(Hypertension. 2000;36:1002.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Heterozygous Knock-Out of ETB Receptors Induces BQ-123–Sensitive Hypertension in the Mouse
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{at}courrier.usherb.ca
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Abstract |
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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.
Key Words: receptors, genetic • arterial pressure • mice
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Introduction |
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The ETA or ETB receptor homozygous (-/-) knock-out (KO) mice show lethal embryonic defects and a deleterious megacolon phenotype, respectively.1 2 Unlike endothelin receptors, the total deletion of the B2 receptor for bradykinin or AT-1 receptor subtypes for angiotensin II does not induce short-term lethal effects in these genetically modified animals,3 4 albeit the former is sensitive to high salt diets.5 Furthermore, heterozygous knock-out of the B2 or AT-1 receptor does not significantly affect the vasoactive response to bradykinin or angiotensin II (Ang II), respectively,5 6 in the murine model.
Unexpectedly, the heterozygous knock-out of endothelin-1 (ET-1) induced a paradoxical mild yet significant elevation of basal mean arterial blood pressure (MAP) in these animals when compared with wild-type (WT) congeners.7 This hypertensive state may be caused by the adaptation of the ET-1 (+/-) KO mouse through enhanced central and/or peripheral sympathetic influences on the cardiovascular function.8 Whether the same hypertensive state as in ET-1 (+/-) KO occurs after heterozygous knock-out of ETA or ETB receptors remains to be reported.
In the present study, we have therefore explored whether a partial defect in endothelin receptors, as in heterozygous ETA or ETB KO mice, would be sufficient to induce significant 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 ETA and/or ETB receptors in the vasoactive effects of endothelins in the WT littermates. We have therefore attempted in this study to characterize the pharmacodynamic characteristics of endothelin in the systemic circulation of the WT mouse by the use of the selective ETA antagonist, BQ-123,9 the selective ETB agonist, IRL-1620,10 and antagonist, BQ-788,11 as well as the mixed ETA/ETB antagonist, SB 209670.12 We have also attempted to demonstrate the respective contribution of ETA or ETB receptor types as well as that of endogenous ET-1 in the regulation of blood pressure in both strains of anesthetized KO mice.
Finally, ETB receptors have been reported to be involved in the clearance of endogenous endothelin.13 The effect of heterozygous knock-out of the ETB receptor on the clearance of radiolabeled ET-1 has been analyzed in this report.
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Methods |
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Animals Used for In Vivo Studies
C57Bl/6xJ129sv WT mice (weighing 25 to 35 g, either sex) served as controls. Also, C57Bl/6xJ129sv ETA or ETB (+/-) KO (25 to 35 g, either sex) mice were used. Colonies for each strain of mice (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 
20 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 µL.
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.
Plasmatic Clearance Studies
In a first series of experiments, radiolabeled
[125I]-ET-1 (0.073 pmol/mouse, subthreshold
dose) or [125I]-Ang II (0.11 pmol/mouse,
subthreshold dose) were injected in the left jugular vein of WT,
ETA, or ETB (+/-) KO
mice. Simultaneously, blood samples were collected through
a cannulated carotid artery at 3-second time intervals for 2 minutes.
Subsequently, radioactivity in each blood sample was measured (counts
per minute) with a 
-emission counter (1470 Wizard Gamma Counter
Wallac).
In a second series of experiments, BQ-123 (1 mg/kg) or BQ-788 (1 mg/kg) was administered through the left jugular vein of WT mice 5 minutes before the injection of radiolabeled [125I]-ET-1 (0.073 pmol/mouse). Blood samples were collected and radioactivity levels were measured as described above.
Drugs
ET-1 and IRL-1620 were purchased from American Peptide Co.
BQ-123 was synthesized in our laboratory. BQ-788 was purchased from
Peptides International. NE was purchased from Sigma. SB 209670 was a
generous gift from SmithKline Beecham.
