Journal of Applied Physiology Watch the video to see how APS reaches out to developing nations.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

J Appl Physiol 81: 2481-2487, 1996;
8750-7587/96 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dunbar Ivy, D.
Right arrow Articles by Abman, S. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dunbar Ivy, D.
Right arrow Articles by Abman, S. H.

Journal of Applied Physiology
Vol. 81, No. 6, pp. 2481-2487, December 1996
PULMONARY CIRCULATION AND LUNG FLUID BALANCE

Endothelin blockade augments pulmonary vasodilation in the ovine fetus

D. Dunbar Ivy, John P. Kinsella, and Steven H. Abman

Divisions of Cardiology, Neonatology, and Pulmonary Medicine and Critical Care, and Department of Pediatrics, University of Colorado School of Medicine and The Children's Hospital, Denver, Colorado 80218

ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES

ABSTRACT

Ivy, D. Dunbar, John P. Kinsella, and Steven H. Abman. Endothelin blockade augments pulmonary vasodilation in the ovine fetus. J. Appl. Physiol. 81(6): 2481-2487, 1996.---The physiological role of endothelin-1 (ET-1) in regulation of vascular tone in the perinatal lung is controversial. Recent studies suggest that ET-1 contributes to high basal pulmonary vascular resistance in the normal fetus, but its role in the modulation of pulmonary vascular tone remains uncertain. We hypothesized that high ET-1 activity opposes the vasodilator response to some physiological stimuli such as increased pressure. To test the hypothesis that ET-1 modulates fetal pulmonary vascular responses to acute and prolonged physiological stimuli, we performed a series of experiments in the late-gestation ovine fetus. We studied the hemodynamic effects of two ET-1 antagonists, BQ-123 (a selective ETA-receptor antagonist) and phosphoramidon (a nonselective ET-1-converting enzyme inhibitor) during mechanical increases in pressure due to partial ductus arteriosus compression in chronically prepared late-gestation fetal lambs. In control studies, partial ductus arteriosus compression decreased the ratio of pulmonary arterial pressure to pulmonary artery flow in the left lung 34 ± 6% from baseline. Intrapulmonary infusions of BQ-123 (0.5 µg/min for 10 min; 0.025 µg/min for 2 h) or phosphoramidon (1.0 mg/min for 10 min) augmented the peak vasodilator response during ductus arteriosus compression (52 ± 3 and 49 ± 6% from baseline, respectively, P < 0.05 vs. control). In addition, unlike the transient vasodilator response to ductus arteriosus compression in control studies, ET-1 blockade with BQ-123 or phosphoramidon prolonged the increase in flow caused by ductus arteriosus compression. In summary, ETA-receptor blockade and ET-1-converting enzyme inhibition augment and prolong fetal pulmonary vasodilation during partial compression of the ductus arteriosus. We conclude that ET-1 activity modulates acute and prolonged responses of the fetal pulmonary circulation to changes in vascular pressure. We speculate that ET-1 contributes to regulation and maintenance of high pulmonary vascular resistance in the normal ovine fetal lung.

endothelin receptors; pulmonary hypertension; persistent pulmonary hypertension of the newborn; nitric oxide; pulmonary circulation; BQ-123; phosphoramidon

INTRODUCTION

PULMONARY VASCULAR RESISTANCE is elevated in the normal fetal lung, as pulmonary blood flow accounts for <8-10% of the combined ventricular output of blood from the heart (19). Mechanisms responsible for the maintenance of high pulmonary vascular resistance in the fetus may include physical factors, such as lack of an air-liquid interface or ventilation, relative low oxygen tension in comparison with the newborn, decreased vasodilator activity, or, perhaps, increased vasoconstrictor activity (6, 16, 43). Endothelium-derived products, including vasodilator stimuli such as nitric oxide and prostacyclin, and vasoconstrictor stimuli such as leukotrienes and endothelin contribute to vascular tone in the fetal lung (6, 11, 13, 16, 23, 43, 46). These endothelial products may contribute not only to basal tone in the fetal lung but also may modulate responses to physiological stimuli such as increases in pressure (11).

Endothelin-1 (ET-1) is a potent vasoactive peptide in the fetal lung (23, 46, 47); however, its role in the fetal lung is uncertain. Acute infusions of ET-1 in the fetal pulmonary circulation cause vasodilation (7, 8, 31, 51), but this response is transient, and pulmonary hypertension predominates with prolonged infusion (8, 30). On the basis of the acute vasodilator effects during brief infusions, some authors (7, 51, 52) suggest that the primary physiological role of ET-1 in the ovine fetal lung is vasodilation. However, other studies (23-25, 46) suggest that ET-1 has predominantly vasoconstrictor properties in the fetal lung.

ET-1 is a 21-amino acid peptide that is produced primarily in vascular endothelial cells on cleavage of its 38-amino acid precursor, Big endothelin-1 (Big ET-1). Big ET-1 is converted to ET-1 by the metalloprotease endothelin-converting enzyme (ECE-1) (54), which is inhibited by the metalloprotease inhibitor phosphoramidon (39). ET-1 is released in response to several stimuli, including hypoxia (14, 15, 26, 29, 47), increased pressure (20), and shear stress (5, 27, 38, 41). In response to these stimuli, ET-1 causes both acute responses, such as vasodilation or vasoconstriction (8, 23, 25), as well as chronic changes, such as smooth muscle proliferation (18, 48, 49, 56). However, the role of ET-1 in response to increases in pressure in the fetal lung is not known. Study of the effect of ET-1 antagonists during increases in pulmonary arterial pressure may allow for further understanding of the acute and prolonged role of ET-1 in modulation of fetal pulmonary tone.

We hypothesized that ET-1 contributes regulation of fetal pulmonary blood flow primarily by causing vasoconstriction. To further examine the role of ET-1 in the ovine fetal lung, we studied the hemodynamic effects of the ET-1 antagonists, BQ-123, a selective ETA-receptor blocker, and phosphoramidon, a nonselective ECE-1 inhibitor, on the hemodynamic response to partial ductus arteriosus compression in the chronically prepared late-gestation fetal lamb.

