(Hypertension. 2001;37:227.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Effect of Adrenomedullin on Placental Arteries in Normal and Preeclamptic Pregnancies
From the Departments of Physiology (S.J., S.T.D., S.K.), Medicine (D.W.M., S.K.), and Obstetrics and Gynecology (S.T.D.), University of Alberta, Edmonton, Alberta, Canada.
Correspondence to Dr Susan Jacobs-Kaufman, 475 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. E-mail susan.jacobs{at}ualberta.ca
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Abstract |
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Adrenomedullin is a potent vasodilatory peptide with plasma levels that increase during pregnancy. Although fetoplacental adrenomedullin levels are reported to increase in preeclampsia, maternal plasma levels may be elevated or decreased, or they may resemble those in normal pregnancy. In other hypertensive conditions, adrenomedullin increases. Therefore, we hypothesized that maternal plasma adrenomedullin levels would be higher in hypertensive pregnancies than in normotensive pregnancies and that the higher placental resistance found in preeclamptic pregnancies results from blunted activity of adrenomedullin on the vasculature. Adrenomedullin concentrations in plasma from women with normotensive pregnancies, gestational hypertension, and preeclampsia were determined by radioimmunoassay. Stem villous arteries from normotensive and preeclamptic pregnancies were dissected and mounted on a wire myograph system. Arteries were first preconstricted to 80% of their maximum constriction with U46619, a thromboxane A2 mimetic, and exposed to cumulative doses of adrenomedullin (1x10-9 to 3x10-7 mol/L). Contrary to our hypothesis, there were no significant differences in maternal plasma adrenomedullin levels among patients with normal pregnancies, gestational hypertension, and preeclampsia. Adrenomedullin significantly relaxed arteries from both normal and preeclamptic placentas, but there was no significant difference between the 2 groups. During normal pregnancy, adrenomedullin may contribute to the low placental vascular resistance. This pathway appears to be intact in preeclampsia. We conclude that the increased placental vascular resistance observed in preeclampsia is due neither to reduced adrenomedullin secretion nor to an attenuated vascular responsiveness. Moreover, unlike other hypertensive disorders, there is no compensatory rise in circulating adrenomedullin levels.
Key Words: adrenomedullin • preeclampsia • arteries • pregnancy
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Introduction |
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Adrenomedullin (ADM) is a 52–amino acid peptide originally discovered in human pheochromocytoma tissue,1 but it has since been identified in numerous other normal tissues. Among the characteristic actions of ADM are reduction in blood pressure, natriuresis, and diuresis.2 3 ADM is secreted from both endothelial cells and vascular smooth muscle cells.4 ADM receptors, specific and nonspecific (calcitonin gene–related peptide), are present on endothelial cells and vascular smooth muscle cells.5 6 7 Depending on the vascular bed and phenotype of the receptive cell, the mechanism of action of ADM may vary8 ; ADM has been shown to exert its effects via stimulation of the NO-cGMP pathway9 10 and activation of adenylate cyclase–cAMP5 and through potassium channel activation.9 Because of the increased levels seen in several hypertensive disorders, a potential protective antihypertensive role of ADM has been suggested.11 12 13 14
Pregnancy is characterized by a decrease in mean arterial blood pressure despite an increase in blood volume and cardiac output of 40% to 50%.15 Because ADM is a potent vasodilator, it has been investigated for its potential role in gestation. The concentration of ADM in maternal plasma increases during pregnancy in the human.16 17 Furthermore, fetoplacental tissues appear to be an additional site of synthesis of ADM during pregnancy.18 The role of ADM in the pathophysiology of preeclampsia is complex. Maternal plasma levels of ADM in preeclamptic pregnancies compared with uncomplicated pregnancies are reported to be either increased,19 decreased,20 or the same,21 22 despite the fact that ADM levels in amniotic fluid and umbilical vein plasma are reported to be significantly increased in preeclampsia.21
Because the placenta is devoid of any autonomic innervation,23 locally produced factors are essential in maintaining the low vascular resistance present within the placental circulation. A paracrine or autocrine mode of action of ADM has been inferred from the elevated concentrations found in fetoplacental tissues.18 We hypothesized that maternal plasma ADM levels should, as in other hypertensive disorders,11 12 14 be higher in hypertensive pregnancies than in normotensive pregnancies and that the higher placental resistance found in preeclamptic pregnancies results not from a lack of locally produced ADM but from blunted activity of ADM on the vasculature. Therefore, we sought to evaluate maternal plasma ADM levels and the effect of ADM on placental arteries in both preeclamptic and normal pregnancies.