[125I]-ET-1 and
[125I]-Ang II were purchased from Peninsula
Laboratories. All agents were prepared and administered in PBS (pH 7.4,
Sigma), except for BQ-123 and BQ-788, which were first dissolved in
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 were dissolved in distilled
water. Finally, NE was prepared in an ascorbic acid solution
(Baker).
Statistics
Data used in the text and figures are expressed as mean±SEM of
the number of observations. Student’s t or Mann-Whitney
U tests (when recommended by the Statistical Program Graph
Pad Instat) were used for parametric grouped data. Probability
values of 
0.05 were considered significant.
Pharmacodynamic Parameters
The apparent affinities (ED50) for ET-1 or
IRL-1620 were calculated by linear regression analysis of the
full dose-response curve for in vivo experiments. The apparent
affinities for antagonists (ID50)
were obtained by monitoring the response of ET-1 or IRL-1620 (at doses
generally selected within the ED50 range) in the
presence of increasing doses (0.01 to 1 mg/kg) of either BQ-123 or
BQ-788. ED50 or ID50 values
were interpolated by linear regression of the dose-response curve in a
0% to 100% limit (no values rejected on the curve) with the Quattro
Pro Program for Windows (Version 5.00). Furthermore, maximal responses
(Emax) were systematically attained for all
peptidic agonists.
Ethics
The care of the animals and all research protocols conform to
the guiding principles for animal experimentation as enunciated by the
Canadian Council on Animal Care and approved by the Ethics Committee on
Animal Research of the Université de Sherbrooke Medical
School.
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Results |
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Baseline Parameters
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, female, n=118), for ETA (+/-) KO (71.6±1.7, male; 69.7±1.5, female, n=23), or for ETB (+/-) KO (93.2±1.1, male; 91.9±2.1, female, n=53), the latter strain showing a significantly higher blood pressure (P<0.05) when compared with ETA (+/-) KO or WT animals. No gender-dependent differences in MAP were depicted. Furthermore, basal heart rate was not significantly different between WT (164.9±11.9 bpm, n=14), and ETA (+/-) KO (154.8±14.9 bpm, n=10) or in ETB (+/-) KO mice (180.2±18.3 bpm, n=12) (data not shown).
Effects of ET-1 and IRL-1620 on MAP of Mouse in Presence or Absence
of ETA- or ETB-Selective Antagonists
ET-1 (0.1 nmol/kg) was more efficient to increase MAP
(25.5±1.2 mm Hg) than IRL-1620 (0.1 nmol/kg, 12.1±1.0; 0.5
nmol/kg, 21.3±2.2 mm Hg). A 5-minute treatment with BQ-123 or
BQ-788 (0.01 to 1 mg/kg IV, 5 minutes) dose-dependently reduced
ET-1–induced vasopressor response (ID50 for
BQ-123, 0.22 mg/kg; for BQ-788, 0.22 mg/kg) (Figure 1, A and B). The IRL-1620–induced
pressor response was also dose-dependently reduced by BQ-788
(ID50, 0.10 mg/kg) but not by BQ-123 (Figure 1, A and B). In contrast, NE-induced increase in MAP was not
altered by treatment with BQ-123 or BQ-788 even at the highest dose of
antagonists (1 mg/kg) (NE before BQ-123 or BQ-788:
30.4±1.7 mm Hg; after BQ-123, 35±3.2 mm Hg; after BQ-788,
33.6±3.5 mm Hg) (data not shown). In another series of
experiments, BQ-123 and BQ-788 showed the same apparent affinities
against ET-1 in ETA (+/-) KO (0.22 mg/kg) and
ETB (+/-) KO (0.21 mg/kg) mice, respectively,
when compared with WT littermates (Figure 1, A and B).
