(Hypertension. 1998;31:1343-1349.)
© 1998 American Heart Association, Inc.
Eclamptic Plasma Stimulates Norepinephrine Release in Cultured Sympathetic Nerve
Selina Khatun;
Naohiro Kanayama;
Eiji Sato;
Hossain M. Belayet;
Takao Kobayashi;
; Toshihiko Terao
From the Departments of Obstetrics and Gynecology (S.K., N.K., H.M.B.,
T.K., T.T.) and Biochemistry (E.S.), Hamamatsu University School of Medicine,
Hamamatsu City, Japan.
 |
Abstract
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Abstract—The purpose of the
present study was to evaluate the effect of plasma from eclamptic
and preeclamptic patients on cultured sympathetic nerve. Sympathetic
neurons from 12- to 14-day-old chick embryos were cultured; the neurons
were then stimulated with 50% plasma from eclamptic, preeclamptic,
hypertensive, normotensive pregnant, hypertensive, and normotensive
nonpregnant women (n=7). Similarly, neurons were individually incubated
with mixtures of 50% corresponding plasma with 0.25% bupivacaine or
bupivacaine only (n=7). Furthermore, the effects of 1%, 10%, and 50%
plasma from eclamptic, preeclamptic, and normotensive pregnant patients
(n=7) were also evaluated. Norepinephrine concentrations
were measured by high-performance liquid
chromatography. Electron microscopic studies of nerve
cells were also performed. Stimulation with plasma from eclamptic and
preeclamptic women significantly increased norepinephrine
concentration (P<0.0001) compared with control. The
release of norepinephrine was found to be
concentration-dependent. Conversely, norepinephrine
secretion was significantly hampered by bupivacaine treatment
(P<0.0001). Electron microscopic studies in eclamptic
and preeclamptic plasma–stimulated nerve cells showed that perikarya
were in close contact with each other and with nerve cell processes.
After treatment with bupivacaine, nerve cells were irregular in shape
and the cell membranes were demyelinated. These results
suggest that eclamptic and preeclamptic plasma has an excitotoxic
effect on sympathetic nerve via axoplasmic membrane depolarization,
thus increasing norepinephrine secretion that is blocked by
bupivacaine. A preeclamptic condition may be improved by depression of
sympathetic nerve stimulation.
Key Words: eclampsia • sympathetic nervous system • norepinephrine • chick embryo • bupivacaine
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Introduction
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Experimental studies
have provided unequivocal evidence that eclampsia and preeclampsia are
states of sympathetic hyperactivity.1 2 NE
concentrations in plasma, platelets, and urine are elevated in
preeclampsia and eclampsia.1 3 4 5 6 NE is a
neurohormone released from the sympathetic nerve endings, and
stimulation of sympathetic nerve facilitates NE
secretion.3 Recently, Schobel et
al7 measured sympathetic activity in the peroneal
nerve with microneurography and found that the postganglionic action
potential was increased in preeclamptic women.
The sympathetic nerve tends to be irritated by various
stimulations such as environmental stress, physical stress, mental
stress, postural change, and insulin. Stimulation of sympathetic nerve
is not only involved in the pathophysiology of preeclampsia but can
also be a major cause of preeclampsia.8 Several other
studies have suggested previously that preeclamptic women exhibiting
heightened sympathetic activity are those with severe disease, with
such activity being a secondary response to other factors such as
plasma volume contraction.9 There is accumulating
evidence for a pathogenic model of preeclampsia, whereby stimulation of
sympathetic nerve results in decreases in placental blood flow, which
are somehow translated into a multisystem maternal disorder
characterized by vasoconstriction, platelet activation, and
intravascular coagulation, as well as increased capillary permeability.
The most popular hypothesis is that the ischemic fetoplacental
unit releases factors into the maternal circulation that lead to
systemic pathological changes with widespread
endothelial cell damage.9 10 For
instance, the repeated vasospasm and increased ET-1 levels found in
eclampsia and preeclampsia are evidence of endothelial
cell disorder in this disease.11 12 Moreover, the
action of ET-1 on peripheral postganglionic sympathetic
neurons mimics neuronal activity that causes rapid alterations in NE
concentrations.13 This attenuation could be
reversed by the replacement of lumbar epidural anesthesia,
which blocks the abdominal sympathetic nerve, thus improving
hypertension and biochemical parameters during preeclamptic
labor. In preeclampsia, the vascular changes are acute and transient
and react more rapidly to sympathetic
blockade.14
Our focus here is to elucidate whether stimulation of the sympathetic
nerve with plasma from eclamptic and preeclamptic women could induce NE
release in cultured sympathetic neurons.
