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1 Department of Physiology, Exogenously administered endothelin (ET)
elicits both pressor and depressor responses through the
ETA and/or the
ETB receptor on vascular smooth
muscle cells and ETB on
endothelial cells. To test whether
ETB has pressor or depressor
effects under basal physiological conditions, we determined arterial
blood pressure (BP) in
ETB-deficient mice obtained by
crossing inbred mice heterozygous for targeted disruption of the
ETB
gene with mice homozygous for the piebald
(s) mutation of the
ETB gene
(ETBs/s).
F1
ETB
endothelin; hypertension; endothelin receptors; gene targeting; indomethacin
ENDOTHELINS (ETs), a family of 21-amino acid peptides
(31), are potent vasoconstrictors that have been implicated in the pathogenesis of several diseases with abnormalities in vascular tone
(10). ETs act on two subtypes of G protein-coupled heptahelical receptors named the ETA and
ETB receptors (1, 26). Vascular smooth muscle cells express ETA
and/or ETB that directly mediates vasoconstriction by ETs (27). In contrast, endothelial cells express
ETB that mediates
endothelium-dependent vasodilatation via nitric oxide and prostacyclin
formation and likely counteracts the predominating pressor effect of
pharmacological doses of ETs (4).
ETB can also act as a
"clearance" receptor for circulating ETs to help limit the plasma
level of these potentially toxic peptides (5). Consequently, the
physiological role of endogenous ETs in the regulation of vascular tone
is likely complex. Elevation of arterial blood pressure (BP) was
recently reported in mice heterozygous for targeted disruption of the
ET-1 gene
(ET-1+/ Neonatal or juvenile lethality is a significant problem for
cardiovascular research using "knockout" mice. For example, a null mutation created by the targeted disruption of the mouse ETB gene
produces a recessive phenotype of white-spotted coat and aganglionic
megacolon, the latter leading to juvenile death (11). A naturally
occurring mutant
ETB allele,
piebald (s), has a retroposon
inserted within intron 1 of the
ETB gene
(Yanagisawa, unpublished data), resulting in about one-fourth the
normal level of expression of structurally intact
ETB mRNA (11) and an approximately fourfold reduction of tissue ETB
density in homozygotes. These mice exhibit reduced coat color spotting
and rarely manifest megacolon. Using the piebald allele, we obtained
healthy adult mice with systemic
ETB deficiency. An identical
genetic background between control and experimental groups was
maintained by crossing the inbred
ETBs/s
mice on the SSL background with
ETB+/ ET and ET receptors are also expressed in the brain, where their
participation in the central control of cardiorespiratory function has
been proposed (18). For example,
ET-1+/ Three specific questions were addressed in this study.
1) Do mice deficient in
ETB have abnormal basal BP?
2) If so, can we reproduce the
abnormality by pharmacological disruption of
ETB? 3) What are the possible mechanisms
of the ETB-mediated BP alteration? To investigate the latter, we looked for changes in immunoreactive ET-1
concentration in plasma, respiratory parameters, and responsiveness to
ETA and
ETB antagonists.
Adult mice.
Inbred piebald homozygotes were purchased from the Jackson Laboratory.
ETB+/
ABSTRACT
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
/s
and
ETB+/s
progeny share an identical genetic background but have
ETB levels that are ~
and 
, respectively, of wild-type mice
(ETB+/+).
BP in
ETB/s
mice was significantly higher, by ~20 mmHg, than that in
ETB+/s
or
ETB+/+
mice. Immunoreactive ET-1 concentration in plasma as well as respiratory parameters was not different between
ETB/s
and
ETB+/s
mice. A selective ETB antagonist,
BQ-788, increased BP in
ETB+/s
and
ETB+/+
but not in
ETB/s
mice. Pretreatment with indomethacin, but not with
NG-monomethyl-L-arginine, can
attenuate the observed pressor response to BQ-788. The selective
ETA antagonist BQ-123 did not
ameliorate the increased BP in
ETB/s
mice. Moreover, BP in mice heterozygous for targeted disruption of the
ETA gene was not
different from that in wild-type controls. These results suggest that
endogenous ET elicits a depressor effect through
ETB under basal conditions, in
part through tonic production of prostaglandins, and not through
secondary mechanisms involving respiratory control or clearance of
circulating ET.
