From the Departments of Farmacologia (C.E., M.P.D.), Biochimica (A.F.M.,
M.B.S.), and Clinica Medica (M.C., P.M.), University of Sassari (Italy);
Department of Clinical Biochemistry, University of Munich (Germany) (E.F.);
and National Institute of Biostructures and Biosystems, Osilo, Italy (P.M.).
Correspondence to Paolo Madeddu, MD, Clinica Medica, University of Sassari, Viale S. Pietro 8, 07100 Sassari, Italy. E-mail madeddu{at}ssmain.uniss.it
BP and HR Measurements
To measure intra-arterial MBP, a polyethylene catheter
(PE-10, Clay Adams) was inserted into the left carotid artery and
advanced into the thoracic aorta of mice anesthetized with
2,2,2-tribromoethanol (88 mmol/100 g body wt IP;
Sigma-Aldrich). The catheter was tunneled under the skin and
exteriorized at the back of the neck. The following day, MBP of
unanesthetized, unrestrained mice was measured by connecting a
Statham transducer (Gould) to the arterial catheter, and it
was recorded on a recorder (Quartet, Ugo Basile). Calibrations
of instruments to measure tail-cuff or intra-arterial BP
were performed with a mercury sphygmomanometer.
Cardiovascular and Renal Effects of DOC
Enantate
In Bk2r-/- and Bk2r+/+,
24-hour urine collections were obtained under basal conditions and then
every day during treatment with DOC or vehicle. Mice were housed in
individual metabolic cages, which allowed for a high degree
of accuracy in the measurement of food and water intake by the
inclusion of spill catches. Urinary volume was determined
gravimetrically. Sodium concentration was measured by flame
photometry.
A separate set of experiments was performed to test whether DOC affects
urinary kinin excretion. Kinin levels were measured in 24-hour urine
obtained from Bk2r-/- or
Bk2r+/+ under basal conditions and during DOC
administration (n=6 per group). Urine was collected in ethanol (1:9,
vol/vol), and sediment was discarded after
centrifugation at 1500g for 10 minutes.
Kinin determination was performed by radioimmunoassay, as described
previously.21
Finally, the MBP responses of Bk2r-/- or
Bk2r+/+ (n=6 per group) to acute blockade of the
bradykinin B1 receptor were assessed after 3
weeks of DOC administration by injection of the
B1 receptor antagonist
AcLys[D-ß-Nal,7Ile8]des-Arg9-bradykinin
(3 nmol/100 g body wt IV), a generous gift from Professor Domenico
Regoli (University of Sherbrooke, Canada) or vehicle. MBP was
recorded under basal conditions and for 10 minutes after
injection.
Statistical Analysis
As shown in Figure 1
Under basal conditions, urinary sodium excretion was similar in
Bk2r-/- and Bk2r+/+
(Table
Previous studies showed pressor effects of the B1
receptor blockade in Bk2r-/- under basal
conditions.20 At variance with these findings,
acute administration of the B1 receptor
antagonist
AcLys[D-ß-Nal,7Ile8]des-Arg9-bradykinin
did not alter the MBP of Bk2r-/- (-3±2 versus
-3±2 mm Hg in vehicle-treated mice; P=NS) or
Bk2r+/+ (-5±3 versus -3±2 mm Hg in
vehicle-treated mice; P=NS) after 3 weeks of DOC
administration. Similarly, no change in HR was observed after the
administration of the antagonist or its vehicle (data not
shown).
Hypertension induced by long-term administration of DOC in combination
with high salt and uninephrectomy in rats is regarded as an
experimental model of human hypermineralocorticoidism. Interestingly,
DOC alone is not able to induce hypertension in adult rats unless they
are exposed to mineralocorticoids from the very early phases of
life.22 23 In comparison with rats, adult mice
show a greater BP sensitivity to DOC, as indicated by our finding that
DOC alone, at the dose of 0.3 µmol/g body wt weekly, is
sufficient to produce a progressive and sustained BP increase (from 114
to 129 and 133 mm Hg at 3 and 6 weeks, respectively, in
Bk2r+/+).
