| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Department of Pediatrics and 2 Cardiovascular Research Institute, University of California, San Francisco, California 94143-0544
 |
ABSTRACT |
|---|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
Endothelin-1
(ET-1) is synthesized within the wall of the ductus arteriosus (DA) and
is a potent constrictor of the DA in vitro. However, the role of
endogenous ET-1 in closure of the DA at birth remains unclear.
Therefore, we studied the effects of a selective
ETA-receptor antagonist
(PD-156707), or its vehicle, on DA closure in 13 late-gestation fetal
lambs during the first 5 h after birth. We also studied the effects of
ETA-receptor blockade on DA
constriction induced by oxygen, indomethacin (a cyclooxygenase inhibitor), and LY-83583 (a soluble guanylate cyclase inhibitor) in
vitro (n = 9 ductus arteriosus rings).
In vehicle-treated lambs in vivo, the DA constricted during the 5-h
study period after birth: DA resistance increased (from 0.007 ± 0.01 to 3.406 ± 4.15 mmHg · ml
1 · min · kg1;
P < 0.05); the pressure gradient
across the DA increased (from 1.4 ± 2.1 to 25.2 ± 9.4 mmHg;
P < 0.05); and DA blood flow
decreased (from 193.5 ± 48.0 to 19.3 ± 14.3 ml · kg1 · min1;
P < 0.05). In vitro, the DA was
constricted by exposure to 30% oxygen (23 ± 14% net active
tension; P < 0.05), indomethacin (5 × 106 M, 22 ± 5%
net active tension; P < 0.05),
LY-83583 (105 M, 24 ± 10% net active tension; P < 0.05),
and ET-1 (107 M, 19 ± 4% net active tension; P < 0.05).
Although PD-156707 blocked both the in vivo and in vitro effects of
exogenous ET-1, it had no effect on postnatal ductus constriction nor
on in vitro ductus contractile responses to oxygen, indomethacin, or
LY-83583. This study suggests that endogenous ET-1 does not play an
important role in closure of the DA at birth.
endothelin receptors; oxygen; prostaglandins
| |
INTRODUCTION |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
THE DUCTUS ARTERIOSUS represents a persistence of the terminal portion of the sixth branchial arch that serves to divert blood away from the lungs toward the descending aorta and placenta during fetal life. At birth, rapid constriction of the ductus separates the right and left sides of the fetal heart and establishes the postnatal pattern of circulation. This rapid constriction is induced by the rise in blood oxygen tension at birth (5, 19). However, the biochemical basis for this oxygen response remains unknown.
Coceani and co-workers (9-12) hypothesized that oxygen-induced ductus constriction depends on the synthesis and release of endothelin-1 (ET-1). ET-1 is a 21-amino acid polypeptide produced by vascular endothelial cells that has potent vasoactive properties (28). Its vasoactive effects are complex and depend on a variety of factors including age, dose, vascular bed, and resting tone. They are mediated by at least two different receptors, ETA and ETB. ETA receptors and a subpopulation of ETB receptors mediate vasoconstriction and are located on vascular smooth muscle cells (1, 25). A second subpopulation of ETB receptors mediate vasodilation and are located on vascular endothelial cells (26). An increasing amount of data suggests that ET-1 is an important mediator of normal vascular tone in many regional circulations, such as the cerebral, renal, and pulmonary circulations, and that aberrations in the ET-1 cascade participate in several pathophysiological disorders (20).
Coceani et al. (9) reported that exogenous ET-1 produces dose-dependent constriction of the ductus arteriosus in vitro; this occurs whether or not an intact endothelium is present. They also found that oxygen stimulates ET-1 release by the ductus arteriosus and that an ETA-receptor antagonist inhibits oxygen-induced contraction of the ductus arteriosus. These in vitro observations suggest an essential role for ET-1 in the closure of the ductus arteriosus after birth (10, 12). However, in vivo, when ET-1 or ET-1-receptor antagonists are administered to the fetus they do not appear to affect the tone of the ductus arteriosus (2, 18). Although these in vivo studies do not support a role for ET-1 in ductus regulation in the low-oxygen environment of the fetus, they do not address its possible role in oxygen-induced ductus closure after birth.