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Methods |
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Experiment A: Maternal Plasma Levels of ADM
Patient Population
The present study was approved by the institutional ethics review board. Preeclampsia was defined by using the criteria of hypertension and proteinuria (dipstick
1+).
Hypertension was defined as >140/90 mm Hg on 2 occasions at
least 6 hours apart and occurring after the 20th week of gestation.
Gestational hypertension (GH) was defined by using the above-mentioned
criteria for hypertension, but with no proteinuria. Women with
uncomplicated pregnancies were normotensive (<140/90 mm Hg) with
no proteinuria. No patient was known to have a history of chronic
hypertension, liver, renal, or metabolic
disease.
Sample Collection
After informed consent was obtained, blood samples
were collected on ice into tubes containing EDTA plus 500 KIU aprotinin
per 5-mL tube. Women had a blood sample drawn on 1 occasion within 1 of
the 3 time intervals. Samples were centrifuged within 30
minutes of collection. Plasma was separated and stored at -70°C
until it was ready for extraction.
Plasma Extraction
Plasma samples (1 mL) were extracted as described by
Lewis et al.24 Briefly,
plasma was mixed with an equal volume of phosphate alkaline–treated
casein buffer. Sep-Pak C-18 columns (Waters Corp) were preequilibrated
with 5 mL of methanol and 10 mL of 0.9% saline. The plasma-buffer
mixture was added, and the columns were washed with 5 mL of 0.9%
saline. ADM was eluted with 2 mL of 80% isopropanol/0.013 mol/L HCl
into a tube containing 10 µL of 1% Triton. The eluate was dried
under nitrogen, and the extract was stored at -70°C until
radioimmunoassay (RIA). Extraction efficiency was measured with the
addition of a known amount of unlabeled ADM to plasma with a known
amount of endogenous ADM. Recovery was calculated by
comparing measured ADM levels with a control of RIA buffer with the
same amount of ADM added without extraction. Recoveries of unlabeled
ADM in this extraction procedure were 85% in normotensive pregnant
plasma, 81% in preeclamptic plasma, and 72% in nonpregnant plasma.
There was no significant difference in recoveries between these
groups.
Radioimmunoassay
Before analysis, plasma extracts were
reconstituted with 250 µL of RIA buffer. Each sample was assayed in
duplicate for human ADM (RIA, Phoenix Pharmaceuticals). Plasma samples
from all 3 groups were analyzed in any given assay. The
intra-assay and interassay coefficients of variance were 7.5% and
10.0%, respectively. Data were not corrected for peptide
recovery.
Solutions
The phosphate alkaline–treated casein buffer
contained 0.05 mol/L phosphate buffer (pH 7.4), 0.1% alkali-treated
casein, 0.1% Triton X-100, 0.1% sodium EDTA, and 0.2% sodium azide.
Alkali-treated casein was prepared according to a method described
previously.25 The RIA buffer
contained 19 mmol/L sodium phosphate, 81 mmol/L dibasic
sodium phosphate, 0.05 mol/L sodium chloride, 0.1% BSA, and 0.01%
sodium azide.
Statistical Analysis
Data were analyzed by using the Mann-Whitney
rank sum test. Significance was accepted at a value of
P<0.05.
Experiment B: ADM-Induced Relaxation in
Placental Arteries
Tissue Preparation
Placentas were obtained after vaginal delivery or
caesarian section from both normotensive and preeclamptic pregnancies.
It has been shown that the mode of delivery has no effect on the
responsiveness of placental
vessels.26 Immediately after
removal of the placenta, a piece was cut from a macroscopically normal
cotyledon and placed in cold HEPES–physiological
salt solution (PSS). Small stem villous arteries, averaging 300 µm in
diameter and 2 mm in length, were then dissected from the placenta
to remove surrounding trophoblastic and connective tissue. The stem
villous artery was chosen because it is the major site of resistance in
the placenta; the umbilical and chorionic plate vessels do not
contribute greatly to vascular
resistance.27 The isolated
arteries were then cut into rings and mounted on a wire myograph
system.28 The arteries were
bathed in HEPES-PSS at 37°C and at pH 7.4 for 30 minutes before any
manipulation and throughout the duration of the experiment. HEPES-PSS
maintains an accurate pH and partial pressure of oxygen similar to air.