In our study we considered that preservation of renal integrity and
maintenance of normosodic conditions would be essential to test
the participation of endogenous kinins in the
cardiovascular response to DOC. In fact, uninephrectomy
plus salt reportedly reduces renal kallikrein release and alters the
magnitude of the BP increments induced by B2
receptor blockade with icatibant in DOC-treated
rats.15 In addition, an enhanced sensitivity to
salt has been demonstrated in Bk2r-/-, and
therefore high salt intake could mask an augmented BP response to
mineralocorticoids.20
The seminal finding that the renal KKS, a potent
natriuretic and vasodilator system, is typically
activated in human
hypermineralocorticosteroidism as well as in rats given
long-term DOC has been interpreted as a compensatory response to
counteract the vasopressor and sodium-retaining effects of
mineralocorticoids.11 12 13 Consistent with
the results obtained in other species is the finding that urinary
kinins are increased in DOC-treated mice. The mechanism by which
mineralocorticoids stimulate the renal KKS is not yet clear.
Examination of the 5' flanking sequence of tissue kallikrein gene
revealed several putative hormone binding
sites.24 Factors such as steroid hormones might
affect tissue kallikrein levels in various tissues by acting at the
level of transcription.
The demonstration that long-term blockade of B2
receptors by icatibant accelerates the development of DOC-induced
hypertension favors a protective role of the
KKS.14 15 Although a large body of evidence
indicates that icatibant is a selective B2
receptor antagonist in the rat,16 17
a recent publication has suggested that it may be able to interact with
B1 receptors in a bovine aortic cell
line.25 In addition, residual agonist effects of
icatibant have been reported in the rat.26
Therefore, caution is appropriate when the hypertensive effect induced
by icatibant is attributed to selective blockade of the
B2 receptor. However, consistent with the
evidence provided by the use of the antagonist is the
report that Brown Norway Katholiek rats, a strain congenitally
deficient in kininogen in plasma and devoid of kinin release in urine,
exhibit a more rapid BP increase during DOC-salt treatment than normal
Brown Norway Kitasato rats.27
The availability of B2 receptor knockout mice
allowed us to evaluate whether the absence of the receptor confers a
greater sensitivity to the vasopressor action of DOC. This was indeed
the case, since the increase in the SBP of
Bk2r-/- was twofold that of wild-type controls
(30 versus 15 mm Hg at 3 weeks). In consideration of our recent
finding that the BP of untreated Bk2r-/-
increases toward elevated levels after 60 days of life, while that of
wild-type controls remains stable with aging (C.E. and P.M.,
unpublished data, 1997), we wished to rule out the possibility that the
BP difference between Bk2r-/- and
Bk2r+/+ under conditions of mineralocorticoid
excess was merely attributable to a time-related effect. Therefore,
experiments were conducted in Bk2r-/- that had
already reached an age (18 weeks) at which no further increase in BP
occurs, as demonstrated in the present study by the lack of BP
changes during the administration of vehicle.
The reduced ratio of urinary sodium to BP reflects a shift in the
relationship between BP and natriuresis in
Bk2r-/-,20 possibly
attributable to an impaired renal excretory ability. This defect could
be compensated for at the cost of higher BP levels under basal
conditions and by incremental rises in BP after the application of salt
loading20 or an excess of sodium-retaining
hormones.
Targeted disruption of the B2 receptor gene might
have altered other components of the KKS. At variance with previous
studies showing that antagonism of the B1
receptor increases the BP of Bk2r-/- under
basal conditions,20 we found that acute
administration of a B1 receptor
antagonist does not alter the BP of DOC-treated mice. Since
the magnitude of BP increases induced by B1
antagonist20 or DOC treatment was
approximately the same, an intriguing explanation might be that, under
basal conditions, activation of the B1 receptor
compensates, in part, for the absence of the B2
receptor, while this compensatory mechanism could be overwhelmed under
conditions of mineralocorticoid excess. Further studies are necessary
to elucidate this possibility. Apart from components of the KKS, we
cannot exclude that long-term adaptation or counterbalancing mechanisms
taking place in animals that are submitted to higher BP during
development might have contributed to amplify the pressor response to
DOC in Bk2r-/-.