METHODS

Surgical Preparation

All procedures and protocols were previously reviewed and approved by the Animal Care and Use Committee at the University of Colorado Health Sciences Center. Nine mixed-breed (Columbia-Rambouillet) pregnant ewes between 125 and 130 days gestation (term = 147 days) were fasted 24 h before surgery. Ewes were sedated with intravenous pentobarbital sodium (2-4 g) and anesthetized with 1% tetracaine hydrochloride (3 mg) by lumbar puncture. Ewes were kept sedated with pentobaribital sodium but breathed spontaneously throughout the surgery. Penicillin (500 mg) and streptomycin (1 g) were administered to the ewe at surgery. Under sterile conditions, the fetal lamb's left forelimb was delivered through a uterine incision. A skin incision was made under the left forelimb after local infiltration with lidocaine (2-3 ml, 1% solution). Polyvinyl catheters were advanced into the ascending aorta and superior vena cava after insertion into the axillary artery and vein. A left axillary to sternal thoracotomy exposed the heart and great arteries. Catheters were inserted into the left pulmonary artery (LPA) and main pulmonary artery (MPA) by direct puncture through purse-string sutures, as previously described (3). Catheters were guided into position with a 14- or 16-gauge intravenous placement unit (Angiocath; Travenol, Deerfield, IL). In four animals without a ductal occluder, a left atrial catheter was placed for measurement of left atrial pressure. Catheters were secured by tightening the purse-string suture as the introducer was withdrawn. The LPA catheter was inserted at the bifurcation of the MPA and the ductus arteriosus and guided through the common pulmonary artery into the LPA. The MPA catheter was inserted between the ductus arteriosus and the pulmonic valve. In five animals, a 10-mm inflatable occluder (In Vivo Metric, Heldsburg, CA) was loosely placed around the ductus arteriosus to avoid any compression before the study period (1). A 6.0-mm ultrasonic flow probe (Transonics, Ithaca, NY) was placed around the LPA to measure blood flow to the left lung. The thoracotomy incision was closed in layers. The uteroplacental circulation was kept intact, and the fetus was gently placed in the uterus, with exposed surfaces bathed in warm towels. Ampicillin (500 mg) was added to the amniotic cavity before closure of the hysterotomy. Ampicillin (250 mg) was infused daily in the fetal vein and amniotic cavity during the first 3 days after surgery. The ewe was allowed to recover, and no further anesthesia was given. Studies were performed after a postoperative recovery time of 48-72 h.

Physiological Measurements

Flow transducer cables were attached to an internally calibrated flowmeter (Transonics, Ithaca, NY) for continuous measurements of LPA flow. The absolute values of flows were determined from phasic blood flow signals obtained during baseline periods, as previously described (28, 32). Zero flow was established by studies in which animals were killed with a Transonics LPA flow transducer in place. Based on these data, zero flow correlated with end-diastolic flow on the Transonics flowmeter. A correction factor between the internally calibrated zero point and end-diastolic flow was added to the mean flow on the Transonics flowmeter. The value obtained from this method correlates with previoulsy determined measures of LPA flow in the late-gestation ovine fetal lung (28). The aortic, MPA, and amniotic cavity catheters were connected to a Gould-Statham P23 ID pressure transducer and recorder. Pressures were referenced to the amniotic cavity pressure. The pressure transducer was calibrated with a mercury column manometer. Heart rate (HR) was determined from the flowmeter or phasic pulmonary blood flow tracings. Calculation of resistances are reported as left lung total pulmonary resistance (RL; mmHg · ml-1 · min = mean MPA pressure/LPA flow). Blood samples for pH, PCO2, PO2, and hemoglobin were drawn from the MPA catheter before, during, and after partial ductus arteriosus compression and were measured at 39.50°C with a Radiometer OSM-3 blood gas analyzer and hemoximeter (Radiometer, Copenhagen, Denmark).

Experimental Design

Protocol 1: hemodynamic response to 2 h of partial ductus arteriosus compression after ETA-receptor blocade (n = 5 animals; mean gestational age = 130 ± 2 days). During the control study, the ductus arteriosus was compressed by progressive inflation of the vascular occluder with saline, until mean MPA pressure was increased to 10 mmHg above baseline values. Mean MPA pressure was kept constant throughout the study period by readjusting the degree of inflation of the occluder, as determined by continuous monitoring of mean MPA pressure during the 2-h study period. LPA flow and aortic pressure were measured during ductus arteriosus compression. After 2 h, the occluder was rapidly deflated, and hemodynamic measurements were recorded for 30 min.

On alternate days and in random order, BQ-123 (Peptides International, Lousiville, KY; 1 mg/ml saline) (0.5 µg/min for 10 min) was infused directly into the LPA immediately before ductus arteriosus compression. The dose of BQ-123 selected for the study was determined from previous dose-response studies, which demonstrated blockade of Big ET-1-mediated pulmonary hypertension for at least 1 h after treatment with BQ-123 at 0.5 µg/min for 10 min (23). However, BQ-123 at this dose may lower basal pulmonary vascular tone, and other authors have reported vasodilation with much higher doses of BQ-123 (51). Therefore, to determine whether continuous infusion of BQ-123 at a lower dose was as effective as BQ-123 at a dose of 0.5 µg/min for 10 min, we studied the effects of low dose BQ-123 (0.025 µg/min for 2 h) during prolonged infusion in the LPA in four animals without a ductal occluder. To determine whether a low dose of BQ-123 achieved sufficient ETA-receptor blockade, Big ET-1 (1.5 µg/min in the LPA) was infused before and 1 h after treatment with low dose of BQ-123 (n = 4). Finally, low dose of BQ-123 (0.025 µg/min for 2 h) was infused during prolonged ductus arteriosus compression.