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Methods
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Subjects
This study was approved in April 1995 by the research committees
of the institutes concerned, and all studies were performed in
accordance with institutional guidelines for human and animal research.
Consent was obtained from the patients or the patients' guardians (in
the case of eclamptic patients). We investigated eclamptic,
preeclamptic, hypertensive, and normotensive pregnant patients (n=7) in
the third trimester of pregnancy who were admitted to Dhaka Medical
College Hospital, Bangladesh. Normotensive and hypertensive nonpregnant
volunteer women (n=7) were also enrolled in this study. All the
eclamptic patients essentially met the criteria for preeclampsia and
also had had at least one episode of eclamptic convulsion either in the
hospital or at home. Based on history and clinical findings, there was
no other reason for the onset of seizures in the eclamptic patients.
Preeclampsia was defined as the development of hypertension with
proteinuria induced by pregnancy after the 20th week of gestation.
Hypertension was defined as a diastolic blood pressure of
at least 90 mm Hg or systolic blood pressure of at least
140 mm Hg, or a rise in the former of at least 15 mm Hg or
in the latter of 30 mm Hg over baseline values on two consecutive
readings at least 6 hours apart, with blood pressure reverting to
normal within 2 months after delivery. Proteinuria was defined as the
presence of 
300 mg protein in a 24-hour urine collection or a protein
concentration of 1 g/L in at least two random urine specimens
collected 6 hours or more apart.4 None of the
patients had hypertension before the 20th week of pregnancy. All cases
complicated by essential hypertension, cardiovascular
disease, diabetes, chronic renal disease, platelet disorder,
maternal or fetal infection, autoimmune disorders, and epilepsy were
excluded from this study. All hypertensive pregnant patients suffered
from essential hypertension, and none of the patients had proteinuria.
This indicates that the hypertension found in these patients was not
related to preeclampsia. The subjects were comparable with respect to
age, body weight, and duration of gestation. The important clinical
characteristics of the patients are summarized in Table 1
.
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Table 1. Characteristics of Eclamptic, Preeclamptic,
Hypertensive, Normotensive Pregnant, Hypertensive, and Normotensive
Nonpregnant Women
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Sample Collection
Blood was drawn in the morning in all except eclamptic patients,
for whom it was taken during admission to the emergency department of
the hospital. None of the eclamptic patients had received any
antihypertensive or anticonvulsive drugs before collection of blood.
Peripheral venous blood samples were collected immediately
after measurement of blood pressure by Korotkoff first and fifth sounds
with the patient in the recumbent position. Plasma samples (prepared
from blood collected in EDTA) were studied to avoid the confounding
effects of cellular products released into serum during blood
coagulation. Briefly, samples were maintained at 26°C for 2 to 4
hours before centrifugation at 2000g for 20
minutes; they were then portioned into aliquots under sterile
conditions and stored at -80°C. Samples obtained in Bangladesh were
transported by air in dry ice (at -40°C, within 16 hours) to
Hamamatsu University School of Medicine, Japan, where all experiments
were performed. There were no significant differences between subject
groups in time of storage or time from venipuncture to
centrifugation.
Analytical Methods
Platelets in plasma from 1-mL EDTA anticoagulated blood
samples were counted with a Coulter model ZM with a 70-µm aperture
tube.15 Platelet-rich plasma was prepared by
centrifugation at 120g for 10 minutes,
separated from the sedimented red blood cells with a plastic pipette,
and transferred to a capped polystyrene tube. Platelet counts were
done with platelets in isotonic NaCl solution at room temperature.