In Bk2r-/- we have observed higher HR levels
under basal conditions.20 In the present
study these animals did not show any reflex HR change in response to
the BP increase induced by DOC. It is hard to reconcile the accelerated
HR of Bk2r-/- with the ability of bradykinin to
enhance the release of norepinephrine via the
B2 receptor.28 However,
similar tachycardia was observed in rats given icatibant in
utero,29 thus suggesting that
peripheral and/or central B2
receptors may be involved in the early developmental processes that
determine the adult HR phenotype in rodents. Reduced
parasympathetic activity, sympathoexcitation, and/or alteration in
baroreceptor reflex sensitivity could be responsible for the
alterations in HR. Consistent with the latter possibility is
our previous observation that rat baroreceptor reflex response to
increments in BP is reduced by central administration of
icatibant.30
Heterozygous animals are useful not only because they help us to
understand the effect of varying the number of functional copies of the
targeted gene, but also because they resemble more closely a condition
of "partial deficiency" that might occur in human hypertensive
patients. We found that Bk2r+/- are
indistinguishable from wild-type animals regarding BP under basal
conditions as well as in response to DOC. In addition, the
vasodepressor response to exogenous bradykinin is similar in
Bk2r+/- and
Bk2r+/+.20 These findings
are compatible with a great deal of redundancy or spare capacity of
B2 receptors (ie, only a fraction has to be
occupied to elicit a full response). A different pattern was observed
regarding the response to other stimuli, as heterozygous animals showed
mildly augmented BP response to long-term angiotensin II
infusion compared with wild-type controls.20
Therefore, it is likely that the enhanced BP sensitivity to
angiotensin II is related to a direct vasoconstrictor
action of this peptide rather than to its ability to stimulate
mineralocorticoid release.
In conclusion, our findings confirm that a normally functioning
B2 receptor is essential for the regulation of BP
and HR under basal conditions and indicate that endogenous
kinins can protect against the development of mineralocorticoid-induced
hypertension.
Received November 10, 1997;
first decision December 4, 1997;
accepted January 14, 1998.
© 1998 American Heart Association, Inc.
Scientific Contributions
Enhanced Blood Pressure Sensitivity to Deoxycorticosterone in Mice With Disruption of Bradykinin B2 Receptor Gene
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Abstract—The renal kallikrein-kinin
system is activated under conditions of mineralocorticoid
excess. To evaluate whether endogenous kinins exert a
protective role against the development of mineralocorticoid-induced
hypertension, we studied the cardiovascular effects
induced by long-term administration of deoxycorticosterone (DOC;
0.3 µmol/g body wt SC once per week for 6 weeks) or vehicle in
transgenic mice (Bk2r-/-) lacking the bradykinin
B2 receptor gene and in wild-type controls
(Bk2r+/+). Under basal conditions, Bk2r-/-
mice showed higher systolic blood pressure (tail-cuff
plethysmography) than wild-type Bk2r+/+ and heterozygous
Bk2r+/- mice (121±2 versus 114±2 and 115±2 mm Hg,
respectively; P<0.05 for both comparisons). Heart rate
was higher in Bk2r-/- and Bk2r+/- than in
Bk2r+/+ (459±12 and 418±7 versus 390±7 bpm;
P<0.05 for both comparisons). Systolic blood
pressure was increased by DOC in transgenic as well as in wild-type
mice, whereas no change was induced by the vehicle. The pressor
response to DOC was more rapid and pronounced in Bk2r-/-
than in Bk2r+/+ and Bk2r+/- (30±5 versus
15±4 and 6±3 mm Hg, respectively, at 3 weeks;
P<0.01 for both comparisons). The difference in
systolic blood pressure was consistent with that
detected by direct intra-arterial measurements of mean
blood pressure. Neither DOC nor its vehicle altered heart rate or gain
in body weight over time. Under basal conditions, urinary sodium
excretion did not differ between strains. During DOC administration,
cumulative urinary sodium excretion was lower in Bk2r-/-
than in Bk2r+/+ (2.59±0.15 versus 3.31±0.22 mmol,
respectively, during the first week; P<0.05). Urinary
kinin excretion was increased by DOC in both Bk2r-/-
(from 0.65±0.17 to 4.27±0.80 pmol/24 h; P<0.01) and
Bk2r+/+ (from 0.55±0.09 to 6.27±1.48 pmol/24 h;
P<0.05). The increase in urinary kinin excretion was
similar between strains. These results show that integrity of the
bradykinin B2 receptor is essential for regulation of blood
pressure and heart rate under basal conditions. In addition, they
indicate that activation of the kallikrein-kinin system
represents a compensatory response against the development of
hypertension induced by mineralocorticoid excess.