Protocol 2: hemodynamic response to 2 h of partial ductus arteriosus compression after ECE-1 inhibition with phosphoramidon (n = 5 animals; mean gestational age = 130 ± 2 days). After 30 min of baseline hemodynamic measurements, saline or phosphoramidon (Sigma Chemical, St. Louis, MO; 10 mg/1 ml saline or 1.0 mg/min for 10 min phosphoramidon) was infused in the LPA. The vascular occluder was inflated to compress the ductus arteriosus until mean MPA pressure increased at least 10 mmHg above baseline values (as described above). This dose of phosphoramidon has no effect on basal pulmonary tone but it blocked Big ET-1-mediated pulmonary hypertension for up to 2 h after treatment (25).

Data Analysis

Data are presented as means ± SE. Statistical analysis was performed with the analysis of variance Super ANOVA software package (Abacus Concepts, Berkeley, CA). Comparisons were made by using univariate repeated measures by linear contrast analysis. P < 0.05 was considered significant.

RESULTS

Protocol 1: Hemodynamic Response to 2 h of Ductus Arteriosus Compression After ETA-Receptor Blockade

During the control study, inflation of the ductus arteriosus occluder increased mean MPA pressure from 41 ± 3 mmHg at baseline to 55 ± 4 mmHg (P < 0.05), which was maintained constant throughout the study period (Fig. 1). During ductus arteriosus compression, LPA flow increased 59 ± 6% above baseline values at 20 min (P < 0.05) (Fig. 2). However, LPA flow fell steadily toward baseline after 50 min, despite constant compression (Fig. 1). RL initially decreased by 34 ± 6% from baseline at 30 min (Fig. 3) (P < 0.05); however, despite constant compression, RL progressively increased and was not different from baseline values by 70 min (Fig. 1). RL increased by 16 ± 8% from baseline by 120 min (Fig. 3). Mean aortic pressure, pH, PCO2, PO2, and hemoglobin did not change from baseline during the study (Table 1). HR increased during compression from 170 ± 4 to 188 ± 5 beats/min at 120 min of ductus arteriosus compression (P < 0.05).
Fig. 1. ETA-receptor blockade augments peak flow during partial ductus arteriosus (PDA) compression (n = 5 lambs). A: left pulmonary artery (LPA) flow. BQ-123 (BQ; 0.5 µg/min for 10 min and 0.025 µg/min for 2 h) augmented fetal pulmonary vasodilation in comparison with control studies. Main pulmonary artery (MPA; B) pressure during PDA compression was not different between groups. BQ-123 (0.5 µg/min for 10 min and 0.025 µg/min for 2 h) augmented early fall in lung resistance (RL; mean pulmonary arterial pressure/LPA flow; C) in comparison with control studies.
[View Larger Version of this Image (29K GIF file)]

Fig. 2. Endothelin-1 (ET-1) antagonists augment %increase in LPA flow during ductus arteriosus compression in comparison with control (Ctrl) (n = 5 lambs). ETA-receptor antagonist BQ-123 caused a greater increase in LPA flow during early (Early; 30 min) and late (Late; 120 min) ductus arteriosus compression, whereas endothelin-converting enzyme inhibitor phosphoramidon (Phos) caused a greater increase in LPA flow only during early ductus arteriosus compression.
[View Larger Version of this Image (29K GIF file)]

Fig. 3. ET-1 antagonists augment %decrease in RL during ductus arteriosus compression in comparison with control (n = 5 lambs). ETA-receptor antagonist BQ-123 and Phos caused a greater fall in total pulmonary resistance during early (30 min) and late (120 min) ductus arteriosus compression.
[View Larger Version of this Image (29K GIF file)]

Table 1. Effects of partial ductus arteriosus compression with BQ-123 (0.5 µg/min for 10 min) or phosphoramidon (1.0 mg/min for 10 mi n)

Baseline Ductus Compression Post Compression
Mean aortic pressure, mmHg
  Control 43 ± 3  42 ± 2  41 ± 4 
  BQ-123 40 ± 2  41 ± 3  39 ± 2 
  Phosphoramidon 42 ± 3  42 ± 2  41 ± 2 
pH, units
  Control 7.34 ± 0.02  7.33 ± 0.02  7.32 ± 0.01 
  BQ-123 7.32 ± 0.02  7.31 ± 0.02  7.33 ± 0.02 
  Phosphoramidon 7.36 ± 0.01  7.32 ± 0.02  7.31 ± 0.02 
PCO2, Torr
  Control 53 ± 2  54 ± 2  50 ± 2 
  BQ-123 53 ± 2  55 ± 3  54 ± 1 
  Phosphoramidon 50 ± 2  53 ± 3  53 ± 2 
PO2, Torr
  Control 22 ± 3  22 ± 4  22 ± 3 
  BQ-123 20 ± 2  24 ± 5  19 ± 1 
  Phosphoramidon 21 ± 3  22 ± 4  22 ± 3 
Hemoglobin, g/dl
  Control 6.9 ± .50  7.3 ± .44  7.3 ± .60 
  BQ-123 6.4 ± .50  6.7 ± .55  6.6 ± .30 
  Phosphoramidon 6.9 ± .30  7.0 ± .50  6.5 ± .20 
Heart rate, beats/min
  Control 170 ± 4  174 ± 4  188 ± 5*
  BQ-123 170 ± 13  173 ± 6  172 ± 6 
  Phosphoramidon 175 ± 6  174 ± 5  174 ± 6
Values are means ± SE. Comparisons between ductus compression (60 min), postcompression (150 min), and baseline were made by Super ANOVA (n = 5 lambs). * P < 0.05.

BQ-123 (0.5 µg/min in saline for 10 min) augmented the vasodilator response during ductus arteriosus compression (Figs. 2 and 3). Mean pulmonary arterial pressure was increased by ductus arteriosus compression to identical levels achieved during the control study (Fig 1). Maximal LPA flow at 30 min of partial ductus compression was 117% greater than control value (P < 0.05) (Fig. 2), and, unlike in the control study, LPA flow remained elevated above baseline values throughout the 2-h study period (P < 0.05) (Fig. 1). RL was lower than control from 10 to 100 min of ductus compression (P < 0.05) (Fig. 1) and was greater than control at 120 min (Fig. 3). Baseline values for aortic pressure, pH, PCO2, PO2, hemoglobin, and HR did not change (Table 1).