In the present investigation, we used 13 late-gestation fetal lambs that were infused with a selective ETA-receptor antagonist (PD-156707) to study the role of endogenous ET-1 on ductus closure during the first 5 h after birth. In addition, we used nine fetal lambs to examine the effects of ETA-receptor blockade on oxygen-induced ductus arteriosus constriction in vitro. Our findings do not support a role for ET-1 in the initial constriction of the ductus arteriosus after birth.
| |
METHODS |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
In Vivo Studies
Surgical preparation.
Thirteen mixed-breed Western ewes (133.4 ± 0.8 days of gestation,
term = 145 days) were operated on under sterile conditions with the use
of local (2% lidocaine hydrochloride) and intravenous (0.001 mg · kg1 · min1 diazepam and 0.24 mg · kg1 · min1
ketamine hydrochloride) anesthesia. Fetal anesthesia consisted of local
anesthesia with 2% lidocaine hydrochloride and ketamine hydrochloride
(20 mg/kg im). Through a uterine incision, the fetal forelimb was
exposed. Polyvinyl catheters were inserted into the fetal pedal artery
and vein and were advanced to the aorta and the superior vena cava,
respectively. A left lateral thoracotomy was performed in the fourth
intercostal space. Polyvinyl catheters were inserted into the internal
thoracic artery and vein. The pericardium was incised along the main
pulmonary trunk. A Teflon cannula attached to a polyvinyl catheter was
inserted into the proximal main pulmonary trunk. Ultrasonic flow
transducers (Transonic Systems, Ithaca, NY) were placed around the left
pulmonary artery (no. 4 or 6) and ductus arteriosus (no. 6 or 8). The
thoracotomy incision was closed in layers. Warm saline was instilled to
replace the lost amniotic fluid, and the uterine incision was closed. A
polyvinyl catheter was placed in the amniotic cavity. The catheters were filled with heparin sodium, plugged, and brought to the skin along
with the transducer cables, where they were protected in a pouch
secured to the ewe's flank. After recovery from anesthesia, the ewe
was returned to the cage. Antibiotics (2 × 106 U penicillin G procaine and
100 mg gentamicin sulfate) were administered intravenously to the ewe
and into the amniotic cavity during surgery and daily thereafter. All
protocols were approved by the Committee on Animal Research of the
University of California, San Francisco.
Measurements.
Arterial and venous pressures were measured by Statham P23 Db pressure
transducers (Statham Instruments, Hato Rey, PR). Mean pressures were
obtained by electrical integration. All pressures obtained in utero
were zeroed against the amniotic cavity pressure. Left pulmonary and
ductus arteriosus blood flows were measured on an ultrasonic flowmeter
(Transonic Systems). All hemodynamic variables were continuously
recorded on a Gould multichannel electrostatic recorder (Gould,
Cleveland, OH). Systemic arterial blood gases and pH were measured on a
Corning 158 pH/blood gas analyzer (Corning Medical and Scientific,
Medfield, MA). Ductus arteriosus resistance was calculated as (mean
pulmonary arterial pressure 
mean systemic arterial
pressure)/ductus arteriosus blood flow per kilogram. The fetal weight
before the infusions began was estimated using standardized fetal sheep
growth charts established in our laboratory.
Experimental protocol.
After a 48-h recovery period, an intravenous infusion of PD-156707 (10 mg/kg bolus over 10 min followed by an infusion of 10 mg · kg1 · h1)
or its vehicle (sterile water) was begun in the fetus; the infusion was
begun 60 min before the ventilation study began and continued throughout the study period. Preliminary pharmacokinetic studies found
that this infusion rate produced plasma concentrations of 5.4 µg/ml
(105 M) of PD-156707.