Key Words: mineralocorticoids • blood pressure • kallikrein-kinin system
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Kinins, the enzymatic
products of kininogen cleavage by kallikrein, induce
vasodilatation, diuresis, and natriuresis by promoting the
release of endothelium-derived relaxing factors and
prostaglandins.1 2 3 4 They act as local
hormones by activating specific receptors named
B1 and B2, with most of the
cardiovascular and renal effects being mediated by the
B2 receptor.5 It has been
hypothesized that a dysfunction of the KKS, leading to unbalanced
predominance of vasoconstrictor and antinatriuretic
systems, may contribute to the pathogenesis of arterial
hypertension. Interestingly, at variance with other models of genetic
or experimental hypertension characterized by a defective renal
synthesis and excretion of kallikrein,6 7 8 9 10
clinical forms of primary aldosteronism as well as experimental
hypertension induced by DOC show an activated
KKS.11 12 13 The possibility that this alteration
represents a compensatory response to counteract the
development of hypertension induced by DOC is based mainly on
pharmacological studies in rats,14 15 showing
that the hypertensive effect of mineralocorticoid administration is
enhanced by the concomitant blockade of B2
receptors with icatibant, a long-acting analogue antagonist
of bradykinin.16 17 Unfortunately, receptor
antagonists are not devoid of unspecificity. Recent
advances in molecular biology have allowed the development of
genetically engineered animals in which the relevant receptor gene has
been disrupted. This novel approach has the potential to overcome some
of the limitations related to the use of antagonists.
Studies on a mouse strain (Bk2r-/-) lacking the
coding sequence for the B2 receptor demonstrated
that a normally functioning B2 receptor is
necessary for the maintenance of cardiovascular
homeostasis.18 19 20 In addition to elevated basal
levels of BP and HR, these transgenic mice show exaggerated BP
sensitivity to acute or chronic administration of
angiotensin II or moderate salt
loading.20 To test the hypothesis of a protective
role of kinins against the development and maintenance of
mineralocorticoid hypertension, we evaluated the BP response to
long-term administration of DOC in mice lacking the
B2 receptor gene and in wild-type controls.
Because a partial deficiency rather than the complete absence of the
B2 receptor is more likely to occur in humans,
heterozygous animals were also studied.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Gene targeting was performed by transfecting embryonic stem
cells derived from 129Sv/Ev mice with a vector designed to disrupt the
entire coding sequence for the B2 receptor by
homologous recombination.18 The
Bk2r-/- mice used in the present studies
were provided by Merck Research Laboratories (Rahway, NJ). They were
compared with 129Sv/Ev mice (Bk2r+/+, from
Jackson Laboratory, Bar Harbor, Maine) and with heterozygous mice
(Bk2r+/-) obtained by breeding pairs of
Bk2r-/- and Bk2r+/+. Mice
were housed at a constant room temperature (24±1°C) and humidity
(60±3%) with a 12-hour light/dark cycle. They had free access to chow
with a normal content of sodium (0.12 mmol/g chow, Mucedola) and
tap water for the duration of the experiments. All procedures complied
with the standards for the care and use of animal subjects as stated in
the Guide for the Care and Use of Laboratory Animals (NIH
publication 93–23, revised 1985, Institute of Laboratory Animal
Resources, National Academy of Sciences, Bethesda, Md) and were
approved by the local animal care and use committee.