Continuous infusion of low doses of BQ-123 (0.025 µg/min for 2 h in the LPA) did not alter basal pulmonary vascular tone in the fetus. Baseline values for LPA flow (126 ± 17 ml/min), mean pulmonary arterial pressure (47 ± 8 mmHg), mean aortic pressure (44 ± 5 mmHg), and RL (0.42 ± 0.10 mmHg · ml-1 · min) did not change during the 2-h intrapulmonary infusion of BQ-123 at this dose. Similarly, pH (7.34 ± 0.02), PCO2 (53 ± 3 Torr), PO2 (19 ± 1 Torr), hemoglobin (7.2 ± 1.2 g/dl), and HR (142 ± beats/min) did not change from baseline during the infusion of BQ-123. Infusion of BQ-123 at 0.025 µg/min for 1 h attenuated the rise in RL caused by Big ET-1 (Table 2). Blood gas variables including pH (7.39 ± 0.02), PCO2 (44 ± 5 Torr), PO2 (19 ± 1 Torr), and hemoglobin (7.3 ± 0.4 g/dl) did not change before and after Big ET-1 infusion.

Table 2. Hemodynamic effects of Big ET-1 (1.5 µg/min for 10 min) with and without pretreatment with BQ-123 (0.025 µg/min for 60 min)

Baseline Big ET-1
LPA flow, ml/min
  Control 87 ± 4  73 ± 4*
  BQ-123 94 ± 12  92 ± 16 
Mean pulmonary artery pressure, mmHg
  Control 51 ± 1  61 ± 2*
  BQ-123 52 ± 1  54 ± 1 
Mean aortic pressure, mmHg
  Control 51 ± 2  60 ± 2*
  BQ-123 52 ± 1  53 ± 1 
Left atrial pressure, mmHg
  Control 3 ± 1  4 ± 1 
  BQ-123 4 ± 1  3 ± 1 
RL, mmHg · ml-1 · min
  Control 0.59 ± 0.03  0.84 ± 0.06*
  BQ-123 0.57 ± 0.06  0.64 ± 0.09 
Heart rate, beats/min
  Control 163 ± 6  156 ± 7 
  BQ-123 174 ± 14  177 ± 11
Values are means ± SE. Comparisons between Big endothelin-1 (Big ET-1) and baseline were made by Super ANOVA. LPA, left pulmonary artery; RL, left lung vascular resistance. Baseline column denotes values immediately before Big ET-1 infusion; Big ET-1 column denotes values 30 min after infusion (n = 4 lambs). * P < 0.05.

Low dose of BQ-123 (0.025 µg/min for 2 h) also augmented pulmonary vasodilation during ductus arteriosus compression (Fig. 1). Mean MPA pressure was maintained at similar levels to those in the control study. BQ-123 at this dose augmented LPA flow, compared with control ductus arteriosus compression. LPA flow was elevated above baseline values from 30 to 120 min (P < 0.05), and peak LPA flow at 30 min of partial ductus arteriosus compression was greater than control value (P < 0.05). RL was significantly lower than control from 30 to 120 min of partial ductus compression (P < 0.05) (Fig. 1). Baseline values for aortic pressure (41 ± 3 mmHg), pH (7.30 ± 0.03), PCO2 (50 ± 2 Torr), PO2 (21 ± 3 Torr), hemoglobin (6.8 ± 0.4 g/dl), and HR (165 ± 12 beats/min) did not change.

Protocol 2: Hemodynamic Response to 2 h of Partial Ductus Compression After ECE-1 Inhibition With Phosphoramidon

Phosphoramidon augmented pulmonary vasodilation in response to ductus arteriosus compression (Fig. 4). Mean MPA pressure was increased by 10 mmHg above baseline for the 2 h of partial ductus compression (P < 0.05) and was maintained at similar levels to those in the control study (Fig. 4). LPA flow increased by 52% above control (Fig. 2) and was elevated above baseline values from 10 to 120 min (P < 0.05). Peak LPA flow at 30 min of partial ductus arteriosus compression was greater than control value (P < 0.05). RL was significantly lower than control from 10 to 150 min of partial ductus compression (P < 0.05) (Figs. 3 and 4). Baseline values for aortic pressure, pH, PCO2, PO2, hemoglobin, and HR did not change (Table 1).
Fig. 4. ET-1-converting enzyme inhibition augments fetal pulmonary vasodilation during PDA compression (n = 5 lambs). Pretreatment with phosphoramidon (1.0 mg/min for 10 min) augmented peak rise in comparison with control studies. MPA pressure during PDA compression was not different between groups. Treatment with phosphoramidon augmented early fall in RL (mean pulmonary arterial pressure/LPA flow) in comparison with control studies.
[View Larger Version of this Image (23K GIF file)]

DISCUSSION

We found that intrapulmonary infusions of BQ-123 (a selective ETA-receptor antagonist) as well as phosphoramidon (a nonspecific endopeptidase inhibitor of ECE-1) augment fetal pulmonary vasodilation during partial ductus arteriosus compression. Pulmonary blood flow is augmented with doses of BQ-123 that do not alter basal pulmonary hemodynamics. Flow is augmented during early (within minutes) as well as late (within hours) ductus arteriosus compression. These findings suggest that ET-1 activity increases rapidly during the early response to physiological stimulation of the ovine fetal lung circulation by increased pulmonary arterial pressure. Furthermore, endogenous production of ET-1 causes vasoconstriction in response to increases in pressure, and this effect is likely mediated by ETA-receptor stimulation. Thus ET-1 contributes to regulation and maintenance of high pulmonary vascular resistance in the ovine fetal lung and opposes the dilator response to mechanical increases in pressure.