PD-156707 concentrations in this range are five times greater than
those needed to block ETA
receptors in vivo (17). In addition, our preliminary studies also
showed that the vasoconstricting response of exogenous ET-1 (250 ng/kg)
was blocked by this infusion rate. Before the ventilation study began, the pregnant ewe was given epidural anesthesia (4 ml of 1% tetracaine hydrochloride) and intravenous sedation (100 mg ketamine
hydrochloride). The fetus was then exposed through a midline uterine
incision and given ketamine hydrochloride (30 mg/kg im) and pancuronium bromide (0.3 mg/kg iv). The fetal trachea was intubated through a
tracheostomy with a 4.5-mm-OD endotracheal tube, and Infasurf (3 ml/kg;
Ony, Amherst, NY) was instilled into the airway to preclude the
possibility of surfactant deficiency. The fetal lamb was then mechanically ventilated with a time-cycled pressure-limited ventilator (Sechrist, Anaheim, CA) while still connected to the placenta. The
ventilator settings were: peak inspiratory pressure 28 cmH2O, positive end-expiratory
pressure 5 cmH2O, inspiratory time
0.4 s, respiratory rate 50 breaths/min, and fractional inspired
O2 concentration = 1.0. Peak
inspiratory pressures and ventilatory rates were reduced to maintain an
arterial PCO2 between 30 and 35 Torr;
other ventilator settings remained constant. The beginning of
mechanical ventilation was considered the time of delivery (0 h). After 30 min of ventilation, the umbilical cord was clamped,
the lamb was delivered through the hysterotomy into a 37-38°C
water bath, and mechanical ventilation was continued. The initial
30-min period of ventilation, with the lamb still attached to the
placenta, was used to ensure adequate lung expansion without the need
for high inspiratory pressures.
In Vitro Studies
Nine fetal lambs (130.4 ± 4.7 days gestation) were delivered by cesarean section. The ewe was anesthetized with a constant intravenous infusion of ketamine HCl and diazepam throughout the procedure. The fetus was given ketamine HCl (30 mg/kg im) before rapid exsanguination. These procedures were approved by the Committee on Animal Research at the University of California, San Francisco. The ductus arteriosus was dissected free of loose adventitial tissue and divided into 1-mm-thick rings (50 ± 17 mg) that were placed in separate 10-ml organ baths and kept in a dark room, as described previously (7). Throughout the experiment, the rings were suspended between two stainless steel hooks at 38°C in a modified Krebs solution [(in mM): 118 NaCl, 4.7 KCl, 2.5 CaCl2, 0.9 MgSO4, 1 KH2PO4, 11.1 glucose, and 23 NaHCO3] equilibrated with 5% CO2 (pH 7.4), balance either 95% N2 or 30% O2-65% N2. The bath solution was changed every 20 min. Isometric responses of circumferential tension were measured by Grass FT03C force transducers (Quincy, MA). Each of the rings was stretched to an initial length, which results in a maximal contractile response to increases in oxygen tension. Initially the rings were stretched during a 30-min interval in medium equilibrated with low fetal PO2 20-34 mmHg, 0.15-0.26 kPa (starting tension). During this period PD-156707 (105 M;
n = 7) or its vehicle (sterile water;
n = 7) was added to the bath solution.
After 30 min of gas bubbling the bath solution was changed to 30%
O2-65%
N2-5%
CO2
(PO2 175-200 mmHg, 1.31-1.50 kPa), and the tension was allowed to reach a new plateau (~90-120 min). Indomethacin (5.6 × 106 M, an inhibitor of
prostaglandin production) then was added to the bath solution, and the
rings were allowed to reach a new steady-state tension over the next
60-90 min. We previously showed (6, 7) that this concentration of
indomethacin maximally inhibits prostaglandin E2 and
I2 production in the ductus. After
indomethacin, 6-anilino-5,8-quinolinedione (LY-83583, an inhibitor of
soluble guanylate cyclase,
105 M) and ET-1
(108 and
107 M) were added to the
bath solution. These concentrations of ET-1 were chosen because they
produce 15 and 80%, respectively, of the maximal contractile response
of the ductus to ET-1 (data not shown). In all experiments, we allowed
the tension in the rings to reach a new steady-state plateau after a
drug addition before another experimental agent was added to the bath.
After the addition of all contractile drugs, potassium Krebs solution
(containing 100 mM KCl substituted for an equimolar amount of NaCl) was
used to measure the maximal amount of tension that could be developed by the ductus (maximal contraction). The maximal relaxation of each
ductus ring was then determined by the response to sodium nitroprusside
(SNP; 103 M).
The difference in tensions between the maximal contraction and the maximal relaxation was considered the net active tension developed by the ring. Changes in tension for each experimental condition were expressed as a percentage of net active tension. The net active tension was always greater than the difference in tension between the maximal contraction and the starting tension by 12 ± 15% (P < 0.05, n = 9 rings). This indicates that the ductus rings were actively contracting even at the time of their initial mounting in the organ bath. After the experiment the rings were removed from the baths and blotted dry, and their wet weights were determined.