The passive-tension internal circumference measurements were then
determined.28 Briefly, the
diameter of the artery was progressively increased in stepwise
increments while the force generated was recorded. The Laplace
relationship was used to estimate transmural pressure. The stem villous
arteries were then set to 90% of the internal circumference they would
have had when relaxed under a normal physiological
transmural pressure of 
40 mm Hg. Arteries were then allowed to
equilibrate for 30 minutes. At the end of each experiment, the
viability of the arteries was tested by use of a potassium
chloride–depolarizing solution.
Effect of ADM on Normal and Preeclamptic
Placental Arteries
Cumulative concentration-response curves were carried
out by use of the thromboxane A2
mimetic U46619
(1x10-9 to
1x10-5 mol/L)
followed by a washout period of 60 minutes. Arteries were then
preconstricted with the EC80 dose of U46619 (7
minutes), and a cumulative ADM concentration-response curve was
completed
(1x10-9 to
3x10-7 mol/L,
5-minute increments). A time-control experiment was performed on a
parallel preparation of the same artery without added ADM (time
control).
Solutions
The arteries were bathed in HEPES-PSS containing
(mmol/L) sodium chloride 142, potassium chloride 4.7, magnesium sulfate
1.17, calcium chloride 1.56, potassium phosphate 1.18, HEPES 10, and
glucose 5.5. The potassium chloride–depolarizing solution was made by
equimolar replacement of sodium chloride with potassium
chloride.
Drugs
U46619 (Cayman Chemical Co) stock solutions were
prepared in methyl acetate. ADM (Phoenix Pharmaceuticals) was obtained
in lyophilized aliquots so that fresh ADM could be used for each
experiment. Further dilutions were made with HEPES-PSS for all
drugs.
Statistical Analysis
Repeated-measures ANOVA was used to investigate the
relaxation response with ADM or without (time control) in both normal
and preeclamptic placentas. A value of
P<0.05 was considered
significant.
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Results |
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Experiment A
Subjects
Table 1 summarizes the characteristics of the patient groups. Comparisons were made between the GH and preeclamptic group and the normotensive group. Maternal age, hematocrit, and hemoglobin were comparable between groups. Parity was significantly lower in women with preeclampsia (P<0.05).
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Maternal Plasma ADM Levels in Normotensive, GH,
and Preeclamptic Pregnancies
Comparisons of plasma ADM levels in normotensive, GH,
and preeclamptic patients by gestational age grouping are shown in
Figure 1. There were no significant differences between
groups. Values are expressed as
mean±SEM.
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Experiment B
Subjects
Table 2 summarizes the characteristics of women with
preeclampsia and uncomplicated pregnancies. Maternal age, parity,
gravidity, hematocrit, and hemoglobin were comparable between the 2
groups. Gestational age at delivery and infant birth weight were
significantly lower in the preeclampsia group
(P<0.05). Compared with
normotensive pregnant women, women with preeclampsia had significantly
higher systolic and diastolic blood pressures
(P<0.05).
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Effect of U46619 and Potassium
Chloride–Depolarizing Solution on Normal and Preeclamptic Placental
Arteries
Concentration-dependent constriction occurred in the
presence of U46619
(1x10-9 to
1x10-6 mol/L).
There was no significant difference in the EC80
values between normal arteries
(4.04x10-8±0.86 mol/L) and preeclamptic
arteries (3.73x10-8±0.37 mol/L). Maximum
tension development was significantly greater in normal arteries
(2.74±0.24 mN/mm) than in preeclamptic arteries (1.80±0.28 mN/mm,
P<0.05). In response to the
potassium chloride–depolarizing solution (140 mmol/L), maximum
tension development was also greater in normal arteries (3.03±0.26
mN/mm) than in preeclamptic arteries (1.90±0.36 mN/mm,
P<0.05).
Effect of ADM on Normal and Preeclamptic
Placental Arteries
Concentration-dependent relaxation occurred in the
presence of ADM
(1x10-9 to
3x10-7 mol/L)
compared with its time control in normal
(Figure 2A) and preeclamptic
(Figure 2B) placental arteries
(P<0.05). For both normal and
preeclamptic placental arteries, the effect of treatment on percent
relaxation depends on time as indicated by the treatment and time
interaction. For normal placental arteries, relaxation with the highest
dose of ADM
(3x10-7 mol/L)
was 42±6% compared with its time control (14±5% of U46619-induced
contraction,
Figure 2A). For preeclamptic placental arteries, relaxation
with the highest dose of ADM
(3x10-7 mol/L)
was 26±11% compared with its time control (-1±7% of
U46619-induced contraction,
Figure 2B). The behavior of these 2-way interaction effects
in normal and preeclamptic groups is not statistically different, as
shown by the 3-way interaction effect between treatment, time, and
group. This was supported by the similarity in the dose-response curves
depicted in
Figure 2.