ET-1, a potent endothelium-derived vasoactive peptide (55), is present in the perinatal lung (34) and is vasoactive in the fetus (8, 23, 25, 44); however, its physiological role in the perinatal lung remains uncertain. Evidence suggests that ET-1 acts as a local autocrine and paracrine factor rather than as a circulating hormone. Circulating plasma concentrations of ET-1 are lower than those reported to be biologically active (12), and secretion of ET-1 by endothelial cells is polar and directed abluminally toward the interstitial region (45). Therefore, exogenous infusion of ET-1 may not accurately describe the hemodynamic effects of endogenous production of ET-1 in the fetal lung. Brief infusion of ET-1 causes potent vasodilation acutely (7, 31, 51-53); however, with prolonged infusion, hypertension prevails (8, 30). The effects of ET-1 infusion are tone dependent; brief infusions of ET-1 cause vasodilation in the setting of high pulmonary vascular resistance, but vasoconstriction after pulmonary tone is decreased during mechanical ventilation (7). However, other studies in the newborn piglet pulmonary vasculature have shown a biphasic effect of ET-1 with transient vasodilation followed by sustained vasoconstriction in the isolated perfused lung preparation with elevated tone from U-46619 (30).

Some studies of exogenous infusion of ET-1 have emphasized that the major effect of ET-1 in the late-gestation fetus is vasodilation and that the majority of ET-1-receptor activation in the ovine fetal lung is in the ETB1 receptors (7, 51), which mediate only vasodilation (23). In contrast, the present study and others (23, 46, 47) suggest that the ETA receptors play an important role in mediating vasoconstriction in the late-gestation ovine fetus. Intrapulmonary infusion of Big ET-1, the precursor to ET-1, causes progressive and sustained pulmonary hypertension without even transient vasodilation (23, 25), suggesting that stimulation of endogenous ET-1 may have very different effects than brief exogenous infusions of ET-1. Blockade of the ETA receptors causes vasodilation (23, 51), whereas selective blockade of the ETB1 (vasodilation) or ETB2 (vasoconstriction) receptors does not change basal pulmonary tone in the ovine fetus (24). However, brief and prolonged stimulation of the ETB receptors with sarafotoxin S6c causes only vasodilation, suggesting the presence of only ETB1 receptors in the ovine fetal lung (23). In contrast, studies in newborn piglets suggest the presence of both ETB1 (vasodilation) and ETB2 (vasoconstriction) receptors in the neonatal lung (40). Interestingly, blockade of ECE-1 with phosphoramidon (23, 25) and combined ETA and ETB-receptor blocade with CGS-27830 or Ro-47-0203 (23, 50) do not change basal pulmonary tone in the ovine fetal lung. Recent studies (50) have shown that combined ETA- and ETB-receptor blocade with Ro-47-0203 does not change the increase in pulmonary blood flow or decrease in pulmonary vascular resistance with in utero oxygen ventilation, suggesting that endogenous ET-1 activity does not play a major role in the increased pulmonary blood flow during the normal transitional circulation at birth. With partial ductus arteriosus compression, blockade of ET-1 augments the initial pulmonary vasodilation, suggesting that ET-1 contributes to maintenance of pulmonary vascular tone in the fetus.

The pulmonary vascular response during ductus arteriosus compression is characterized by two processes: transient vasodilation followed by vasoconstriction and increased pulmonary vascular resistance. During ductus arteriosus compression, the initial increase is followed by a steady fall in pulmonary artery flow. Prior studies have shown that nitric oxide (11) and a dilator prostaglandin (1) contribute to the initial increase in pulmonary artery flow during partial ductus arteriosus compression. The present study further suggests that ET-1-mediated vasoconstriction opposes this dilator response, since the initial increase in pulmonary flow is augmented with ET-1 antagonists. Mechanisms contributing to the decline in pulmonary flow with prolonged ductus arteriosus compression remain unclear, but we speculate that the inability to sustain the release of nitric oxide or prostaglandins (1) or increased ET-1 activity contributes to the increase in pulmonary vascular resistance. Recent studies suggest that chronic pulmonary hypertension from ligation of the ductus arteriosus (2, 37) increases ETA-receptor activity and immunoreactive lung ET-1 content (24).

The physiological effects of ET-1 depend on production of ET-1 and activation of different receptor subtypes. The ETA receptor is selective for ET-1 and ET-2 and is believed to be the receptor in vascular smooth muscle mediating vasoconstriction (4). BQ-123 potently and selectively binds to the ETA receptor (10, 21, 22). ET-1 stimulation of the ETA receptor may contribute to maintenance of high pulmonary vascular resistance in the normal fetus (23, 46, 51). Phosphoramidon is a nonselective metalloproteinase inhibitor of ECE-1 (17, 36). Both BQ-123 and phosphoramidon markedly attenuate the rise in fetal pulmonary vascular resistance seen with Big ET-1, the precursor to ET-1 (23, 25). Phosphoramidon does not change basal pulmonary tone in the ovine fetal lung (23, 25), suggesting that stimulation of the ETA and ETB receptors may be more equivalent in the normal ovine lung. As a nonspecific endopeptidase, phosphoramidon may also increase circulating levels of atrial natriuretic peptide or bradykinin, causing vasodilation. These nonspecific effects of phosphoramidon limit its usefulness as an inhibitor of ECE-1.

Stimuli for increased ET-1 production include hypoxia (14, 15, 26, 29, 47), increased pressure (20), and increased shear stress (5, 27, 38, 41). Initial reports of ET-1 release speculated that ET-1 was not rapidly released, as ET-1 was thought to be generated only by de novo synthesis with regulation of ET-1 production at the level of mRNA transcription (42, 55). However, recent studies have shown that endothelial cells can store ET-1 and release preformed stores of ET-1 acutely (33, 35). In the adult rat, the ETA-receptor antagonist BQ-123 completely blocks acute (within minutes) and chronic (within weeks) pulmonary vasoconstriction (9). Furthermore, in the perinatal pulmonary circulation, ET-1 activity may increase rapidly in response to hypoxia (47) or increased pressure, as in this study. We have shown that ET-1 blockade augmented pulmonary vasodilation within 10 min of the increase in pulmonary arterial pressure caused by ductus arteriosus compression. We speculate that ductus arteriosus compression leads to increased pressure, which causes a rapid increase in ET-1-mediated vasoconstriction.

In summary, ET-1 antagonists augment pulmonary vasodilation during partial ductus arteriosus compression. We conclude that in response to mechanical increases in pressure ET-1 causes primarily vasoconstriction and that this effect may be mediated by ETA-receptor stimulation. We speculate that ET-1-mediated vasoconstriction contributes to regulation and maintenance of high pulmonary vascular resistance in the normal ovine fetal lung.