Drug preparation.
PD-156707 and PD-14505 were synthesized by the Medicinal Chemistry
Department of Parke-Davis Pharmaceutical Research (Ann Arbor, MI). ET-1
(Sigma, St. Louis, MO) was resuspended in 10 ml of sterile water and
stored at 20°C. Immediately before
administration, each dose of ET-1 was measured and diluted to 1 ml with 0.9% saline.
2 M) and LY-83583 (2 × 102 M) were
prepared in ethanol. The final concentration of ethanol in the organ
bath did not affect tissue contractility. All other compounds were
dissolved directly in Krebs solution.
Statistical Analysis
In vivo studies. Hemodynamic variables, arterial blood gases, and pH were compared over time within each study group by ANOVA for repeated measures. Comparisons of these variables between study groups were made by the unpaired t-test. Comparisons of ductus arteriosus resistance were made by the Mann-Whitney U-test. Values are expressed as means ± SD. P < 0.05 was considered significant.
In vitro studies. Statistical analysis was performed by the paired Student's t-test. When more than one comparison was made, Bonferroni correction was used. Values are expressed as means ± SD. Drug doses refer to final molar concentration in the bath.
| |
RESULTS |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
In Vivo Studies
The baseline fetal hemodynamic variables and systemic arterial blood gases and pH were similar between the two groups and within the normal range for the laboratory. There were no differences in birth weight [PD-156707: 3.59 ± 0.7 kg (n = 6) vs. vehicle: 4.17 ± 0.7 kg (n = 7)], sex distribution, amount of sodium bicarbonate, saline, or 5% dextrose administered, or mean airway pressure used during the study. PD-156707 infusion had no effect on fetal hemodynamics or blood gas and pH variables (data not shown).In the vehicle-treated lambs, ductus arteriosus resistance rapidly increased and ductus arteriosus blood flow rapidly decreased after ventilation was initiated (P < 0.05). Mean pulmonary arterial pressure decreased, whereas left pulmonary blood flow and arterial PO2 (PaO2) increased (P < 0.05; Table 1).
|
Similarly, in PD-156707-treated lambs, ductus arteriosus resistance, left pulmonary blood flow, and PaO2 increased, whereas ductus arteriosus blood flow and mean pulmonary arterial pressure decreased after birth (P < 0.05; Table 2). There were no differences in ductus arteriosus resistance or the mean pulmonary-to-systemic arterial pressure gradient between the two groups throughout the 5-h study period (Fig. 1). Ductus arteriosus blood flow was lower in the PD-156707-treated lambs at 2, 3, and 4 h after birth (P < 0.05; Fig. 1B). At autopsy, the ductus was constricted in all lambs [narrowest diameter: PD-156707, 0.8 ± 0.5 mm (n = 6); control = 1.1 ± 0.9 mm, (n = 7)].
|
|
In Vitro Studies
The presence of 30% oxygen (PO2 175-200 mmHg, 1.31-1.50 kPa) caused the vehicle-treated ductus arteriosus rings to contract to a tension that was 23 ± 14% of the net active tension (Fig. 2). Previously, we (8) and Coceani et al. (9) showed that this contraction is independent of the presence of a luminal endothelium. Indomethacin (22 ± 5% net active tension) and LY-83583 (24 ± 10% net active tension) caused additional increases in tension. When ET-1 was added to the oxygen plus indomethacin plus LY-83583-contracted ductus rings, there were additional increases in tension (108 M ET-1, 4.0 ± 4%;
107 M ET-1, 19 ± 4%
net active tension). The responses of the ductus arteriosus to 30%
oxygen, indomethacin, and LY-83583 were similar in rings pretreated
with PD-156707 (105 M) both
in magnitude and time course. However, the constricting response to
ET-1 was completely blocked in PD-156707-treated rings (Fig. 2).
|
| |
DISCUSSION |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
Relative patency of the ductus arteriosus is regulated by both dilating and contracting factors. Extensive in vivo and in vitro data suggest that oxygen is the primary stimulus for the initial constriction of the ductus arteriosus after birth (reviewed in Ref. 5). However, exposure of the ductus arteriosus to oxygen is associated not only with vasoconstriction but also with the release of vasodilators like prostaglandin E2, nitric oxide, and cGMP (4, 7, 8, 12, 15).