INTRODUCTION
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
)
(16). This observation suggests that ET-1 may act as a depressor rather
than a pressor agent in normal states, although the exact mechanism is unknown.
mice on an inbred 129/SvEv background. Using this strategy, we were
able to examine the role(s) of ETB
in the regulation of BP in adult animals.
,
ET-1/
(17), and
ETA/
mice (3) have impaired ventilatory responses to hypoxia and hypercapnia. Altered interaction between the cardiovascular and respiratory centers in the central nervous system may explain some of
the hypertension in
ET-1+/
mice (16, 17, 19). Therefore, we also investigated whether hypertensive
ETB-deficient mice have
ventilatory abnormalities.
MATERIALS AND METHODS
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
mice on an inbred 129/SvEv background were obtained as previously described (11). By crossing inbred (SSL)
ETBs/s
homozygotes with
ETB+/
mice (Fig.
1A),
we obtained F1
ETB/s
and
ETB+/s
mice genetically identical except for the
ETB gene, with a
systemic expression dosage of ~ and of wild-type
mice, respectively. They were easily identified by the coat color (11):
ETB/s
mice exhibit white spotting over 40-50% of body surface area, whereas all
ETB+/s
mice have a homogeneous agouti coat. A small number of
ETB/s
mice (7 of 37) manifested megacolon; data obtained from these animals
were excluded. Inbred 129/SvEv wild-type
(ETB+/+)
mice were used as controls.
View larger version (39K):
[in a new window]
Fig. 1.
Genetic strategy to obtain endothelin (ET) receptor-B
(ETB)-deficient mice and
comparison of blood pressure (BP), heart rate (HR), and plasma ET-1
concentration. A: crossing inbred
ETBs/s
mice on the SSL background with
ETB+/
mice on an inbred 129/SvEv background resulted in
ETB/s
and
ETB+/s
F1 mice that have an identical
genetic background except for
ETB gene. They
can easily be identified by coat color. BP
(B) and
(C) HR measured and averaged over 2 h while mice were under conscious and unrestrained condition.
D: plasma concentration of ET-1
determined by enzyme immunoassay. ns, Not significant. Data are means ± SE.
mice on an inbred 129/SvEv background (3). Only
ETA+/
mice and their wild-type littermates are useful for physiological studies, because
ETA/
mice die soon after birth. There is no known hypomorphic allele of the
ETA gene.
Genotype of these animals was determined by PCR on DNA extracted
from a tail cut biopsy (3).
All experiments were performed in male mice to avoid possible
differences related to menstrual cycling in females. All animal procedures conformed to the Guiding Principles for the Care and Use of
Animals in the Field of Physiological Sciences recommended by the
Physiological Society of Japan.
Newborn mice.
Although BP measurement in newborn mice is difficult at present, we
developed a reliable method to measure ventilation in newborn mice
(17). Using this method (see below), we measured ventilation in inbred
ETB/
mice of both sexes obtained by crossing inbred
ETB+/
mice (11). They are easily identified by coat color 2-3 days after
birth in a manner similar to that in
ETB/s
mice. Three- to five-dayold
ETB/
pups with a mean body weight of 2.08 ± 0.10 g
(n = 10, mean ± SE) were
used. At this age,
ETB/
pups did not show any signs of megacolon. They all survived at least 6 days after the experiments.
Measurement of BP, plasma concentration of immunoreactive ET-1,
arterial blood gas, and pH.
Four series of experiments were performed using different sets of the
animals. First, baseline BP was determined in experimental groups of
mice and their controls: 17- to 28-wk-old
ETB/s
(n = 9), 17- to 28-wk-old
ETB+/s
(n = 9), 17- to 28-wk-old
ETB+/+
(n = 7), 34- to 44-wk-old
ETA+/
heterozygotes (n = 8), and 34- to
44-wk-old wild-type mice (n = 7).
Arterial BP was measured by cannulation of the femoral artery with
polyethylene tubing under halothane anesthesia. The following day,
pulsatile BP was measured continuously for 2 h under conscious and
unrestrained conditions in a quiet environment after at least 30 min of
acclimatization (16). Heart rate (HR) was calculated by a tachometer
monitoring BP signals. After completion of the BP measurements,
arterial blood was collected from the femoral catheter. An aliquot
(40-50 µl) of blood was used for arterial blood gas measurement
(17), and plasma from the remainder was prepared for other studies.
