deficient mice brought somehow
variable results under physiological conditions. No
echocardiographic alteration was reported for 10-week
B2R-/- male mice (Yang et al. 2001, Duka et al. 2008) or
5-month female (Trabold et al. 2002) or in male mice of
several B1R-/- strains (Duka et al. 2008, Westermann et
al. 2009, Wende et al. 2010). In contrast, diastolic LVID
was increased in female 12-week-old B1R-/- mice (Xu et
al. 2009), and 2-month-old B2R-/- mice showed higher LV
mass and LVID at end-systole together with lower
ejection fraction (Osorio et al. 2008). Older B2R-/- mice
(12-month-old) had moderately altered LV contractility
and diastolic function (Madeddu et al. 1997). Alterations
were more severe in the 129/J strain, showing the impact
of interaction of B2R signaling with other genetic
determinant (two renin gene copy number) (Maestri et al.
2003). Collectively, described cardiac alterations of B1R-/-
and B2R-/- mice remain moderate. Discrepancies may
result from variation in the physiological conditions, i.e.
gender, age or genetic background, isolated hearts or
anesthetized animals or from differences in the methods
to evaluate cardiac function. In this present study, a
normal cardiac phenotype was observed in B2R-/- mice.
Although not significantly, most ventricular wall
measures (posterior or anterior wall, in systole or
diastole) were slightly lower for B1R-/- hearts. These
results argue for conditions of mild volume overload
causing cavity dilation and thinning of the ventricular
wall (Ram et al. 2011). Some measurements obtained
from WT mice appeared lower than previously published
values (Ram et al. 2011); this might be due to anesthesia-
induced minor cardiac depression (also suggested by
heart beats <500/min). However, in our study anesthesia
conditions were comparable for the three mice strains.
We showed a decrease of fractional shortening in B1R-/-
6-month-old male mice. Consistently, previous ex vivo
data showed a lower systolic function without
hypertrophy in isolated hearts of 16-week-old male mice
(Lauton-Santos et al. 2007). In B1R or B2R deficient
mouse hearts, the other kinin receptor was found up-
regulated in physiological state (Duka et al. 2008).
Although moderate, the present systolic dysfunction in
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the B1R-/- hearts may be the consequence of B2R up-
regulation and subsequent
chronotropic effect (Ribuot et al. 1993) but may also
argued for a role of B1R in the control of basal cardiac
function. Our study is the first to assess the diastolic LV
function by noninvasive conventional Doppler in mice
lacking B1R or B2R. Transmitral pressure gradient and
LV filling pressure were estimated as generally
performed in patients. There was no difference between
B1R-/-, B2R-/- and WT mice with regard to the diastolic
function, as evaluated by the early to late diastolic filling
ratio and the time between aortic valve closure and mitral
valve opening. A prolonged time between mitral valve
closure and aortic valve opening was observed in B1R-/-
mice, which confirms an impaired LV contraction.
Deficiency in either kinin receptor altered the
plasma oxidant/antioxidant balance, however with
specific patterns. In addition, B1R deficiency induced a
moderate systolic dysfunction consistent with a role of
B1R in the control of the basal cardiac function.
Consequences of such differential roles of B1R and B2R
remain to be investigated in oxidative pathological
conditions and metabolic cardiovascular diseases.
Conflict of Interest
There is no conflict of interest.
Vevo770® echocardiograph was funded by European
Community Funds (FEDER), Burgundy Regional
Council and French Ministry for Research (MESR).
Victor Plate reader was funded by French Ministry for
Higher Education & Research (MESR). Mice were bred
at the Animal Unit of INSERM Rangueil (Genotoul
Anexplo Plateforme, Toulouse) then housed in the
Zootechnic Center of Université de Bourgogne (Dijon).
This work was supported by grants from University
Paul Sabatier Toulouse, INSERM, and from the
(R. Couture/J.-P. Girolami).
516 Delemasure et al.
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