Heterozygous Knock-Out of ETB Receptors Induces BQ-123-Sensitive Hypertension in the Mouse
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Heterozygous Knock-Out of ETB Receptors Induces
BQ-123–Sensitive Hypertension in the Mouse
Nathalie Berthiaume, Masashi Yanagisawa, Julie Labonté, Pedro D’Orléans-Juste
Abstract—Homozygous knock-out of ETA or ETB receptor genes results in lethal developmental phenotypes in the mouse. Such
deleterious phenotypes do not occur in heterozygous littermates. However, it remains to be determined whether mice partially
defective in ETA or ETB receptors display significant alterations in their responses to exogenous or endogenous endothelin-1
(ET-1). Furthermore, the anesthetized ETB (⫹/⫺) knock-out mice showed a significantly higher mean arterial blood pressure
than the ETA (⫹/⫺) knock-out or their wild-type littermates. The pressor response to ET-1 but not to a selective ETB agonist,
IRL-1620, was significantly reduced in the ETA (⫹/⫺) knock-out mice. In ETB (⫹/⫺) knock-out mice, the pressor effect of
IRL-1620 was more markedly altered than those induced by ET-1. In wild-type mice, both ETA and ETB receptors were found
to be involved in the pressor effect of ET-1, as confirmed by the significant and specific antagonism induced by either BQ-123
(ETA antagonist) or BQ-788 (ETB antagonist). Also, ETA-selective or mixed ETA/ETB- but not ETB-selective antagonists
reversed the hypertensive state of the ETB (⫹/⫺) knock-out mice to the level of wild-type littermates. Finally, radiolabeled
ET-1 plasmatic clearance was altered in ETB (⫹/⫺) but not ETA (⫹/⫺) knock-out mice when compared with wild-type
animals. Thus, heterozygous knock-out of ETB receptors results in a hypertensive state, suggesting an important physiological
role for that particular receptorial entity in opposing the endogenous ET-1– dependent pressor effects in the mouse.
(Hypertension. 2000;36:1002-1007.)
Key Words: receptors, genetic 䡲 arterial pressure 䡲 mice
T he ETA or ETB receptor homozygous (⫺/⫺) knock-out
(KO) mice show lethal embryonic defects and a delete-
rious megacolon phenotype, respectively.1,2 Unlike endothe-
phenotypic alterations in the cardiovascular pharmacology of
exogenous and endogenous ET-1. However, it was first
required to fully identify the respective contribution of the
lin receptors, the total deletion of the B2 receptor for brady- ETA and/or ETB receptors in the vasoactive effects of endo-
kinin or AT-1 receptor subtypes for angiotensin II does not thelins in the WT littermates. We have therefore attempted in
induce short-term lethal effects in these genetically modified this study to characterize the pharmacodynamic characteris-
animals,3,4 albeit the former is sensitive to high salt diets.5 tics of endothelin in the systemic circulation of the WT
Furthermore, heterozygous knock-out of the B2 or AT-1 mouse by the use of the selective ETA antagonist, BQ-123,9
receptor does not significantly affect the vasoactive response the selective ETB agonist, IRL-1620,10 and antagonist, BQ-
to bradykinin or angiotensin II (Ang II), respectively,5,6 in the 788,11 as well as the mixed ETA/ETB antagonist, SB 209670.12
murine model. We have also attempted to demonstrate the respective con-
Unexpectedly, the heterozygous knock-out of endothelin-1 tribution of ETA or ETB receptor types as well as that of
(ET-1) induced a paradoxical mild yet significant elevation of endogenous ET-1 in the regulation of blood pressure in both
basal mean arterial blood pressure (MAP) in these animals strains of anesthetized KO mice.
when compared with wild-type (WT) congeners.7 This hy- Finally, ETB receptors have been reported to be involved in
pertensive state may be caused by the adaptation of the ET-1 the clearance of endogenous endothelin.13 The effect of
(⫹/⫺) KO mouse through enhanced central and/or peripheral heterozygous knock-out of the ETB receptor on the clearance
sympathetic influences on the cardiovascular function.8 of radiolabeled ET-1 has been analyzed in this report.
Whether the same hypertensive state as in ET-1 (⫹/⫺) KO
occurs after heterozygous knock-out of ETA or ETB receptors Methods
remains to be reported.