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) or presence of (A) BQ-123 0.01 mg/kg (
), 0.1 mg/kg (
), 0.25 mg/kg (
), or 1 mg/kg (
) or (B) BQ-788 0.01 mg/kg (
Treatment With ETA-Selective Antagonist
Reverses Hypertensive State of ETB (+/-) KO Mice
Intravenous administration of the highest dose
of BQ-123 or BQ-788 (10 mg/kg each) was avoided because of a
significant depressor effect of the vehicle (PBS+DMSO, 20%). In
contrast, the same vehicle did not significantly affect MAP when
administered intraperitoneally in WT mice (0
minutes, 72.1±4.1 mm Hg; 10 minutes, 69.1±3.5 mm Hg; 30
minutes, 69.1±3.2 mm Hg; and 90 minutes, 71.7±3.6 mm Hg
after administration). Furthermore, BQ-123 and BQ-788 (1 mg IP)
significantly reduced the pressor response to ET-1 (0.1 nmol/kg)
(control, 25.8±1.2; +BQ-123, 12.5±1.5 mm Hg,
P<0.05) and IRL-1620 (0.5 nmol/kg) (control, 21.3±2.2;
+BQ-788, 8.6±0.2 mm Hg, P<0.05), respectively, 90
minutes after administration of the antagonists.
BQ-123 (1 mg/kg IP) had no influence on the basal MAP of WT mice. In contrast, the same dose of the ETA antagonist induced a significant reduction in MAP of ETB (+/-) KO mice. The hypotensive response to BQ-123 (1 mg/kg IP) reached significance 20 minutes after administration. However, ETB (+/-) KO mice treated for 90 minutes still displayed significantly higher MAP (P<0.05 at all time points) than the BQ-123–treated WT littermates (Figure 2A).
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Figure 2B shows that BQ-123 (10 mg/kg) administered
intraperitoneally significantly reduced (by
10 mm Hg) basal MAP of WT mice after 1 or 2 minutes after
injection of the antagonist. This reduction in MAP was
maintained for 90 minutes. Interestingly, the same treatment also
reduced by 30 mm Hg the MAP of ETB
(+/-) KO mice, bringing it back to the level of the BQ-123–treated
WT counterparts. BQ-123 (10 mg/kg) administered
intraperitoneally for 60 minutes in WT mice had no
significant effect on the pressor 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 BQ-788 (10 mg/kg) administered
intraperitoneally had no effect on basal MAP either
in WT or in ETB (+/-) KO mice (Figure 2D). Finally, SB 209670 (10 mg/kg IP) induced a significant
hypotensive response (starting at time point 1 minute with a maximal
hypotension of 18 mm Hg) in ETB (+/-)
KO but not in WT animals (Figure 2C).
Effect of Partial KO of ETB Receptors or of BQ-123 or
BQ-788 on Plasmatic Clearance of Exogenously Applied
[125 I]-ET-1
Figure 3A illustrates the increase
in [125I]-ET-1 (expressed in counts per minute)
in blood samples collected from ETB (+/-) KO
mice when compared with WT animals. Our results show a reduced
clearance of [125I]ET-1 in
ETB (+/-) KO (Figure 3A) but not in
ETA (+/-) KO mice (Figure 3B) when
compared with the WT littermates (n=8, P<0.05) starting at
the 9-second time point. In contrast, no differences were found in the
clearance of [125I]-Ang II in blood samples of
ETB (+/-) KO mice when compared with WT mice
(Figure 3C) (n=8). In a fashion similar to the partial KO of the
ETB receptors, a treatment with an
ETB antagonist, BQ-788, but not with
BQ-123 induced an increase in [125I]-ET-1 in
the blood of WT mice (n=6, P<0.05) (Figure 4, A and B).