Plasma concentration of immunoreactive ET-1 was determined by a highly
specific ET-1 enzyme immunoassay (28). BP determination in
ETA+/
mice and their controls was performed in a blinded manner.
/s,
and five
ETB+/s
male mice were cannulated, under halothane anesthesia, with
polyethylene tubing into the right femoral and left carotid arteries
for measurement of BP and injection of agents, respectively. The
carotid cannula was advanced so that the tip lay near the aortic arch.
The following day, pulsatile BP was measured while mice were under
conscious and unrestrained conditions, in the manner described above.
BQ-788, a highly selective ETB
antagonist (14), was administered at a constant volume of 0.5 µl/g
body wt to deliver doses of 0, 0.1, 0.3, 1, and 3 mg/kg. Possible
volume effect from repeated injections in individual animals was
negligible because repeated administration of vehicle five times did
not affect BP in preliminary experiments. BQ-788 stock solution (6 mg/ml) was dissolved in 0.6%
Na2CO3, and subsequent dilutions were made with saline. BQ-123, a selective ETA antagonist (13), was dissolved
in saline and injected intra-arterially as a single dose in another
group of four
ETB/s
mice. The dose of BQ-123 (1 mg/kg) was selected so that it could completely inhibit the pressor response induced by a subsequent injection of 1 nmol/kg of ET-1 (13).
In the next group of experiments, the effects of intra-arterial
injections of BQ-788 on BP were studied in six wild-type mice under
ketamine (100 mg/kg ip) and xylazine (0.5 mg/kg ip) anesthesia to
exclude secondary influences such as emotional stress from higher brain
centers (9). Rectal temperature was monitored by a thermistor and
maintained between 36 and 37°C (ATB-1100; Nihon Kohden, Tokyo, Japan).
Finally, pretreatment with indomethacin (0, 14, and 28 µmol/kg ia;
n = 5, 6, and 5, respectively), an
inhibitor of prostaglandin production, or
NG-monomethyl-L-arginine
(L-NMMA; 250 µmol/kg ip,
n = 5), an inhibitor of nitric oxide
synthase, on the pressor response to acute
ETB blockade was examined in
wild-type mice. After recovery from the transient pressor response to
the injection of each drug, BQ-788 was administered in the manner
described above. Indomethacin was dissolved in 95% ethanol, and
L-NMMA was dissolved in saline. Doses of indomethacin and L-NMMA
were chosen according to doses reported in previous investigations (4,
16).
Measurement of ventilation.
Ventilation in adult (17- to 28-wk old)
ETB/s
and
ETB+/s
mice and newborn (3- to 5-day old)
ETB/
and
ETB+/+
mice was measured according to the method described previously (3, 17,
24). In brief, respiratory cycle time and tidal volume
were determined for every breath by whole body plethysmography, with
respiratory frequency and minute volume calculated over a 1- to 2-min
measurement period. In each animal, measurement was repeated four times
in each experimental gas condition: room air (control for hypoxia),
hypoxic (1:1 room air-N2) gas
mixtures, 100% O2 (control for
hypercapnia), and hypercapnic (5%
CO2-95% O2) gas mixture. Changes in
respiratory frequency and minute volume in response to hypoxia and
hypercapnia were calculated. Special attention was paid to maintaining
a constant body temperature in studies with newborn mice (3, 17, 24).
Statistical analysis. According to the data structure, statistical analysis of the results was carried out with either the Student's t-test (paired and unpaired) or Dunnett's test for multiple comparison. Statistical analysis was performed with a statistics package program (SuperANOVA; Abacus Concepts, Berkeley, CA). Differences were considered to be significant at P < 0.05. Results are expressed as means ± SE.
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RESULTS |
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BP, HR, arterial blood gas and pH, and plasma concentration of
immunoreactive ET-1.