Animals Used for In Vivo Studies
In the present study, we have therefore explored whether a C57Bl/6⫻J129sv WT mice (weighing 25 to 35 g, either sex) served
partial defect in endothelin receptors, as in heterozygous ETA as controls. Also, C57Bl/6⫻J129sv ETA or ETB (⫹/⫺) KO (25 to
or ETB KO mice, would be sufficient to induce significant 35 g, either sex) mice were used. Colonies for each strain of mice
Received November 29, 1999; first decision January 3, 2000; revision accepted June 6, 2000.
From the Department of Pharmacology, Institute of Pharmacology Medical School, Université de Sherbrooke, Sherbrooke (Québec), Canada (N.B.,
J.L., P.D.-J.); and Howard Hughes Medical Institute and Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, Tex (M.Y.).
Correspondence to Pedro D’Orléans-Juste, Department of Pharmacology, Institute of Pharmacology Medical School, Université de Sherbrooke,
Sherbrooke (Québec), J1H 5N4, Canada. E-mail labpdj@courrier.usherb.ca
© 2000 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
1002
Downloaded from http://hyper.ahajournals.org/ by guest on July 27, 2015Berthiaume et al Endothelins in Heterozygous Knock-Out Mice 1003
(WT or KO) were developed from heterozygous [ETA (⫹/⫺) or ETB
(⫹/⫺) KO] genitor couples that were derived from previously
characterized colonies in the laboratory of Dr Masashi Yanagisawa.
In Vivo Experiments
The mice were anesthetized with ketamine/xylazine (74/9.3 mg/kg
IP, supplemented as needed). Polyethylene catheters (PE-10) were
inserted into the left external jugular vein for drug administration and
in the right carotid artery to monitor MAP and heart rate, according
to a previously reported method14; a cannula (PE-50) was also
inserted into the trachea to facilitate breathing. After surgery, the
anesthetized animals were allowed to stabilize for 15 to 20 minutes. The
pharmacological responses to the various agonists were assessed for
ⱖ20 minutes after the administration of a single bolus dose ranging
from 0.01 to 2.5 nmol/kg (ET-1 and Suc-[Glu,9 Ala11,15]-ET-1 [8-21]
[IRL-1620]) or 5 nmol/kg (norepinephrine, NE); injection volumes
never exceeded 40 L.
Effects of Endothelin Antagonists on ET-1– or
IRL-1620 –Induced Pressor Response and on Basal
MAP in Mice
For some experiments, BQ-123 or BQ-788 (0.01, 0.1, 0.25, and 1
mg/kg) were administered intravenously 5 minutes before a single
bolus injection of either agonist. In another series of experiments, the
direct hemodynamic effects of BQ-123 (1 and 10 mg/kg IP), BQ-788
(10 mg/kg IP), or the metabolically stable ETA/ETB antagonist SB
209670 (10 mg/kg IP) were monitored for 90 minutes in WT or ETB
(⫹/⫺) KO mice.
Figure 1. Vasopressor responses to ET-1 (0.1 nmol/kg) or IRL-
Plasmatic Clearance Studies 1620 (0.5 nmol/kg) in absence (䡺) or presence of (A) BQ-123 0.01
In a first series of experiments, radiolabeled [125I]-ET-1 (0.073 mg/kg (o), 0.1 mg/kg (f), 0.25 mg/kg (v), or 1 mg/kg (z) or (B)
pmol/mouse, subthreshold dose) or [125I]-Ang II (0.11 pmol/mouse, BQ-788 0.01 mg/kg (o), 0.1 mg/kg (f), 0.25 mg/kg (v) or 1 mg/kg
subthreshold dose) were injected in the left jugular vein of WT, ETA, (z) in WT (A and B), ETA (⫹/⫺) KO (A) or ETB (⫹/⫺) KO (B) mice.
or ETB (⫹/⫺) KO mice. Simultaneously, blood samples were Each column with bar represents mean⫾SEM of 4 to 6 experi-
ments. *P⬍0.05, **P⬍0.01, ***P⬍0.001 (when compared with con-
collected through a cannulated carotid artery at 3-second time
trol). Probability values were derived from Student’s t test.