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) or ETB (+/-) KO mice (•) (A and C) or ETA (+/-) KO mice (
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Discussion |
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We have shown that intravenously administered ET-1 and IRL-1620 both induced a dose-dependent increase in MAP of the anesthetized mouse, illustrating the significant contribution of both ETA and ETB receptors on systemic resistance in that species. Those results have been confirmed by the use of the selective ETA or ETB antagonists BQ-123 and BQ-788. With either of these antagonists, a significant reduction of ET-1–induced pressor response was observed, and the two receptor blockers show similar apparent affinity against the response to ET-1. Curiously, unlike the observations reported in many other animal species, such as the rabbit,14 the rat,11 the dog,15 and humans,16 selective blockade of ETB receptors with BQ-788 did not potentiate the pressor responses to ET-1 in the mouse. On the other hand, in WT mice, ETA and ETB receptor activation accounts for
70% and 30%, respectively, of the maximal
pressor responses induced by ET-1, as shown in the present study
(Table). ETA
but not ETB receptors for endothelin appear 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 in both the rabbit and
humans promotes an enhancement of vascular resistance, suggesting a
predominant role for this receptor type in the modulation of
endogenous endothelin-dependent
constriction.14 16 The above-mentioned considerations
illustrate that the mouse model is quite different from the majority of
other species studied, as far as the contribution of
ETA and ETB receptors is
concerned in the vasoactive effects of endothelins.
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The important contribution of ETB receptors in the pressor and constrictive effects of ET-1 in the murine model confirms the observations by Giller et al17 in nonlethal piebald mice, in which only 25% of normal mRNA for the ETB receptor has been reported. In this model, it was shown that another selective ETB agonist, sarafotoxin S6C, was devoid of initial hypotensive effect albeit it induced a marked pressor response.17 In the piebald lethal mice, in which the ETB receptor is fully mutated and functionally null, the response to sarafotoxin S6C was abolished when compared with the nonlethal piebald mice.17
Albeit not demonstrated in the present report, heterozygous knock-out of the receptor gene for ETA or ETB receptors results in a significant reduction (40% to 50%) in the mRNA and protein in the genetically manipulated mice2 (M. Yanagisawa, personal communication). In our hands, this partial knock-out of either gene resulted in a significant alteration in the cardiovascular properties of endothelins in the mouse (see Table). Heterozygous knock-out of the ETB receptor, in contrast to that of the ETA receptor gene, resulted in a significant increase in MAP of nearly 25 mm Hg, as also previously reported in heterozygous KO mice for the ET-1 gene.7 Albeit the hypertensive state occurring in ET-1 KO mice was demonstrated to involve cardioreflex dysregulation,7 8 one can postulate that partial knock-out of the ETB receptor will preferably result in a modification of the ETB-dependent clearance mechanisms initially reported by Fukuroda et al.13 We suggest that partial knock-out of the ETB receptor may first affect the high-affinity ETB clearance receptors that have been reported on the endothelium.18 Such alterations in ETB receptor clearance mechanisms would favor a significant increase in luminal and basolateral ET-1 concentrations, as recently reported by Ohuchi et al.19 In support of that hypothesis, Giller et al17 suggested a role for increased ET-1 plasma levels in the hypertensive state occurring in piebald lethal mice. In conditions in which the ETB receptor is fully repressed, as in ETB KO (-/-) mice, this particular phenomenon (ie, reduction in ETB receptor clearance) is compensated by the complete loss of this receptorial entity at the vascular smooth muscle level. The significant contribution of ETB receptors in resistance vessels is substantiated by the fact that in ETB heterozygous KO mice, the maximal pressor response to ET-1 is unaltered, unlike that of the selective ETB agonist IRL-1620 (Table).
The pivotal role of increased ET-1 levels in the hypertensive state of ETB KO (+/-) mice is further substantiated by the fact that we were able to significantly reverse the hypertensive state of these animals with the ETA-selective and specific antagonist BQ-123 as well as with the orally available ETA/ETB antagonist SB 209670 but not with the ETB blocker BQ-788. We also demonstrated an increase in exogenously applied [125I]-ET-1 in blood samples of ETB (+/-) KO mice when compared with WT animals. This suggests an altered ETB-dependent clearance mechanism in mice partially deficient in ETB receptors. Furthermore, a treatment with the ETB blocker BQ-788 but not with the ETA blocker BQ-123 also significantly increased radiolabeled ET-1 in the blood of WT mice.