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Discussion |
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The present study supports previous findings showing unchanged maternal plasma levels of ADM in normotensive and preeclamptic pregnancies.21 22 In addition, we have found no difference in the GH group. The GH subgroup, which has not been previously studied, was included because of the potential difference in etiology compared with preeclampsia.29 Other hypertensive diseases, including essential hypertension,11 12 13 renal failure,11 heart failure,12 13 and primary aldosteronism,14 all show an increase in plasma ADM levels. In these conditions, ADM may serve to compensate for the elevation of blood pressure. In contrast, we have demonstrated that in preeclampsia and GH, there is no compensatory increase in plasma ADM. This could potentially contribute to the hypertension seen in GH and preeclampsia.
Because the placenta is devoid of autonomic innervation,23 locally produced factors are essential in maintaining the low vascular resistance characteristic of the placental circulation. A paracrine or autocrine mode of action of ADM has been inferred from the elevated concentrations found in fetoplacental tissues.18 We showed that ADM induces relaxation in the placental circulation in both normotensive and preeclamptic pregnancies. We originally formulated the hypothesis that an attenuated relaxation to ADM would exist in placental arteries from preeclamptic compared with normotensive pregnancies. However, we found no such difference. It has been previously reported that ADM levels are increased in amniotic fluid and umbilical vein plasma in women with preeclampsia compared with women with normotensive pregnancies, suggesting that greater concentrations of ADM are available locally in preeclampsia.21 Because placental arteries from preeclamptic pregnancies retain their ability to respond to ADM, this could potentially reflect a compensatory mechanism to counteract the increase in vascular resistance characteristic of the condition. It should be noted that we preconstricted the arteries with U46619. It is possible that in the presence of other vasoconstrictor agents, the relaxation response to ADM may differ.
Although we did not find a difference in ADM-induced relaxation between groups, we did find that the tension developed in response to U46619 and potassium chloride–depolarizing solution was significantly less in arteries from preeclamptic pregnancies than from normotensive pregnancies. Therefore, altered vasoconstrictive activity may exist in placentas obtained from women with preeclampsia. A placental lobule perfusion method likewise demonstrated a reduced pressure increase created by U46619 in placentas from women with preeclampsia compared with those with normotensive pregnancies.30 In addition, the constrictor response elicited in umbilical arteries from women with preeclampsia demonstrated a decreased sensitivity to a potassium chloride–depolarizing solution.31 32 The decreased constrictor response to these agents in preeclampsia suggests a compensatory mechanism to counteract the increased resistance seen in this condition. However, no such change has been found in chorionic plate arteries.33
In summary, although ADM levels are elevated in many other hypertensive disorders, we did not find a significant difference in maternal plasma concentrations in either preeclampsia or GH compared with normal pregnancy. This lack of a compensatory response to the increased blood pressure may potentially worsen the cardiovascular state of such patients. We have also shown, for the first time, that ADM causes a dose-dependent relaxation of placental arteries. We conclude that ADM-induced vasodilation may contribute to the low vascular resistance seen in normal pregnancy. Furthermore, retention of this vasorelaxant activity in placental arteries derived from preeclamptic pregnancies may serve to attenuate the significant increase in placental vascular resistance associated with this condition. Studies are ongoing to investigate the mechanisms underlying the vasorelaxation caused by ADM in the placenta.
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Acknowledgments |
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This research was supported by the Medical Research Council. Dr Davidge is a scholar of the Alberta Heritage Foundation for Medical Research and the Heart and Stroke Foundation. We gratefully acknowledge Stacy Freeman and Walter Sumoski for their invaluable help in sample collection and Damon Mayes (Perinatal Research Center, University of Alberta) for his help in biostatistics. We wish to thank the Obstetricians at the Royal Alexandra Hospital, Edmonton, for permitting us to obtain blood samples.
Received April 26, 2000; first decision May 16, 2000; accepted August 2, 2000.
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