intervals for 2 minutes. Subsequently, radioactivity in each blood
sample was measured (counts per minute) with a ␥-emission counter
(1470 Wizard Gamma Counter Wallac). obtained by monitoring the response of ET-1 or IRL-1620 (at doses
In a second series of experiments, BQ-123 (1 mg/kg) or BQ-788 generally selected within the ED50 range) in the presence of increas-
(1 mg/kg) was administered through the left jugular vein of WT mice ing doses (0.01 to 1 mg/kg) of either BQ-123 or BQ-788. ED50 or
5 minutes before the injection of radiolabeled [125I]-ET-1 (0.073 ID50 values were interpolated by linear regression of the dose-
pmol/mouse). Blood samples were collected and radioactivity levels response curve in a 0% to 100% limit (no values rejected on the
were measured as described above. curve) with the Quattro Pro Program for Windows (Version 5.00).
Furthermore, maximal responses (Emax) were systematically attained
Drugs for all peptidic agonists.
ET-1 and IRL-1620 were purchased from American Peptide Co.
BQ-123 was synthesized in our laboratory. BQ-788 was purchased Ethics
from Peptides International. NE was purchased from Sigma. SB The care of the animals and all research protocols conform to the
209670 was a generous gift from SmithKline Beecham. [125I]-ET-1 guiding principles for animal experimentation as enunciated by the
and [125I]-Ang II were purchased from Peninsula Laboratories. All Canadian Council on Animal Care and approved by the Ethics
agents were prepared and administered in PBS (pH 7.4, Sigma), Committee on Animal Research of the Université de Sherbrooke
except for BQ-123 and BQ-788, which were first dissolved in Medical School.
PBS⫹20% dimethylsulfoxide (DMSO) to obtain 10 mg/mL stock
solutions. DMSO was used because these antagonists are insoluble in
aqueous solution at that concentration. [125I]-ET-1 and [125I]-Ang II
Results
were dissolved in distilled water. Finally, NE was prepared in an Baseline Parameters
ascorbic acid solution (Baker). The basal MAP (in mm Hg) of mice under ketamine/xylazine
anesthesia was averaged for WT (70.1⫾0.7, male; 70.2⫾0.6,
Statistics
Data used in the text and figures are expressed as mean⫾SEM of the
female, n⫽118), for ETA (⫹/⫺) KO (71.6⫾1.7, male;
number of observations. Student’s t or Mann-Whitney U tests (when 69.7⫾1.5, female, n⫽23), or for ETB (⫹/⫺) KO (93.2⫾1.1,
recommended by the Statistical Program Graph Pad Instat) were male; 91.9⫾2.1, female, n⫽53), the latter strain showing a
used for parametric grouped data. Probability values of ⱕ0.05 were significantly higher blood pressure (P⬍0.05) when compared
considered significant. with ETA (⫹/⫺) KO or WT animals. No gender-dependent
differences in MAP were depicted. Furthermore, basal heart rate
Pharmacodynamic Parameters
The apparent affinities (ED50) for ET-1 or IRL-1620 were calculated was not significantly different between WT (164.9⫾11.9 bpm,
by linear regression analysis of the full dose-response curve for in n⫽14), and ETA (⫹/⫺) KO (154.8⫾14.9 bpm, n⫽10) or in ETB
vivo experiments. The apparent affinities for antagonists (ID50) were (⫹/⫺) KO mice (180.2⫾18.3 bpm, n⫽12) (data not shown).
Downloaded from http://hyper.ahajournals.org/ by guest on July 27, 20151004 Hypertension December 2000
Figure 2. Profile of basal MAP after in-
traperitoneal administration of BQ-123 (1
mg/kg) (A), BQ-123 (10 mg/kg) (B), SB
209670 (10 mg/kg) (C), or BQ-788 (10
mg/kg) (D) in WT (䡺) or ETB (⫹/⫺) KO
mice (F). Each symbol with bar repre-
sents mean⫾SEM of 5 to 15 experi-
ments. A and C: *P⬍0.05 compared with
MAP before administration of BQ-123 (1
mg/kg) or SB 209670 (10 mg/kg). B:
*P⬍0.05, ETB (⫹/⫺) KO vs WT; #P⬍0.05,
WT in presence vs absence of antago-
nist. Probability values were derived from
Mann-Whitney U test.
Effects of ET-1 and IRL-1620 on MAP of Mouse IRL-1620 (0.5 nmol/kg) (control, 21.3⫾2.2; ⫹BQ-788,
in Presence or Absence of ETA- or 8.6⫾0.2 mm Hg, P⬍0.05), respectively, 90 minutes after ad-
ETB-Selective Antagonists ministration of the antagonists.