On the other hand, one should note that the interpretation of our results should be limited to the condition of anesthesia prevailing in the studied animals. Whether this hypertensive state occurs in physiological situations, such as in conscious ETB (+/-) KO mice, remains to be investigated.
It is concluded that heterozygous knock-out of ETA or ETB receptors is sufficient to alter the pharmacodynamic properties of ET-1. Furthermore, ETB KO (+/-) mice display an ETA antagonist–sensitive hypertension suggested to be related to the impaired clearance of endogenous ET-1.
Interestingly, a significant correlation has been reported between the mutation of the ETB receptor gene locus and the occurrence of Hirschprung disease.20 Thus, it may be of interest to monitor the parents of these patients for a possibly higher prevalence of hypertensive states.
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Acknowledgments |
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This project was financially supported by the Medical Research Council of Canada (MT-12889 and R-13272) and the Heart and Stroke Foundation of Québec. M. Yanagisawa is an investigator of the Howard Hughes Medical Institute, P. D’Orléans-Juste is a scholar of the Fonds de la recherche en santé du Québec, and N. Berthiaume is in receipt of a studentship of the Heart and Stroke Foundation of Canada. The authors gratefully acknowledge the secretarial assistance of Pascale Martel and Helen Morin and the efficient technical assistance of Shelley Dixon and Sahar Seyedkalal.
Received November 29, 1999; first decision January 3, 2000; accepted June 6, 2000.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Clouthier DE, Hosoda K, Richardson JA, Williams SC, Yanagisawa H, Kuwaki T, Kumada M, Hammer RE, Yanagisawa M. Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice. Development. 1998;125:813–824.[Abstract]
- Hosoda K, Hammer RE, Richardson RA, Baynash AG, Cheung JC, Giaid A, Yanagisawa M. Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice. Cell. 1994;79:1267–1276.[Medline] [Order article via Infotrieve]
-
Borkowski JA, Ransom RW, Seabrook GR, Trumbauer M,
Chen H, Hill RG, Strader CD, Hess JF. Targeted disruption of a
B2 bradykinin receptor gene in mice eliminates
bradykinin action in smooth muscle and neurons. J Biol
Chem. 1995;270:13706–13710.
[Abstract/Free Full Text] - Matsusaka T, Fogo A, Ichikawa I. Targeting the genes of angiotensin receptors. Semin Nephrol. 1997;17:396–403.[Medline] [Order article via Infotrieve]
- Alfie ME, Yang XP, Hess F, Carretero OA. Salt-sensitive hypertension in bradykinin B2 receptor knock-out mice. Biochem Biophys Res Commun. 1996;224:625–630.[Medline] [Order article via Infotrieve]
- Tsuchida S, Matsusaka T, Chen X, Okubo S, Niimura H, Fogo A, Utsunomiya H, Inagami T, Ichikawa I. Murine double nullizygotes of the angiotensin types 1A and 1B receptor genes duplicate severe abnormal phenotypes of angiotensinogen nullizygotes. J Clin Invest. 1998;101:755–760.[Medline] [Order article via Infotrieve]
- Kurihara Y, Kurihara H, Suzuki H, Kodama T, Maemura K, Nagai R, Oda H, Kuwaki T, Cao WH, Kamada N, Jishage K, Ouchi Y, Azuma S, Toyoda Y, Ishikawa T, Kumada M, Yasaki Y. Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature. 1994;368:703–710.[Medline] [Order article via Infotrieve]