We measured BP of the
ETB-deficient and control animals
under conscious and unrestrained conditions via an indwelling femoral artery catheter. Systolic, mean, and diastolic pressures were 142 ± 3, 127 ± 3, and 110 ± 5 mmHg, respectively, in
ETB/s
mice and 127 ± 4, 109 ± 4, and 89 ± 5 mmHg, respectively,
in ETB+/s
mice. BPs in
ETB/s
mice were significantly higher than those in
ETB+/s
mice (Fig. 1B,
P < 0.01), but no significant
difference was found between
ETB+/s
and
ETB+/+
mice. HR was not different among
ETB/s,
ETB+/s,
and
ETB+/+
mice (Fig. 1C). Plasma concentration
of immunoreactive ET-1 was not different between
ETB/s
and
ETB+/s
mice (Fig. 1D).
mice and wild-type littermates. Systolic, mean, and diastolic pressures
were 130 ± 5, 116 ± 5, and 102 ± 5 mmHg in
ETA+/
mice and 125 ± 4, 110 ± 4, and 95 ± 5 mmHg in age-matched
wild-type mice, with mean HR of 653 ± 23 and 664 ± 21 beats/min, respectively. In addition, plasma concentration
of immunoreactive ET-1 was not different between
ETA+/
mice (11.1 ± 2.0 pg/ml) and wild-type littermates (10.2 ± 0.9 pg/ml).
There was no difference in arterial
PO2,
PCO2, or pH between
ETB/s
and
ETB+/s
mice or between
ETA+/
mice and wild-type littermates (Table 1).
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Effect of intra-arterial injections of BQ-788 or BQ-123 in conscious
mice.
The initial results with
ETB-deficient mice suggested that
ET may function as a depressive factor through the activation of ETB under basal conditions in
mice. To corroborate the genetic findings with pharmacological
perturbation of the ETB, we
investigated whether acute blockade of
ETB with the
ETB-specific antagonist BQ-788
affects baseline BP. An intra-arterial bolus injection of BQ-788
increased BP in a dose-dependent manner (Fig.
2, A and B) in
ETB+/s
and wild-type mice. The increase in BP was observed immediately after
administration and lasted several minutes depending on the dose of
BQ-788. A small delayed decrease in HR was also observed, presumably
due to an intact baroreceptor reflex (Fig.
2A). Although ETB+/s
and
ETB+/+
mice had almost identical pressor responses to BQ-788 injection, BP in
ETB/s
mice showed little change (Fig. 2, A
and B). The attenuated response to
BQ-788 in
ETB/s
mice is not likely due to their increased basal BP, because
pretreatment of wild-type mice with
L-NMMA, which raises BP ~20
mmHg above baseline, did not affect their pressor response to BQ-788
(Fig. 3). These results indicate that
BQ-788 increases BP through acute blockade of
ETB-mediated signaling in mice. In
contrast, BP in ETB/s
mice is not affected (change in BP = 
2 ± 2 mmHg,
n = 4) by intra-arterial injection of
the ETA-specific antagonist
BQ-123, indicating that the elevation of basal BP in
ETB/s
mice is unlikely to be due to stimulation of pressor
ETA.
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Effect of intra-arterial injections of BQ-788 in anesthetized mice. A similar dose-dependent pressor effect was seen in mice anesthetized with ketamine and xylazine, indicating that the effect of BQ-788 was probably not due to antagonism of ETB in the central nervous system (Fig. 2C).
Effect of pretreatment with indomethacin or L-NMMA on pressor response to acute ETB blockade. Activation of endothelial ETB is known to induce the production of the depressor agents prostacyclin and nitric oxide (4). We found that pretreatment with indomethacin dose-dependently and significantly attenuates the pressor response to acute ETB blockade with BQ-788 in wild-type mice (Fig. 3). In contrast, L-NMMA increases basal BP by ~20 mmHg for >30 min, yet has no effect on the response to BQ-788 (Fig. 3). These findings suggest that the increase in BP in response to BQ-788 in wild-type mice may be mediated, at least in part, by inhibition of tonic prostaglandin (probably prostacyclin) production.
Ventilation.
Abnormal central cardiorespiratory control is speculated to be one of
the mechanisms of hypertension in ET-1-deficient mice (16, 17, 19). To
determine whether a similar mechanism might contribute to the
hypertension in ETB-deficient
mice, we examined basal ventilation and changes in response to hypoxia
and hypercapnia using whole body plethysmography. No difference in any
studied ventilatory parameters between
ETB/s
and
ETB+/s
adult mice was observed under basal or stimulated conditions (Table
2). Residual
ETB in
ETB/s
mice is unlikely to have influenced this study because no abnormality was detected in ETB-null newborn
mice (Table 2).