SBP and HR were measured by the tail-cuff plethysmography method
in unanesthetized mice prewarmed for 10 minutes at 37°C in a
thermostatically controlled heating cabinet as described
previously.20 Tail-cuff SBP is defined as the
inflation pressure at which the waveform becomes indistinguishable from
baseline noise. As an inclusion criterion, we required that at least 10
of 12 measurements were successful. Final SBP value was obtained by
averaging 10 to 12 successful readings. Experimental measurements were
performed between 10 AM and 2 PM by a single
investigator (C.E.) and then judged by an independent investigator in a
"blinded" fashion. HR was recorded automatically by a counter
triggered by the pulse wave.
After basal measurements, Bk2r-/-,
Bk2r+/+, and Bk2r+/- were
assigned to treatments with vehicle (sesame oil, n=8 each group) or a
slow-release preparation of DOC (DOC enantate, Shering) at a dose of
0.3 µmol/g body wt SC once per week for 6 weeks
(Bk2r-/-, n=19; Bk2r+/+,
n=19; Bk2r+/-, n=10). In preliminary
experiments, we found that this dose increases plasma DOC concentration
by fivefold (14.2±0.13 versus 2.8±0.11 nmol/L in controls). Tail-cuff
SBP, HR, and body weight were measured every week during the
experimental period. In additional groups of
Bk2r-/- and Bk2r+/+,
direct MBP was measured at 3 weeks (n=6 per group).
All data are expressed as mean±SEM. Changes in SBP from
baseline are expressed as absolute values as well as areas under the BP
curves. Multivariate repeated-measures ANOVA was
performed to test for interaction between time and grouping factor.
Univariate ANOVA then was used among groups and over time.
Differences within and between groups were determined with the use of
paired or unpaired Student's t test, respectively, with the
Bonferroni multiple-comparison adjustment.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Under basal conditions (before vehicle or DOC administration),
Bk2r-/- showed higher SBP values than
Bk2r+/+ and Bk2r+/-
(vehicle, 121±2 versus 113±2 and 114±1 mm Hg, respectively;
DOC, 121±2 versus 114±2 and 115±2 mm Hg, respectively;
P<0.05 for both comparisons). HR values of
Bk2r-/- and Bk2r+/- were
higher than those of Bk2r+/+ (vehicle, 463±8 and
415±6 versus 386±5 bpm, respectively; DOC, 459±12 and 418±7 versus
390±7 bpm; P<0.05 for both comparisons). 
, no significant
change from baseline was observed regarding the SBP of groups given
vehicle. By contrast, SBP was increased by DOC administration. The
pressure effect was more pronounced in Bk2r-/-
than in Bk2r+/+ and
Bk2r+/- (30±5 versus 15±4 and 6±3
mm Hg, respectively, at 3 weeks; P<0.01). In addition, the
average increase in SBP, expressed as the area under the curve of the
SBP increments, was significantly higher in
Bk2r-/- than in Bk2r+/+
and Bk2r+/- (18.0±2.1 versus 9.8±1.9 and
10.3±1.8 mm Hg/wk, respectively; P<0.05 for both
comparisons). As shown in Figure 2, the
effect induced by DOC on SBP was consistent with measurements
of MBP at 3 weeks (Bk2r-/-, 140±2 versus
112±1 mm Hg in vehicle-treated mice, P<0.01;
Bk2r+/+, 113±1 versus 102±1 mm Hg in
vehicle-treated mice, P<0.05;
Bk2r+/-, 112±2 versus 104±2 mm Hg in
vehicle-treated mice, P<0.05). Neither vehicle nor DOC
altered HR in any strain. Thus, the difference observed under basal
conditions was maintained at the end of the experimental period
(vehicle, 466±17 in Bk2r-/- and 405±12 in
Bk2r+/- versus 368±14 bpm in
Bk2r+/+, P<0.05 for both comparisons;
DOC, 464±21 in Bk2r-/- and 401±10 in
Bk2r+/- versus 378±16 bpm in
Bk2r+/+, P<0.05 for both
comparisons). Body weight gain was similar among groups (data not
shown).