Recent in vitro studies by Coceani and co-workers (9-11) implicate a role for ET-1 in oxygen-induced constriction of the ductus arteriosus. Exogenous ET-1 produces dose-dependent constriction of isolated ductus arteriosus rings, and endogenous ET-1 is released from the ductus arteriosus with oxygen exposure (9-11). In addition, both the synthesis of ET-1 and its contractile response in the ductus appear to be dependent on a cytochrome P-450 pathway that has been implicated in oxygen-mediated ductus constriction (10, 11, 13). Finally, both phosphoramidon, which blocks the conversion of proendothelin-1 into its functional form, and BQ-123, which selectively blocks the ETA receptor, attenuate oxygen-induced ductus constriction in vitro (11).
The predominant vasoconstricting effects of ET-1 are mediated by
ETA receptors, which are located
on vascular smooth muscle cells. Therefore, to investigate the role of
endogenous ET-1 on ductus closure in vivo, we studied the effects of an
ETA-receptor antagonist,
PD-156707, on ductus closure during the first 5 h after birth. This was
assessed by ductus arteriosus blood flow, the pressure gradient
generated across the ductus arteriosus, the calculated ductus
resistance, and postmortem lumen measurements. PD-156707 is highly
selective for the ETA receptor and
inhibits the binding of
[125I]-labeled ET-1 to
cloned human ETA receptor and
ETB receptor with inhibitory
constant values of 0.17 and 133.8 nM, respectively (23). In rabbits,
PD-156707 infusion rates of 0.03 mg · kg1 · h1
completely blocked the vasoconstricting effects of exogenous ET-1, with
corresponding plasma concentrations that were <0.05 µg/ml
(107 M; Refs. 17, 24). In
newborn lambs, we have demonstrated that PD-156707 infusion rates of
1.0 mg · kg1 · h1
completely and selectively block the vasoconstricting effects of
exogenous ET-1 (250 ng/kg) with corresponding plasma concentrations of
1.4 µg/ml (2.5 × 106 M; data not shown). To
ensure adequate ETA-receptor
blockade we used a 10-fold higher infusion rate in the present study
(10 mg · kg1 · h1),
which resulted in a stable plasma concentration of 5.4 µg/ml (105 M) and blocked the
vasoconstricting effects of exogenous ET-1 in our animals. We found
that the infusion of PD-156707 did not alter ductus arteriosus closure
during the first 5 h after birth, suggesting that endogenous ET-1 does
not play a significant role in closure of the ductus arteriosus after birth.
We also investigated the effects of
ETA-receptor blockade on
oxygen-induced ductus constriction in vitro. We examined the effects of
oxygen alone, oxygen plus indomethacin (an inhibitor of prostaglandin
production), and oxygen plus indomethacin and LY-83583 (a soluble
guanylate cyclase inhibitor, the secondary messenger for nitric oxide
production). We found that
ETA-receptor blockade altered
neither the constriction produced by oxygen alone nor the constriction
produced by oxygen in association with prostaglandin and soluble
guanylate cyclase blockade. We used concentrations of the
ETA-receptor blocker PD-156707
that were 10-fold higher than those needed to inhibit near-maximal
concentrations of exogenous ET-1
(107 M). Although data from
Coceani's laboratory (11) suggest that oxygen-induced ET-1 release by
the ductus is quite low, higher concentrations of endogenously produced
ET-1 at the receptor site during oxygen-induced ductus constriction
cannot be excluded.
ETB receptors occur predominantly
on vascular endothelial cells and mediate vasodilation by generation of
prostacyclin and nitric oxide (16). However, a subpopulation of
ETB receptors has recently been
identified on vascular smooth muscle cells that mediate
vasoconstriction (3, 26). Although the overwhelming hemodynamic effect
of ETB-receptor activation in vivo
is vasodilation, we performed additional experiments using a
nonselective ETA- and
ETB-receptor antagonist, PD-14505,
to exclude the possibility that our inability to demonstrate an
inhibitory effect with PD-156707 was caused by
ETB-receptor-mediated ductus
constriction (14, 22). Both in vivo (n = 1 lamb, 50 µg · kg1 · min1)
and in vitro (n = 2 rings,
105 M), PD-14505 did not
alter ductus constriction, whereas it completely blocked the
hemodynamic effects of exogenous ET-1. This suggests that ductus
constriction is not mediated by the
ETB receptor.