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ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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The present study, using
ETB-deficient mice that are
healthy into adulthood, suggests that
ETB not only counteracts the
potent pressor effect of elevated levels of ETs in pharmacological (and possibly pathophysiological) settings (10), but also maintains BP at a
relatively lower level when circulating ETs are within the normal
range. We hypothesize that endogenous ET-1 acts as a peripheral
depressor agent at least in part through activation of the endothelial
ETB. Alternatively, mice deficient
in ETB might have abnormal central
cardiorespiratory control, with impaired chemoreceptor reflexes and
abnormally high sympathetic outflow like that seen in ET-1-deficient
mice (15, 17-19). However, this seems unlikely, because arterial
blood pH, PCO2,
PO2 (Table 1), ventilatory frequency
and volume, and the magnitude of the ventilatory response to hypoxia
and hypercapnia are not different between
ETB/s
and
ETB+/s
mice (Table 2). In our preliminary experiments, power spectral analysis
of fluctuations in the R-R intervals recorded by electrocardiogram (15)
revealed that cardiac sympathetic and vagal activities were not
different between
ETB/s
and
ETB+/s
mice. Therefore, the mechanism(s) of the hypertension in
ETB-deficient mice and that in
ET-1 deficient mice (16, 17, 19) appear to be different.
It is also possible that the elevated BP in
ETB/s
mice might be a result of developmental rather than homeostatic
effects, in light of the fact that null mutations of
ET-1 (16),
ET-3 (2),
ETA (3),
ECE-1 (30), or
ETB genes (11)
result in congenital malformations. However, our pharmacological data
demonstrating an elevation of BP in
ETB+/s
mice elicited by the acute administration of an
ETB antagonist to levels
comparable to those in
ETB/s
mice strongly suggest that the elevated BP in
ETB/s
mice reflects a disruption of homeostatic function of the
ETB. Genetic evidence presented in
this study is further supported by preliminary experiments using
ETB/
mice that are rescued from the lethal megacolon phenotype by a
tissue-specific transgene that expresses
ETB in enteric neurons (23). These
mice, which are healthy into adulthood, lack vascular ETB and exhibit hypertension of
similar magnitudes (
20 mmHg) to that seen in
ETB/s
mice. These results also support the view that the endothelial ETB plays an essential depressor
role to maintain BP in the normal range. Recently, Giller et al. (8)
reported hypertension in piebald-lethal
(sl) mice,
another naturally occurring mutant with
ETB deletion; however, this
observation might be the result of circulatory distress in the
intestine associated with megacolon.
It has been suggested that ETB is
possibly a clearance receptor for circulating ETs (5). Our study found
that plasma concentrations of immunoreactive ET-1 in
ETB/s
and
ETB+/s
mice (both ~17 pg/ml) are significantly higher than those in ETA+/
mice and wild-type mice (~11 pg/ml). The elevated BP in
ETB/s
mice may be a consequence of reduced clearance of circulating ETs, with
increased levels of ETs available at
ETA and subsequent vasoconstriction. However, this possibility seems unlikely for the
following four reasons. First, the apparent discrepancy in plasma
concentrations of immunoreactive ET-1 may only reflect the difference
in genetic background. Specifically,
ETB/s
and
ETB+/s
are F1 of
ETBs/s
and
ETB+/
mice, whereas
ETA+/
and wild-type mice have a pure 129/SvEv background. Moreover, the rank
order of BP
(ETB/s > ETB+/s ETB+/+)
cannot be explained by the plasma concentrations of immunoreactive ET-1
(ETB/s ETB+/s > ETB+/+).
Furthermore, there is no significant correlation between BP and the
ET-1 levels in plasma collected immediately after the BP measurement
(data not shown). Second, BP in
ETB/s
mice is not affected by intra-arterial injection of BQ-123, a selective
ETA antagonist (13). Third, the
fact that BP is indistinguishable between
ETA+/
mice and wild-type littermates suggests that a small change in the
ratio of ETA to ET-1 may be
readily compensated by other vasoregulatory mechanisms. Finally, it is
difficult to explain the short duration of the pressor response to
BQ-788 in the present study by the clearance hypothesis, because ET-1
characteristically evokes a long-lasting vasoconstriction that is
extremely resistant to washout (31). Therefore, the role of
ETB as a clearance receptor, if any, is unlikely to account for the observed elevation of BP in ETB/s mice.