ACKNOWLEDGEMENTS

This work was supported in part by grants from the National Institutes of Health (HL-241012 and HL-46481), the March of Dimes Birth Defects Foundation, the Bugher Physician-Scientist Training Program, the American Heart Association of Colorado (CF-035-93), and the American Heart Association- Established Investigator Award.

FOOTNOTES

Address for reprint requests: D. D. Ivy, Dept. of Cardiology, Box B100, The Children's Hospital, 1056 E. 19th Ave., Denver, CO 80218.

Received 23 February 1996; accepted in final form 8 August 1996.

REFERENCES

1. Abman, S. H., and F. J. Accurso. Acute effects of partial compression of ductus arteriosus on fetal pulmonary circulation. Am. J. Physiol. 257 (Heart Circ. Physiol. 26): H626-H634, 1989.
2. Abman, S. H., P. F. Shanley, and F. J. Accurso. Failure of postnatal adaptation of the pulmonary circulation after chronic intrauterine pulmonary hypertension in fetal lambs. J. Clin. Invest. 83: 1849-1858, 1989.
3. Abman, S. H., R. B. Wilkening, R. M. Ward, and F. J. Accurso. Adaptation of fetal pulmonary blood flow to local infusion of tolazoline. Pediatr. Res. 20: 1131-1135, 1986.
4. Arai, H., S. Hori, I. Aramori, H. Ohkubo, and S. Nakanishi. Cloning and expression of a cDNA encoding an endothelin receptor. Nature Lond. 348: 730-732, 1990.
5. Bodin, P., P. Milner, R. Winter, and G. Burnstock. Chronic hypoxia changes the ratio of endothelin to ATP release from rat aortic endothelial cells exposed to high flow. Proc. R. Soc. Lond. B Biol. Sci. 247: 131-135, 1992.
6. Cassin, S. Role of prostaglandins, thromboxanes, and leukotrienes in the control of the pulmonary circulation in the fetus and newborn. Semin. Perinatol. 11: 53-63, 1987.
7. Cassin, S., V. Kristova, T. Davis, P. Kadowitz, and G. Gause. Tone-dependent responses to endothelin in the isolated perfused fetal sheep pulmonary circulation in situ. J. Appl. Physiol. 70: 1228-1234, 1991.
8. 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.
9. Chen, Y. F., H. Li, T. S. Elton, R. H. Yang, H. Jin, and S. Oparil. The role of atrial natriuretic peptide and endothelin in hypoxia-induced pulmonary hypertension. Chin. J. Physiol. 37: 165-183, 1994.
10. Cioffi, C. L., R. F. Neale, Jr., R. H. Jackson, and M. A. Sills. Characterization of rat lung endothelin receptor subtypes which are coupled to phosphoinositide hydrolysis. J. Pharmacol. Exp. Ther. 262: 611-618, 1992.
11. Cornfield, D. N., B. A. Chatfield, J. A. McQueston, I. F. McMurtry, and S. H. Abman. Effects of birth-related stimuli on L-arginine-dependent pulmonary vasodilation in ovine fetus. Am. J. Physiol. 262: H1474-H1481, 1992.
12. Creminon, C., Y. Frobert, A. Habib, J. Maclouf, C. Patrono, P. Pradelles, and J. Grassi. Enzyme immunometric assay for endothelin using tandem monoclonal antibodies. J. Immunol. Methods 162: 179-192, 1993.
13. Davidson, D. Pulmonary hemodynamics at birth: effect of acute cyclooxygenase inhibition in lambs. J. Appl. Physiol. 64: 1676-1682, 1988.
14. Donahue, D. M., M. E. Lee, H. C. Suen, T. Quertermous, and J. C. Wain. Pulmonary hypoxia increases endothelin-1 gene expression in sheep. J. Surg. Res. 57: 280-283, 1994.
15. Elton, T. S., S. Oparil, G. R. Taylor, P. H. Hicks, R. H. Yang, H. Jin, and Y. F. Chen. Normobaric hypoxia stimulates endothelin-1 gene expression in the rat. Am. J. Physiol. 263 (Regulatory Integrative Comp. Physiol. 32): R1260-R1264, 1992.
16. Enhorning, G., F. H. Adams, and A. Norman. Effect of lung expansion on the fetal lamb circulation. Acta Paediatr. Scand. 55: 441-451, 1966.
17. Gardiner, S. M., A. M. Compton, P. A. Kemp, and T. Bennett. The effects of phosphoramidon on the regional haemodynamic responses to human proendothelin [1-38] in conscious rats. Br. J. Pharmacol. 103: 2009-2015, 1991.
18. Hassoun, P. M., V. Thappa, M. J. Landman, and B. L. Fanburg. Endothelin 1: mitogenic activity on pulmonary artery smooth muscle cells and release from hypoxic endothelial cells. Proc. Soc. Exp. Biol. Med. 199: 165-170, 1992.
19. Heymann, M. A., R. K. Creasy, and A. M. Rudolph. Quantitation of Blood Flow Patterns in the Foetal Lamb in Utero. Cambridge, UK: Cambridge Univ. Press, 1973.
20. Hishikawa, K., T. Nakaki, T. Marumo, H. Suzuki, R. Kato, and T. Saruta. Pressure enhances endothelin-1 release from cultured human endothelial cells. Hypertension Dallas 25: 449-452, 1995.
21. Ihara, M., K. Ishikawa, T. Fukuroda, T. Saeki, K. Funabashi, T. Fukami, H. Suda, and M. Yano. In vitro biological profile of a highly potent novel endothelin (ET) antagonist BQ-123 selective for the ETA receptor. J. Cardiovasc. Pharmacol. 20, Suppl. 12: S11-S14, 1992.
22. Ihara, M., K. Noguchi, T. Saeki, T. Fukuroda, S. Tsuchida, S. Kimura, T. Fukami, K. Ishikawa, M. Nishikibe, and M. Yano. Biological profiles of highly potent novel endothelin antagonists selective for the ETA receptor. Life Sci. 50: 247-255, 1992.
23. 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.
24. Ivy, D. D., J. W. Ziegler, M. F. Dubus, J. J. Fox, J. P. Kinsella, and S. H. Abman. Chronic intrauterine pulmonary hypertension alters endothelin receptor activity in the ovine fetal lung. Pediatr. Res. 39: 435-442, 1996.
25. Jones, O. W., and S. H. Abman. Systemic and pulmonary hemodynamic effects of big endothelin-1 and phosphoramidon in the ovine fetus. Am. J. Physiol. 266 (Regulatory Integrative Comp. Physiol. 35): R929-R955, 1994.
26. Kourembanas, S., P. A. Marsden, L. P. McQuillan, and D. V. Faller. Hypoxia induces endothelin gene expression and secretion in cultured human endothelium. J. Clin. Invest. 88: 1054-1057, 1991.
27. Kuchan, M. J., and J. A. Frangos. Shear stress regulates endothelin-1 release via protein kinase C and cGMP in cultured endothelial cells. Am. J. Physiol. 264 (Heart Circ. Physiol 33): H150-H156, 1993.