Hematocrit level was determined in these blood samples before plasma
was spun off by the microhematocrit method using heparinized capillary
tubes (SRL) centrifuged in an MB centrifuge
(International Equipment Company). For measurement of ET-1, plasma
samples were subjected to a sandwich-type EIA (Takeda Chemical
Industries Ltd). ET-1 was extracted from 0.5 mL plasma using Sep-Pak
C-18 cartridges (Waters, Millipore Corp). The extracts were dissolved
in 250 µL of buffer D and measured with a sandwich EIA. Briefly,
microtest plates coated with rabbit anti–ET-1 C-terminal heptapeptide
(15–21) antibodies (30821) were incubated at 37°C for 1 hour with
100 µL of standard solutions or plasma samples. After a washing with
PBS, the plates were allowed to react at 37°C for 30 minutes with 100
µL horseradish peroxidase–labeled rabbit anti–ET-1 N-terminal loop
domain antibody (30846). The plates were washed with PBS, and the bound
enzyme activities were measured using
o-phenylenediamine as a chromogen. The EIA
did not cross-react with big ET-1. The detection limit of ET-1 was 0.4
nmol per well.
Neuron Culture
Sympathetic neurons were obtained from the paravertebral lumbar
sympathetic chains of 12- to 14-day-old chick embryos (White Leghorn
strain). The culture was done as previously described by
Freshney.16 Briefly, the lumbar sympathetic
trunks were separated, and the individual ganglia were then dissected
by cutting the trunks between each ganglion, using a stereomicroscope
(Zeiss, Stemi 2000). The sympathetic neurons were comparable in size
and weight. The ganglia were immersed in a culture nutrient medium on
glass coverslips in Petri dishes (35x10 mm, Falcon Becton
Dickinson). The media consisted of cockerel plasma (50 µL, Japan
Biotest Institute), chick embryonic extract (5 µL), Eagle's minimal
essential medium (45 µL, MEM, Nissui Pharmaceutical Co, Ltd), and
nerve growth factor (5 µL, 100 ng/mL concentration 7S NGF, Wako).
Plasma clots were made of equal parts of heparinized cockerel plasma
and chick embryonic extract with Eagle's minimal essential medium. The
dishes were kept in a chamber of an incubator (Astec) that was gassed
with 5% CO2/95% O2 and
incubated for 24 hours at 37°C.
Stimulation With Different Percentages of Plasma and
Bupivacaine
After 24 hours of culture, the sympathetic nerves were
randomized and incubated for 6 hours with 1%, 10%, and 50% plasma
from eclamptic, preeclamptic, hypertensive, normotensive pregnant,
hypertensive, and normotensive nonpregnant women. In addition,
sympathetic neurons were incubated with mixtures of bupivacaine
(0.25%) with individual plasma (50%) from eclamptic, preeclamptic,
hypertensive, normotensive pregnant, hypertensive, and normotensive
nonpregnant women. Sympathetic nerve stimulation also was conducted
with bupivacaine (0.25%) only. Each incubation was performed in
duplicate wells on seven separate occasions. The samples were collected
and homogeneously mixed for NE measurement. Moreover, the
NE concentration was also measured in plasma in diluted condition (50%
plasma and 50% culture media) from eclamptic, preeclamptic,
hypertensive, normotensive pregnant, hypertensive, and normotensive
nonpregnant women.
Measurement of NE Concentration
The concentrations of NE were measured with the Tosoh automatic
catecholamine analyzer HLC-725CA, an HPLC system
that uses the specific highly sensitive fluorescent reagent
diphenylethylenediamine (DPE) for catecholamine
measurement.17 This analyzer can measure
as little as 0.03 nmol/L of NE. Samples were analyzed in
duplicate after the triplicate determination of the standard solution,
1 nmol/L of NE hydrochloride. Plasma concentrations of NE were
calculated by comparing the peak heights of samples with those of the
standard solution. The standard NE solution and NE concentration in the
samples were measured 15 times consecutively to determine the
reproducibility of the measured free NE concentration. The
reproducibility of the sample's NE concentration was 4.17±0.041
nmol/L. The intra-assay coefficient variation for free NE was
<1.0%.
Electron Microscopic Study
The stimulated sympathetic nerve tissues were fixed for electron
microscopic study with 2% glutaraldehyde in 0.14 mol/L
phosphate buffer (pH 7.4) for 2 hours at 4°C. After a washing with
0.14 mol/L phosphate buffer, the specimens were postfixed with 1%
OsO4 in the same buffer for 2 hours. The
specimens were then dehydrated in an ethanol series, and cells were
embedded in epoxy resin. The ultrathin sections were cut with an
LKB-Ultrotome, using a diamond knife, and poststained with lead citrate
and uranyl acetate. The microscopic observations and photographs were
made using a JEOL JEM 1220 electron microscope at 80 kV.