ET-1 (0.1 nmol/kg) was more efficient to increase MAP BQ-123 (1 mg/kg IP) had no influence on the basal MAP
(25.5⫾1.2 mm Hg) than IRL-1620 (0.1 nmol/kg, 12.1⫾1.0; of WT mice. In contrast, the same dose of the ETA antagonist
0.5 nmol/kg, 21.3⫾2.2 mm Hg). A 5-minute treatment with induced a significant reduction in MAP of ETB (⫹/⫺) KO
BQ-123 or BQ-788 (0.01 to 1 mg/kg IV, 5 minutes) dose- mice. The hypotensive response to BQ-123 (1 mg/kg IP)
dependently reduced ET-1–induced vasopressor response reached significance 20 minutes after administration. How-
(ID50 for BQ-123, 0.22 mg/kg; for BQ-788, 0.22 mg/kg) ever, ETB (⫹/⫺) KO mice treated for 90 minutes still
(Figure 1, A and B). The IRL-1620 –induced pressor response displayed significantly higher MAP (P⬍0.05 at all time
was also dose-dependently reduced by BQ-788 (ID50, 0.10 points) than the BQ-123–treated WT littermates (Figure 2A).
mg/kg) but not by BQ-123 (Figure 1, A and B). In contrast, Figure 2B shows that BQ-123 (10 mg/kg) administered
NE-induced increase in MAP was not altered by treatment with intraperitoneally significantly reduced (by ⬇10 mm Hg)
BQ-123 or BQ-788 even at the highest dose of antagonists basal MAP of WT mice after 1 or 2 minutes after injection of
(1 mg/kg) (NE before BQ-123 or BQ-788: 30.4⫾1.7 mm Hg; the antagonist. This reduction in MAP was maintained for
after BQ-123, 35⫾3.2 mm Hg; after BQ-788, ⱖ90 minutes. Interestingly, the same treatment also reduced
33.6⫾3.5 mm Hg) (data not shown). In another series of by ⬇30 mm Hg the MAP of ETB (⫹/⫺) KO mice, bringing
experiments, BQ-123 and BQ-788 showed the same apparent it back to the level of the BQ-123–treated WT counterparts.
affinities against ET-1 in ETA (⫹/⫺) KO (0.22 mg/kg) and ETB BQ-123 (10 mg/kg) administered intraperitoneally for 60
(⫹/⫺) KO (0.21 mg/kg) mice, respectively, when compared minutes in WT mice had no significant effect on the pressor
with WT littermates (Figure 1, A and B). response to NE (5 nmol/kg) (control, 29.6⫾3.2 mm Hg; in
presence of BQ-123, 30.2⫾3.0 mm Hg). On the other hand, a
Treatment With ETA-Selective Antagonist treatment with BQ-788 (10 mg/kg) administered intraperito-
Reverses Hypertensive State of ETB (ⴙ/ⴚ) neally had no effect on basal MAP either in WT or in ETB
KO Mice (⫹/⫺) KO mice (Figure 2D). Finally, SB 209670 (10 mg/kg IP)
Intravenous administration of the highest dose of BQ-123 or induced a significant hypotensive response (starting at time point
BQ-788 (10 mg/kg each) was avoided because of a significant 1 minute with a maximal hypotension of ⱖ18 mm Hg) in ETB
depressor effect of the vehicle (PBS⫹DMSO, 20%). In contrast, (⫹/⫺) KO but not in WT animals (Figure 2C).
the same vehicle did not significantly affect MAP when admin-
istered intraperitoneally in WT mice (0 minutes, Effect of Partial KO of ETB Receptors or of
72.1⫾4.1 mm Hg; 10 minutes, 69.1⫾3.5 mm Hg; 30 minutes, BQ-123 or BQ-788 on Plasmatic Clearance of
69.1⫾3.2 mm Hg; and 90 minutes, 71.7⫾3.6 mm Hg after Exogenously Applied [125 I]-ET-1
administration). Furthermore, BQ-123 and BQ-788 (1 mg IP) Figure 3A illustrates the increase in [125I]-ET-1 (expressed in
significantly reduced the pressor response to ET-1 (0.1 nmol/kg) counts per minute) in blood samples collected from ETB
(control, 25.8⫾1.2; ⫹BQ-123, 12.5⫾1.5 mm Hg, P⬍0.05) and (⫹/⫺) KO mice when compared with WT animals. Our
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Figure 3. Profile of [125I]-ET-1 (0.073
pmol/mouse) (A and B) or [125I]-Ang II
(0.11 pmol/mouse) (C) plasma levels after
being intravenously administered in WT
(E) or ETB (⫹/⫺) KO mice (F) (A and C)
or ETA (⫹/⫺) KO mice (f) (B) in function
of time. Each symbol with bar represents
mean⫾SEM of 8 experiments. *P⬍0.05.