Our in vitro finding that ET-1 produces dose-dependent constriction of
the fetal lamb ductus arteriosus is consistent with previously reported
data by Coceani et al. (9). However, in contrast to previous reports,
we found that ETA-receptor
blockade did not alter oxygen-induced ductus constriction (11). The
reason for this discrepancy is unclear. Our study used a different
selective ETA-receptor antagonist
(PD-156707) than the study by Coceani and co-workers (BQ-123). Although
side-by-side comparisons of BQ-123 and PD-156707 have not been
performed in identical systems, pharmacological data suggest that
PD-156707 is equally selective and perhaps slightly more potent an
ETA-receptor antagonist than BQ-123 (23). In addition, Coceani et al. (9) induced significant ductus
constriction with only 109
M ET-1, whereas 108 M ET-1
was required in our preparation. Therefore, inherent differences in the
sensitivity of the ductus to ET-1 may explain some of the differences
between our two laboratories. This may be secondary, in part, to
differences in sheep breeds, tissue bath preparation, and/or
handling and storage of ET-1.
Although Kennedy and Clark (19) concluded over 50 years ago that oxygen was responsible for constriction of the ductus arteriosus after birth, its biochemical basis remains unclear. Several mechanisms have been implicated in mediating oxygen-induced constriction of the ductus arteriosus. These include stimulation of a cytochrome P-450 pathway and inhibition of voltage- and/or ATP-sensitive potassium channels (13, 21, 27). Recently, oxygen-induced release of ET-1 has been implicated as a mediator of ductus constriction at birth. However, the present in vivo and in vitro data suggest that ET-1 does not play a significant role in closure of the ductus arteriosus after birth.
| |
ACKNOWLEDGEMENTS |
|---|
The authors thank Dr. Joan Keiser (Medicinal Chemistry Dept., Parke-Davis Pharmaceutical Research, Ann Arbor, MI) for ongoing pharmaceutical expertise and for generously supplying PD-156707 and PD-14505. The authors also thank Dr. Hussein Hallak (Parke-Davis Pharmaceutical Research) for performing the plasma PD-156707 pharmacokinetics, Mario Trujillo for help in obtaining tissue specimens, and Francoise Mauray for help in the in vitro experiments.
| |
FOOTNOTES |
|---|
This research was supported by National Heart, Lung, and Blood Institute Grants HL-46691 and HL-56061 (R. I. Clyman), Grant 9640010N EIG from the American Heart Association (J. R. Fineman), and a grant from the Perinatal Associates Research Foundation.
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: R. I. Clyman, Univ. of California, San Francisco, 505 Parnassus Ave., Box 0544, HSE 1492, San Francisco, CA 94143-0544.
Received 7 April 1998; accepted in final form 15 July 1998.
| |
REFERENCES |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
1.
Arai, H.,
S. Hori,
I. Aramori,
H. Ohkubo,
and
S. Nakanishi.
Cloning and expression of a cDNA encoding an endothelin receptor.
Nature
348:
730-732,
1990[Medline].
2.
Chatfield, B. A.,
I. F. McMurtry,
S. L. Hall,
and
S. H. Abman.
Hemodynamic effects of endothelin-1 on ovine fetal pulmonary circulation.
Am. J. Physiol.
261 (Regulatory Integrative Comp. Physiol. 30):
R182-R187,
1991
3.
Clozel, M.,
G. A. Gray,
V. Breu,
B. M. Loffler,
and
R. Osterwalder.
The endothelin ETB receptor mediates both vasodilation and vasoconstriction in vivo.
Biochem. Biophys. Res. Commun.
186:
867-873,
1992[Medline].
4.
Clyman, R. I.
Ductus arteriosus: current theories of prenatal and postnatal regulation.
Semin. Perinatol.
11:
64-71,
1987[Medline].
5.
Clyman, R. I.
Ductus arteriosus.
In: Pediatrics and Perinatology. The Scientific Basis, edited by P. A. Gluckman,
and M. A. Heymann. Canterbury, UK: Edward Arnold, 1996, p. 755-761.
6.