- Ling GY, Cao WH, Onodera M, Ju KH, Kurihara H, Kurihara Y, Yasaki, Y, Kumada M, Fukuda Y, Kuwaki T. Renal sympathetic nerve activity in mice: comparison between mice and rats and between normal and endothelin-1 deficient mice. Brain Res. 1998;808:238–249.[Medline] [Order article via Infotrieve]
- Ihara M, Noguchi K, Saeki T, Fukuroda T, Tsachida S, Kimura S, Fukami T, Ishikawa K, Nishikibe M, Yano M. Biological profiles of highly potent novel endothelin antagonists selective for the ETA receptor. Life Sci. 1992;50:247–255.[Medline] [Order article via Infotrieve]
- Takai M, Umemura I, Yamasaki K, Watakabe T, Fujitami Y, Oda K, Urade Y, Inui T, Yamamura T, Okada T. A potent and specific agonist, Suc-[Glu9, Ala11,15]-endothelin-1(8–21), IRL-1620, for the ETB receptor. Biochem Biophys Res Commun. 1992;184:953–959.[Medline] [Order article via Infotrieve]
-
Ishikawa K, Ihara M, Noguchi K, Mase T, Mino M, Saeki
T, Fukuroda T, Fukami T, Ozaki S, Nagase T, Nishikibe M, Yano M.
Biochemical and pharmacological profile of a potent and selective
endothelin-B receptor antagonist, BQ-788. Proc Natl
Acad Sci U S A. 1994;91:4892–4896.
[Abstract/Free Full Text] -
Ohlstein EH, Nambi P, Douglas SA, Edwards RM, Gellai M,
Lago A, Leber JD, Cousins RD, Gao A, Frazee JS, Peishoff CE, Bean JW,
Eggleston DS, Elshourbagy NA, Kumar C, Lee JA, Yue TL, Louden C, Brooks
DP, Weinstock J, Feuerstein G, Poste G, Ruffolo RR, Gleason JG, Elliott
JD. SB 209670, a rationally designed potent nonpeptide endothelin
receptor antagonist. Proc Natl Acad Sci U S A. 1994;91:8052–8056.
[Abstract/Free Full Text] - Fukuroda T, Fujikawa T, Ozaki S, Ishikawa K, Yano M, Nishikibe M. Clearance of circulating endothelin-1 by ETB receptors in rats. Biochem Biophys Res Commun. 1994;199:1461–1465.[Medline] [Order article via Infotrieve]
-
Gratton JP, Cournoyer G, Löffler BM, Sirois P,
D’Orléans-Juste P. ETB receptor and nitric
oxide synthase blockade induce BQ-123-sensitive pressor effects in the
rabbit. Hypertension. 1997;30:1204–1209.
[Abstract/Free Full Text] - Tsuchiya K, Naruse M, Sanaka T, Naruse K, Zeng ZP, Nitta K, Demura H, Shizume K, Sugino N. Renal and hemodynamic effects of endothelin in anaesthetized dogs. Am J Hypertens. 1990;3:792–795.[Medline] [Order article via Infotrieve]
-
Verhaar MC, Strachan FE, Newby DE, Cruden NL, Koomans
HA, Rabelink TJ, Webb DJ. Endothelin-A receptor
antagonist-mediated vasodilatation is attenuated by
inhibition of nitric oxide synthesis and by endothelin-B receptor
blockade. Circulation. 1998;97:752–756.
[Abstract/Free Full Text] - Giller T, Breu V, Valdenaire O, Clozel M. Absence of ETB-mediated contraction in piebald-lethal mice. Life Sci. 1997;61:255–263.[Medline] [Order article via Infotrieve]
- Ozaki S, Ohwaki K, Ihara M, Fukuroda T, Ishikawa K, Yano M. ETB mediated regulation of extracellular levels of endothelin-1 in cultured human endothelial cells. Biochem Biophys Res Commun. 1995;209:483–489.[Medline] [Order article via Infotrieve]
- Ohuchi T, Kuwaki T, Ling GY, deWit D, Ju KH, Onodera M, Cao WH, Yanagisawa M, Kumada M. Elevation of blood pressure by genetic and pharmacological disruption of the ETB receptor in mice. Am J Physiol. 1999;276:R1071–R1077.