28. Lewis, A. B., M. A. Heymann, and A. M. Rudolph. Gestational changes in pulmonary vascular responses in fetal lambs in utero. Circ. Res. 39: 536-541, 1976.
29. Li, H., S. J. Chen, Y. F. Chen, Q. C. Meng, J. Durand, S. Oparil, and T. S. Elton. Enhanced endothelin-1 and endothelin receptor gene expression in chronic hypoxia. J. Appl. Physiol. 77: 1451-1459, 1994.
30. Liben, S., D. J. Stewart, J. De Marte, and T. Perreault. Ontogeny of Big endothelin-1 effects in newborn piglet pulmonary vasculature. Am. J. Physiol. 265 (Heart Circ. Physiol 34): H139-H145, 1993.
31. Lippton, H. L., G. A. Cohen, I. F. McMurtry, and A. L. Hyman. Pulmonary vasodilation to endothelin isopeptides in vivo is mediated by potassium channel activation. J. Appl. Physiol. 70: 947-952, 1991.
32. Lock, J. E., F. Hamilton, H. Luide, F. Coceani, and P. M. Olley. Direct pulmonary vascular responses in the conscious newborn lamb. J. Appl. Physiol. 48: 188-196, 1980.
33. Macarthur, H., T. D. Warner, E. G. Wood, R. Corder, and J. R. Vane. Endothelin-1 release from endothelial cells in culture is elevated both acutely and chronically by short periods of mechanical stretch. Biochem. Biophys. Res. Commun. 200: 395-400, 1994.
34. MacCumber, M. W., C. A. Ross, B. M. Glaser, and S. H. Snyder. Endothelin: visualization of mRNAs by in situ hybridization provides evidence for local action. Proc. Natl. Acad. Sci. USA 86: 7285-7289, 1989.
35. McClellan, G., A. Weisberg, D. Rose, and S. Winegrad. Endothelial cell storage and release of endothelin as a cardioregulatory mechanism. Circ. Res. 75: 85-96, 1994.
36. McMahon, E. G., M. A. Palomo, M. A. Brown, S. R. Bertenshaw, and J. S. Carter. Effect of phosphoramidon (endothelin-converting enzyme inhibitor) and BQ-123 (endothelin receptor subtype A antagonist) on blood pressure in hypertensive rats. Am. J. Hypertens. 6: 667-673, 1993.
37. Morin, F. C. D. Ligating the ductus arteriosus before birth causes persistent pulmonary hypertension in the newborn lamb. Pediatr. Res. 25: 245-250, 1989.
38. Morita, T., H. Kurihara, K. Maemura, M. Yoshizumi, and Y. Yazaki. Disruption of cytoskeletal structures mediates shear stress-induced endothelin-1 gene expression in cultured porcine aortic endothelial cells. J. Clin. Invest. 92: 1706-1712, 1993.
39. Opgenorth, T. J., J. R. Wu-Wong, and K. Shiosaki. Endothelin-converting enzymes. FASEB J. 6: 2653-2659, 1992.
40. Perreault, T., and J. Baribeau. Characterization of endothelin receptors in newborn piglet lung. Am. J. Physiol. 268 (Lung Cell. Mol. Physiol. 12): L607-L614, 1995.
41. Sharefkin, J. B., S. L. Diamond, S. G. Eskin, L. V. McIntire, and C. W. Diffenbach. Fluid flow decreases preproendothelin mRNA levels and suppresses endothelin-1 peptide release in cultured human endothelial cells. J. Vasc. Surg. 14: 1-9, 1991.
42. Simonson, M. S., and M. J. Dunn. Cellular signaling by peptides of the endothelin gene family. FASEB J. 4: 2989-3000, 1990.
43. Soifer, S. J., R. D. Loitz, C. Roman, and M. A. Heymann. Leukotriene end organ antagonists increase pulmonary blood flow in fetal lambs. Am. J. Physiol. 249 (Heart Circ. Physiol. 18): H570-H576, 1985.
44. Tod, M. L., and S. Cassin. Endothelin-1-induced pulmonary arterial dilation is reduced by Nomega -nitro-L-arginine in fetal lambs. J. Appl. Physiol. 72: 1730-1734, 1992.
45. Wagner, O. F., G. Christ, J. Wojta, H. Vierhapper, S. Parzer, P. J. Nowotny, B. Schneider, W. Waldhausl, and B. R. Binder. Polar secretion of endothelin-1 by cultured endothelial cells. J. Biol. Chem. 267: 16066-16068, 1992.
46. Wang, Y., and F. Coceani. Isolated pulmonary resistance vessels from fetal lambs. Contractile behavior and responses to indomethacin and endothelin-1. Circ. Res. 71: 320-330, 1992.
47. Wang, Y., Y. Coe, O. Toyoda, and F. Coceani. Involvement of endothelin-1 in hypoxic pulmonary vasoconstriction in the lamb. J. Physiol. Lond. 482: 421-434, 1995.
48. Wang, Y., P. M. Rose, M. L. Webb, and M. J. Dunn. Endothelins stimulate mitogen-activated protein kinase cascade through either ETA or ETB. Am. J. Physiol. 267: C1130-C1135, 1994.
49. Weissberg, P. L., C. Witchell, A. P. Davenport, T. R. Hesketh, and J. C. Metcalfe. The endothelin peptides ET-1, ET-2, ET-3, and sarafotoxin S6b are co- mitogenic with platelet-derived growth factor for vascular smooth muscle cells. Atherosclerosis 85: 257-262, 1990.
50. Winters, J. W., J. Wong, D. Van Dyke, M. Johengen, M. A. Heymann, and J. R. Fineman. Endothelin receptor blockade does not alter the increase in pulmonary blood flow due to oxygen ventilation in fetal lambs. Pediatr. Res. 40: 152-157, 1996.
51. Wong, J., J. R. Fineman, and M. A. Heymann. The role of endothelin and endothelin receptor subtypes in regulation of fetal pulmonary vascular tone. Pediatr. Res. 35: 664-670, 1994.
52. Wong, J., P. A. Vanderford, J. R. Fineman, R. Chang, and S. J. Soifer. Endothelin-1 produces pulmonary vasodilation in the intact newborn lamb. Am. J. Physiol. 265 (Heart Circ. Physiol. 34): H1318-H1325, 1993.
53. Wong, J., P. A. Vanderford, J. Winters, S. J. Soifer, and J. R. Fineman. Endothelin B receptor agonists produce pulmonary vasodilation in intact newborn lambs with pulmonary hypertension. J. Cardiovasc. Pharmacol. 25: 207-215, 1995.
54. Xu, D., N. Emoto, A. Giaid, C. Slaughter, S. Kaw, D. deWit, and M. Yanagisawa. ECE-1: a membrane-bound metalloprotease that catalyzes the proteolytic activation of big endothelin-1. Cell 78: 473-485, 1994.
55. 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 Lond. 332: 411-415, 1988.
56. Zamora, M. A., E. C. Dempsey, S. J. Walchak, and T. J. Stelzner. BQ123, an ETA-receptor antagonist, inhibits endothelin-1-mediated proliferation of human pulmonary artery smooth muscle cells. Am. J. Respir. Cell. Mol. Biol. 9: 429-433, 1993.
0161-7567/96 $5.00 Copyright © 1996 the American Physiological Society