Probability values were derived from Stu-
dent’s t test.
results show a reduced clearance of [125I]ET-1 in ETB (⫹/⫺) induced pressor response was observed, and the two receptor
KO (Figure 3A) but not in ETA (⫹/⫺) KO mice (Figure 3B) blockers show similar apparent affinity against the response to
when compared with the WT littermates (n⫽8, P⬍0.05) ET-1. Curiously, unlike the observations reported in many other
starting at the 9-second time point. In contrast, no differences animal species, such as the rabbit,14 the rat,11 the dog,15 and
were found in the clearance of [125I]-Ang II in blood samples humans,16 selective blockade of ETB receptors with BQ-788 did
of ETB (⫹/⫺) KO mice when compared with WT mice not potentiate the pressor responses to ET-1 in the mouse. On the
(Figure 3C) (n⫽8). In a fashion similar to the partial KO of other hand, in WT mice, ETA and ETB receptor activation
the ETB receptors, a treatment with an ETB antagonist, accounts for ⬇70% and 30%, respectively, of the maximal
BQ-788, but not with BQ-123 induced an increase in [125I]- pressor responses induced by ET-1, as shown in the present
ET-1 in the blood of WT mice (n⫽6, P⬍0.05) (Figure 4, A study (Table). ETA but not ETB receptors for endothelin appear
and B). to be importantly involved in the vasoconstrictive properties of
endogenous endothelin in the human brachial arteries.16 In
addition, it has been shown that blockade of ETB receptors per se
Discussion in both the rabbit and humans promotes an enhancement of
We have shown that intravenously administered ET-1 and vascular resistance, suggesting a predominant role for this
IRL-1620 both induced a dose-dependent increase in MAP of receptor type in the modulation of endogenous endothelin-
the anesthetized mouse, illustrating the significant contribution dependent constriction.14,16 The above-mentioned considerations
of both ETA and ETB receptors on systemic resistance in that illustrate that the mouse model is quite different from the
species. Those results have been confirmed by the use of the majority of other species studied, as far as the contribution of
selective ETA or ETB antagonists BQ-123 and BQ-788. With ETA and ETB receptors is concerned in the vasoactive effects of
either of these antagonists, a significant reduction of ET-1– endothelins.
Figure 4. Profile of [125I]-ET-1 plasma lev-
els before (F) or after (E) treatment with
BQ-788 (1 mg/kg IV) (A) or BQ-123 (1
mg/kg IV) (B) in WT mice. Each symbol
with bar represents mean⫾SEM of 6
experiments. *P⬍0.05. Probability values
were derived from Student’s t test.
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Pharmacodynamic Characteristics of ET-1ⴚInduced and contribution of ETB receptors in resistance vessels is substan-
IRL-1620ⴚInduced Pressor Response in Anesthetized WT, ETA, tiated by the fact that in ETB heterozygous KO mice, the
or ETBⴙ/ⴚKO Mouse In Vivo maximal pressor response to ET-1 is unaltered, unlike that of
Agonist/Genotype ED50, nmol/kg RA, % Emax, mm Hg the selective ETB agonist IRL-1620 (Table).