- Puffenburger EG, Hosoda K, Washington SS, Nakao K, deWit D, Yanagisawa M, Chakravarti A. A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung’s disease. Cell. 1994;79:1257–1266.[Medline] [Order article via Infotrieve]
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 M.-Y. Chang, E. Parker, M. El Nahas, J. L. Haylor, and A. C.M. Ong Endothelin B Receptor Blockade Accelerates Disease Progression in a Murine Model of Autosomal Dominant Polycystic Kidney Disease J. Am. Soc. Nephrol., February 1, 2007; 18(2): 560 - 569. [Abstract] [Full Text] [PDF]
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 Y. Zhou, S. Mitra, S. Varadharaj, N. Parinandi, J. L. Zweier, and N. A. Flavahan Increased Expression of Cyclooxygenase-2 Mediates Enhanced Contraction to Endothelin ETA Receptor Stimulation in Endothelial Nitric Oxide Synthase Knockout Mice Circ. Res., June 9, 2006; 98(11): 1439 - 1445. [Abstract] [Full Text] [PDF]
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 X. Guo and T. Yang Endothelin B receptor antagonism in the rat renal medulla reduces urine flow rate and sodium excretion. Experimental Biology and Medicine, June 1, 2006; 231(6): 1001 - 1005. [Abstract] [Full Text] [PDF]
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 L. J. Mullins, M. A. Bailey, and J. J. Mullins Hypertension, Kidney, and Transgenics: A Fresh Perspective Physiol Rev, April 1, 2006; 86(2): 709 - 746. [Abstract] [Full Text] [PDF]
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 J. D. Paasche, T. Attramadal, K. Kristiansen, M. P. Oksvold, H. K. Johansen, H. S. Huitfeldt, S. G. Dahl, and H. Attramadal Subtype-Specific Sorting of the ETA Endothelin Receptor by a Novel Endocytic Recycling Signal for G Protein-Coupled Receptors Mol. Pharmacol., May 1, 2005; 67(5): 1581 - 1590. [Abstract] [Full Text] [PDF]
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 A. Just, A. J. M. Olson, J. R. Falck, and W. J. Arendshorst NO and NO-independent mechanisms mediate ETB receptor buffering of ET-1-induced renal vasoconstriction in the rat Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2005; 288(5): R1168 - R1177. [Abstract] [Full Text] [PDF]
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 K. Laflamme, C. J. Roberge, J. Labonte, S. Pouliot, P. D'Orleans-Juste, F. A. Auger, and L. Germain Tissue-Engineered Human Vascular Media With a Functional Endothelin System Circulation, February 1, 2005; 111(4): 459 - 464. [Abstract] [Full Text] [PDF]
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Y. Zhou, W. P. Dirksen, J. L. Zweier, and M. Periasamy Endothelin-1-induced responses in isolated mouse vessels: the expression and function of receptor types Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H573 - H578. [Abstract] [Full Text] [PDF]
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 X. Zhang, A. F. Clark, and T. Yorio Interactions of Endothelin-1 with Dexamethasone in Primary Cultured Human Trabecular Meshwork Cells Invest. Ophthalmol. Vis. Sci., December 1, 2003; 44(12): 5301 - 5308. [Abstract] [Full Text] [PDF]
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 J. D. Paasche, T. Attramadal, C. Sandberg, H. K. Johansen, and H. Attramadal Mechanisms of Endothelin Receptor Subtype-specific Targeting to Distinct Intracellular Trafficking Pathways J. Biol. Chem., August 31, 2001; 276(36): 34041 - 34050. [Abstract] [Full Text] [PDF]
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