Clyman, R. I.,
F. Mauray,
L. M. Demers,
A. M. Rudolph,
and
C. Roman.
Does oxygen regulate prostaglandin-induced relaxation in the lamb ductus arteriosus?
Prostaglandins
19:
489-498,
1980[Medline].
7.
Clyman, R. I.,
O. D. Saugstad,
and
F. Mauray.
Reactive oxygen metabolites relax the lamb ductus arteriosus by stimulating prostaglandin production.
Circ. Res.
64:
1-8,
1989
8.
Clyman, R. I.,
N. Waleh,
S. Black,
R. K. Reimer,
F. Mauray,
and
Y. Q. Chen.
Regulation of ductus patency by nitric oxide in fetal lambs: the role of gestation, oxygen tension and vasa vasorium.
Pediatr. Res.
43:
1-12,
1998[Medline].
9.
Coceani, F.,
C. Armstrong,
and
L. Kelsey.
Endothelin is a potent constrictor of the lamb ductus arteriosus.
Can. J. Physiol. Pharmacol.
67:
902-904,
1989[Medline].
10.
Coceani, F.,
and
L. Kelsey.
Endothelin-1 release from lamb ductus arteriosus: relevance to postnatal closure of the vessel.
Can. J. Physiol. Pharmacol.
69:
218-221,
1991[Medline].
11.
Coceani, F.,
L. Kelsey,
and
E. Seidlitz.
Evidence for an effector role of endothelin in closure of the ductus arteriosus at birth.
Can. J. Physiol. Pharmacol.
70:
1061-1064,
1992[Medline].
12.
Coceani, F.,
L. Kelsey,
and
E. Seidlitz.
Occurrence of endothelium-derived relaxing factor: nitric oxide in the lamb ductus arteriosus.
Can. J. Physiol. Pharmacol.
72:
82-88,
1994[Medline].
13.
Coceani, F.,
N. C. Hamilton,
J. Labuc,
and
P. M. Olley.
Cytochrome P-450-linked monooxygenase: involvement in the lamb ductus arteriosus.
Am. J. Physiol.
246 (Heart Circ. Physiol. 15):
H640-H643,
1984.
14.
Cody, W. L.,
A. M. Doherty,
J. X. He,
P. L. DePue,
L. A. Waite,
J. Topliss,
S. Haleen,
D. LaDouceur,
M. A. Flynn,
K. E. Hill,
and
E. E. Reynolds.
The rational design of a highly potent combined ETa and ETb receptor antagonist (PD 145065) and related analogs.
Med. Chem. Res.
3:
154-162,
1993.
15.
Fox, J. J.,
J. W. Ziegler,
D. D. Ivy,
A. C. Halbower,
J. P. Kinsella,
and
S. H. Abman.
Role of nitric oxide and cGMP system in regulation of ductus arteriosus tone in ovine fetus.
Am. J. Physiol.
271 (Heart Circ. Physiol. 40):
H2638-H2645,
1996
16.
Hirata, Y.,
T. Emori,
S. Eguchi,
K. Kanno,
T. Imai,
K. Ohta,
and
F. Marumo.
Endothelin receptor subtype B mediates synthesis of nitric oxide by cultured bovine endothelial cells.
J. Clin. Invest.
91:
1367-1373,
1993.
17.
Ignasiak, D. P.,
T. B. McClanahan,
L. J. Saganek,
R. E. Potoczak,
H. Hallak,
and
K. P. Gallagher.
Effects of endothelin ETA receptor antagonism with PD 156707 on hemodynamics and renal vascular resistance in rabbits.
Eur. J. Pharmacol.
321:
295-300,
1997[Medline].
18.
Ivy, D. D.,
J. P. Kinsella,
and
S. H. Abman.
Physiologic characterization of endothelin A and B receptor activity in the ovine fetal pulmonary circulation.
J. Clin. Invest.
93:
2141-2148,
1994.
19.
Kennedy, J. A.,
and
S. L. Clark.
Observations on the physiological reactions of the ductus arteriosus.
Am. J. Physiol.
136:
140-147,
1942.
20.
La, M.,
and
J. J. Reid.
Endothelin-1 and the regulation of vascular tone.
Clin. Exp. Pharmacol. Physiol.
22:
315-323,
1995[Medline].
21.