ET-1
The pivotal role of increased ET-1 levels in the hyperten-
sive state of ETB KO (⫹/⫺) mice is further substantiated by
WT 0.12⫾0.02 100 56.8⫾3.7
the fact that we were able to significantly reverse the
ETA⫹/⫺KO 0.50⫾0.01* 24* 52.4⫾4.8
hypertensive state of these animals with the ETA-selective and
ETB⫹/⫺KO 0.45⫾0.09* 27* 53.0⫾5.4 specific antagonist BQ-123 as well as with the orally avail-
IRL-1620 able ETA/ETB antagonist SB 209670 but not with the ETB
WT 0.08⫾0.01 100 21.3⫾2.2 blocker BQ-788. We also demonstrated an increase in exog-
ETA⫹/⫺KO 0.08⫾0.01 100 19.4⫾1.2 enously applied [125I]-ET-1 in blood samples of ETB (⫹/⫺)
ETB⫹/⫺KO 䡠䡠䡠 7.1⫾3.5* KO mice when compared with WT animals. This suggests an
ED50 indicates effective dose inducing 50% of maximal response of the altered ETB-dependent clearance mechanism in mice partially
agonist; RA, relative affinity in percentage; and Emax, maximal response. deficient in ETB receptors. Furthermore, a treatment with the
Pressor responses (change in MAP) are measured in mm Hg. Each value ETB blocker BQ-788 but not with the ETA blocker BQ-123
represents mean⫾SEM of at least 6 experiments. also significantly increased radiolabeled ET-1 in the blood of
*P⬍0.05 when compared with values in WT animals. WT mice.
On the other hand, one should note that the interpretation
The important contribution of ETB receptors in the pressor of our results should be limited to the condition of anesthesia
and constrictive effects of ET-1 in the murine model confirms prevailing in the studied animals. Whether this hypertensive
the observations by Giller et al17 in nonlethal piebald mice, in state occurs in physiological situations, such as in conscious
which only 25% of normal mRNA for the ETB receptor has ETB (⫹/⫺) KO mice, remains to be investigated.
been reported. In this model, it was shown that another It is concluded that heterozygous knock-out of ETA or ETB
selective ETB agonist, sarafotoxin S6C, was devoid of initial
receptors is sufficient to alter the pharmacodynamic proper-
hypotensive effect albeit it induced a marked pressor re-
ties of ET-1. Furthermore, ETB KO (⫹/⫺) mice display an
sponse.17 In the piebald lethal mice, in which the ETB receptor
ETA antagonist–sensitive hypertension suggested to be related
is fully mutated and functionally null, the response to sarafo-
to the impaired clearance of endogenous ET-1.
toxin S6C was abolished when compared with the nonlethal
Interestingly, a significant correlation has been reported
piebald mice.17
between the mutation of the ETB receptor gene locus and the
Albeit not demonstrated in the present report, heterozygous
occurrence of Hirschprung disease.20 Thus, it may be of
knock-out of the receptor gene for ETA or ETB receptors
interest to monitor the parents of these patients for a possibly
results in a significant reduction (40% to 50%) in the mRNA
higher prevalence of hypertensive states.
and protein in the genetically manipulated mice2 (M. Yanagi-
sawa, personal communication). In our hands, this partial
knock-out of either gene resulted in a significant alteration in Acknowledgments
This project was financially supported by the Medical Research
the cardiovascular properties of endothelins in the mouse (see
Council of Canada (MT-12889 and R-13272) and the Heart and
Table). Heterozygous knock-out of the ETB receptor, in Stroke Foundation of Québec. M. Yanagisawa is an investigator of
contrast to that of the ETA receptor gene, resulted in a the Howard Hughes Medical Institute, P. D’Orléans-Juste is a
significant increase in MAP of nearly 25 mm Hg, as also scholar of the Fonds de la recherche en santé du Québec, and N.
previously reported in heterozygous KO mice for the ET-1 Berthiaume is in receipt of a studentship of the Heart and Stroke
gene.7 Albeit the hypertensive state occurring in ET-1 KO Foundation of Canada. The authors gratefully acknowledge the
secretarial assistance of Pascale Martel and Helen Morin and the
mice was demonstrated to involve cardioreflex dysregula- efficient technical assistance of Shelley Dixon and Sahar Seyedkalal.
tion,7,8 one can postulate that partial knock-out of the ETB
receptor will preferably result in a modification of the References
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Downloaded from http://hyper.ahajournals.org/ by guest on July 27, 2015Heterozygous Knock-Out of ETB Receptors Induces BQ-123 −Sensitive Hypertension in
the Mouse
Nathalie Berthiaume, Masashi Yanagisawa, Julie Labonté and Pedro D'Orléans-Juste
Hypertension. 2000;36:1002-1007
doi: 10.1161/01.HYP.36.6.1002
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