This article has been cited by other articles:


Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
P. Tourneux, M. Chester, T. Grover, and S. H. Abman
Fasudil inhibits the myogenic response in the fetal pulmonary circulation
Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1505 - H1513.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
J. J. Smolich, J. P. Mynard, and D. J. Penny
Simultaneous pulmonary trunk and pulmonary arterial wave intensity analysis in fetal lambs: evidence for cyclical, midsystolic pulmonary vasoconstriction
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2008; 294(5): R1554 - R1562.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
P. Deruelle, T. R. Grover, L. Storme, and S. H. Abman
Effects of BAY 41-2272, a soluble guanylate cyclase activator, on pulmonary vascular reactivity in the ovine fetus
Am J Physiol Lung Cell Mol Physiol, April 1, 2005; 288(4): L727 - L733.
[Abstract] [Full Text] [PDF]

Home page
 J. Histochem. Cytochem.Home page
M. Wendel, W. Kummer, L. Knels, J. Schmeck, and T. Koch
Muscular ETB Receptors Develop Postnatally and Are Differentially Distributed in Specific Segments of the Rat Vasculature
J. Histochem. Cytochem., February 1, 2005; 53(2): 187 - 196.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
L. Storme, T. A. Parker, J. P. Kinsella, R. L. Rairigh, and S. H. Abman
Chronic hypertension impairs flow-induced vasodilation and augments the myogenic response in fetal lung
Am J Physiol Lung Cell Mol Physiol, January 1, 2002; 282(1): L56 - L66.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
B. Thebaud, P. de Lagausie, D. Forgues, Y. Aigrain, J.-C. Mercier, and A. T. Dinh-Xuan
ETA-receptor blockade and ETB-receptor stimulation in experimental congenital diaphragmatic hernia
Am J Physiol Lung Cell Mol Physiol, May 1, 2000; 278(5): L923 - L932.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
D. Dunbar Ivy, T. D. le Cras, T. A. Parker, J. P. Zenge, M. Jakkula, N. E. Markham, J. P. Kinsella, and S. H. Abman
Developmental changes in endothelin expression and activity in the ovine fetal lung
Am J Physiol Lung Cell Mol Physiol, April 1, 2000; 278(4): L785 - L793.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
T. A. Parker, T. D. le Cras, J. P. Kinsella, and S. H. Abman
Developmental changes in endothelial nitric oxide synthase expression and activity in ovine fetal lung
Am J Physiol Lung Cell Mol Physiol, January 1, 2000; 278(1): L202 - L208.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
J. W. ZIEGLER, D. DUNBAR IVY, J. J. FOX, J. P. KINSELLA, W. R. CLARKE, and S. H. ABMAN
Dipyridamole Potentiates Pulmonary Vasodilation Induced by Acetylcholine and Nitric Oxide in the Ovine Fetus
Am. J. Respir. Crit. Care Med., April 1, 1998; 157(4): 1104 - 1110.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
D. Dunbar Ivy, T. D. Le Cras, M. P. Horan, and S. H. Abman
Increased lung preproET-1 and decreased ETB-receptor gene expression in fetal pulmonary hypertension
Am J Physiol Lung Cell Mol Physiol, April 1, 1998; 274(4): L535 - L541.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
B. Ovadia, J. M. Bekker, R. K. Fitzgerald, A. Kon, S. Thelitz, M. J. Johengen, K. Hendricks-Munoz, R. Gerrets, S. M. Black, and J. R. Fineman
Nitric oxide-endothelin-1 interactions after acute ductal constriction in fetal lambs
Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H862 - H871.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dunbar Ivy, D.
Right arrow Articles by Abman, S. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dunbar Ivy, D.
Right arrow Articles by Abman, S. H.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online