View larger version (19K):
[in a new window]
Figure 1. Absolute changes in tail-cuff SBP during
administration of DOC (0.3 µmol/g body wt SC once per week for 6
weeks) (Bk2r-/-, 
, n=19; Bk2r+/+, 
,
n=19; and Bk2r+/-, 
, n=10) or vehicle
(Bk2r-/-, 
, n=8; Bk2r+/+, 
, n=8; and
Bk2r+/-, 
, n=8). Values are mean±SEM.
*P<0.05 vs vehicle (within each strain);
+P<0.05 vs Bk2r+/+ (within each treatment);
§P<0.01 vs Bk2r+/- (within each
treatment).
View larger version (33K):
[in a new window]
Figure 2. MBP levels in mice after 3 weeks of vehicle (V)
( , n=6 per group) or DOC (0.3 µmol/g body wt SC) (
, n=6
per group). Values are mean±SEM. *P<0.05 vs vehicle
(within each strain); +P<0.05 vs Bk2r+/+
(within each treatment); §P<0.01 vs
Bk2r+/- (within each treatment).). No difference regarding urinary volume was
detected between strains before and during the administration of DOC.
Cumulative urinary sodium excretion was increased by DOC in comparison
with vehicle. This effect was less in magnitude in
Bk2r-/- than in Bk2r+/+
(2.59±0.15 versus 3.31±0.22 mmol during the first week,
respectively; P<0.05). A shift in the relationship between
natriuresis and BP in Bk2r-/- is indicated by
the lower ratios of urinary sodium to BP under basal conditions
(2.23±0.04 versus 2.92±0.05 mmol/mm Hg in
Bk2r+/+; P<0.05). A similar pattern
was observed during DOC administration (2.24±0.06 versus
3.09±0.07 mmol/mm Hg in Bk2r+/+ at 1 week;
P<0.01). As shown in Figure 3, urinary kinin excretion was increased
by DOC in Bk2r+/+ (from 0.55±0.09 to 6.27±1.48
and 5.36±0.78 pmol/24 h at 1 and 4 weeks, respectively;
P<0.05 for both comparisons). A similar effect was observed
in Bk2r-/- (from 0.65±0.17 to 4.27±0.80 and
6.79±1.67 pmol/24 h at 1 and 4 weeks, respectively; P<0.01
for both comparisons).
View this table:
[in a new window]
Table 1. Urinary Volume and Urinary Sodium Excretion Before and During
Administration of DOC or
Vehicle
View larger version (36K):
[in a new window]
Figure 3. Urinary kinin excretion under basal conditions
( ) and during administration of DOC (0.3 µmol/g body wt SC)
in Bk2r+/+ and Bk2r-/- at 1 week () and 4
weeks () (n=6 per group). Values are mean±SEM.
*P<0.05, **P<0.01 vs basal value.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
Recently, the presence of an altered
cardiovascular phenotype in mice with
disruption of the bradykinin B2 receptor gene has
been documented by our group.20 These mice are
characterized by higher BP and HR levels under basal conditions and by
an exaggerated BP sensitivity to chronic excess of
angiotensin II or dietary salt. In addition, the
present study indicates that the lack of the
B2 receptor is responsible for a more rapid and
pronounced pressor response under conditions of chronic
mineralocorticoid excess.
Selected Abbreviations and Acronyms
Bk2r-/-
=
bradykinin B2 receptor knockout mice
Bk2r+/+
=
wild-type control mice
Bk2r+/-
=
heterozygous mice
BP
=
blood pressure
DOC
=
deoxycorticosterone
HR
=
heart rate
KKS
=
kallikrein-kinin system
MBP
=
mean blood pressure
SBP
=
systolic blood pressure
Acknowledgments
This study was supported in part by a grant from the Minister of
Universities and Scientific Research. We wish to thank Gudrun Godec for
technical assistance in measuring urinary kinins.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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