Nakanishi, T.,
H. Gu,
N. Hagiwara,
and
K. Momma.
Mechanisms of oxygen-induced contraction of ductus arteriosus isolated from the fetal rabbit.
Circ. Res.
72:
1218-1228,
1993
22.
Reddy, V. M.,
K. D. Hendricks-Munoz,
H. A. Rajasinghe,
E. Petrossian,
F. L. Hanley,
and
J. R. Fineman.
Post-cardiopulmonary bypass pulmonary hypertension in lambs with increased pulmonary blood flow: a role for endothelin-1.
Circulation
95:
1054-1061,
1997
23.
Reynolds, E. E.,
J. A. Keiser,
S. J. Haleen,
D. M. Walker,
B. Olszewski,
R. L. Schroeder,
D. G. Taylor,
O. Hwang,
K. M. Welch,
and
M. A. Flynn.
Pharmacological characterization of PD 156707, an orally active ETA receptor antagonist.
J. Pharmacol. Exp. Ther.
273:
1410-1417,
1995
24.
Rossi, D. T.,
H. Hallak,
and
L. Bradford.
Liquid chromatographic assay for a butenolide endothelin antagonist (PD 156707) in plasma.
J. Chromatogr. B Biomed. Appl.
677:
299-304,
1996[Medline].
25.
Sakurai, T.,
M. Yanagisawa,
Y. Takuwa,
H. Miyazaki,
S. Kimura,
K. Goto,
and
T. Masaki.
Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor.
Nature
348:
732-735,
1990[Medline].
26.
Shetty, S. S.,
O. Toshikazu,
R. L. Webb,
D. DelGrande,
and
R. W. Lapp.
Functionally distinct endothelin b receptors in vascular endothelium and smooth muscle.
Biochem. Biophys. Res. Commun.
191:
459-464,
1993[Medline].
27.
Tristani-Firouzi, M.,
H. L. Reeve,
S. Tolarova,
E. K. Weir,
and
S. L. Archer.
Oxygen-induced constriction of rabbit ductus arteriosus occurs via inhibition of a 4-aminopyridine-, voltage-sensitive potassium channel.
J. Clin. Invest.
98:
1959-1965,
1996[Medline].
28.
Yanagisawa, M.,
H. Kurihara,
S. Kimura,
Y. Tomobe,
M. Kobayashi,
Y. Mitsui,
Y. Yazaki,
K. Goto,
and
T. Masaki.
A novel potent vasoconstrictor peptide produced by vascular endothelial cells.
Nature
332:
411-415,
1988[Medline].
This article has been cited by other articles:
|
|
 |
|
  R. I. Clyman, N. Waleh, H. Kajino, C. Roman, and F. Mauray Calcium-dependent and calcium-sensitizing pathways in the mature and immature ductus arteriosus Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2007; 293(4): R1650 - R1656. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kajino, Y.-Q. Chen, S. R. Seidner, N. Waleh, F. Mauray, C. Roman, S. Chemtob, C. J. Koch, and R. I. Clyman Factors that increase the contractile tone of the ductus arteriosus also regulate its anatomic remodeling Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2001; 281(1): R291 - R301. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. I. Clyman, Y. Q. Chen, S. Chemtob, F. Mauray, T. Kohl, D. R. Varma, and C. Roman In Utero Remodeling of the Fetal Lamb Ductus Arteriosus : The Role of Antenatal Indomethacin and Avascular Zone Thickness on Vasa Vasorum Proliferation, Neointima Formation, and Cell Death Circulation, April 3, 2001; 103(13): 1806 - 1812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kajino, Y.-Q. Chen, S. Chemtob, N. Waleh, C. J. Koch, and R. I. Clyman Tissue hypoxia inhibits prostaglandin and nitric oxide production and prevents ductus arteriosus reopening Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2000; 279(1): R278 - R286. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Takahashi, C. Roman, S. Chemtob, M. M. Tse, E. Lin, M. A. Heymann, and R. I. Clyman Cyclooxygenase-2 inhibitors constrict the fetal lamb ductus arteriosus both in vitro and in vivo Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2000; 278(6): R1496 - R1505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Coceani, Y.-A. Liu, E. Seidlitz, L. Kelsey, T. Kuwaki, C. Ackerley, and M. Yanagisawa Endothelin A receptor is necessary for O2 constriction but not closure of ductus arteriosus Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1521 - H1531. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