Pharmacological studies suggest that under physiological conditions, endogenous ETs stimulate a sustained release of ETB-mediated dilator substance(s) produced by vascular endothelial cells, one of which is prostacyclin. Although BQ-788 antagonizes the effect of subsequent administration of an exogenous ETB agonist, some papers (14), although not all (22), report that it has no detectable effect on basal BP. This inconsistency may result from route of administration, choice of anesthetic, and/or species-specific differences. Our preliminary experiments using intravenous administration of BQ-788 resulted in much smaller pressor responses than when it was delivered intra-arterially. Because the ETB is abundantly expressed in the lung (5), it is possible that a large fraction of intravenously administered BQ-788 is sequestered in the lung and not delivered to the systemic circulation. Recently, Verhaar et al. (29) reported that ETB antagonism by BQ-788 causes local vasoconstriction in human forearm blood vessels. Thus, in both humans and mice, vascular ETB appears to tonically mediate vasodilation.
The importance of prostaglandins in systemic BP regulation has been controversial (7, 20); however, this study supports a potential role. It is unclear which product of cyclooxygenase is responsible for the present observation, because indomethacin is not a specific inhibitor for prostacyclin synthesis. Recently, normotension in prostacyclin receptor-deficient mice was reported (21). This observation does not necessarily contradict the possible involvement of prostacyclin in physiological BP regulation, because compensatory mechanisms such as an increase in nitric oxide cannot be excluded in these mutant mice. Lack of an inhibition by pretreatment with L-NMMA, on the other hand, is not likely to be secondary to insufficient dosing of the drug, because the pressor effect of L-NMMA lasts for >30 min and encompasses all of the resting experimental period with BQ-788. Nevertheless, the residual pressor response to BQ-788 after pretreatment with indomethacin remains to be explained.
Perspectives
Although the pharmacological experiments in this study strongly suggest that deficiency of vascular ETB is the cause of hypertension in ETB/s
mice, we do not exclude the possibility that deficiency of renal ETB also contributes to the
elevation of BP. ETB is richly
distributed in glomerular endothelial cells and vasa recta bundles as
well as tubular epithelial cells in the kidney, and it is proposed to
be involved in water and sodium metabolism (10). We are currently investigating this possibility using transgenically "rescued" ETB/
mice that do not develop megacolon. In this model, the dopamine 
-hydroxylase gene promoter transgenically directs expression of
ETB in enteric neuroblasts during
embryonic development (6, 23). These animals completely lack
ETB in vascular endothelium and
kidney. However, the possibility of ectopic and/or exaggerated expression of the ETB in adrenal
medulla or other catecholamine-synthesizing cells cannot be excluded at
present. We hope that after the complete biochemical and physiological
characterization of cardiovascular and renal function in these
transgenic animals, combined with this present report, we will be able
to come to a conclusion on the roles of vascular and renal
ETB in BP regulation.
Development of clinically useful ET receptor antagonists is expected to be beneficial in treating certain cardiovascular conditions accompanied by an elevation in ET levels, such as congestive heart failure and essential hypertension (12, 25). These endeavors are consistent with the original view of ET as a potent vasoconstriction factor (31). The present results indicate that ET may also play a role as a vasodilator in physiological states. Thus we must carefully consider the potential multifaceted effects of ETB antagonism in the treatment of these disorders.
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ACKNOWLEDGEMENTS |
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Part of this work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Culture and Sports, Japan, from the Tokyo Hypertension Conference; a Grant for Research on Sympathetic Nervous System and Hypertension; and grants from the Perot Family Foundation and W. M. Keck Foundation.
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FOOTNOTES |
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M. Yanagisawa is an Investigator of the Howard Hughes Medical Institute.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: T. Kuwaki, Dept. of Physiology, School of Medicine, Chiba Univ., Inohana 1-8-1, Chuo-ku, Chiba City 260-8670, Japan (E-mail: kuwaki{at}med.m.chiba-u.ac.jp).
Received 25 June 1998; accepted in final form 14 January 1999.
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REFERENCES |
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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and f and their changes in response to
hypoxia and hypercapnia between
ETB