Statistical Analysis
The results are reported as mean±SD. A value of
P<0.05 was considered statistically significant. Repeated
measure ANOVA was used to determine the difference between percent
concentration variables. Factorial ANOVA was used to
analyze the changes in NE concentration after different
stimulations and to compare the clinical parameters in
eclamptic, preeclamptic, hypertensive, normotensive pregnant,
hypertensive, and normotensive nonpregnant women.
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Results
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The concentrations of NE after stimulation of cultured sympathetic
nerve with 50% plasma from eclamptic, preeclamptic, hypertensive,
normotensive pregnant, hypertensive, and normotensive nonpregnant women
and a mixture of 50% corresponding plasma with 0.25% bupivacaine are
shown in Figure 1. The NE concentration
in the control cultured sympathetic nerve was 13.4±1.2 nmol/L, and
after stimulation with bupivacaine this concentration decreased to
9.0±0.7 nmol/L. Stimulation with eclamptic and preeclamptic plasma
showed a significant increase in NE level compared with control
(22.0±1.1 and 19.2±1.3 nmol/L, respectively; P<0.0001). A
marked decrease in NE secretion also was observed after treatment with
the mixture of plasma and bupivacaine, which was greater than that
after stimulation with respective plasma only (16.6±1.6 and 15.5±1.2
nmol/L, respectively; P<0.0001). No significant changes in
NE content were found after stimulation with plasma from hypertensive,
normotensive pregnant, hypertensive, and normotensive nonpregnant women
(14.2±1.2, 13.9±1.3, 13.7±0.9, and 13.4±1.1 nmol/L, respectively)
compared with control. Moreover, a significant decrease in NE secretion
was also found after individual stimulation with the mixtures of
respective plasma and bupivacaine compared with stimulation with
corresponding plasma only (9.8±0.8, 9.3±0.9, 9.2±0.9, and 9.0±1.5
nmol/L, respectively; P<0.0001). NE concentrations in
diluted plasma from eclamptic, preeclamptic, hypertensive, normotensive
pregnant, hypertensive, and normotensive nonpregnant women were found
to be 5.7±0.6, 5.3±0.5, 4.9±0.6, 4.8±0.7, 4.7±0.7, and 4.5±0.6
nmol/L, respectively.
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Figure 1. Concentration of NE in cultured sympathetic nerve
after stimulation with 50% plasma from preeclamptic, eclamptic,
hypertensive, normotensive pregnant, hypertensive, and normotensive
nonpregnant women, with 0.25% bupivacaine, and with mixtures of 50%
corresponding plasma with 0.25% bupivacaine. The concentration of NE
was significantly increased with eclamptic and preeclamptic plasma
stimulation. Stimulation with mixtures of respective plasma with
bupivacaine and with bupivacaine only hampered the secretion of NE more
than respective plasma stimulations. Values represent mean±SD,
n=7. *P<0.05 vs control,  P<0.05 vs
respective plasma stimulation.
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The NE concentrations in the cultured sympathetic nerve after
stimulation with different percentages of plasma from eclamptic,
preeclamptic, and normotensive pregnant patients are illustrated in
Figure 2. Stimulation with 10% and 50%
eclamptic and preeclamptic plasma significantly increased NE secretion
(P<0.0001) compared with stimulation with 1% plasma.
However, the NE concentration was higher after stimulation with
eclamptic than with preeclamptic plasma. Furthermore, 50% eclamptic
and preeclamptic plasma increased NE secretion to a greater extent than
did 10% plasma (P<0.0001). Treatment with 1% plasma from
eclamptic and preeclamptic patients and different percentages of plasma
from normotensive pregnant patients had no significant effect on NE
secretion.
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Figure 2. NE concentrations after stimulation of cultured
sympathetic nerve with 1%, 10%, and 50% plasma from eclamptic,
preeclamptic, and normotensive pregnant women. Stimulation with 10%
and 50% eclamptic and preeclamptic plasma significantly increased the
NE concentration. The level of NE was markedly greater after
stimulation with eclamptic plasma than after preeclamptic stimulation.
Incubation with 1% eclamptic plasma, preeclamptic plasma, and
different concentrations of normotensive pregnancy plasma could not
induce the secretion of NE. Values represent mean±SD, n=7.
*P<0.05 vs control.
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The platelet count, hematocrit level, and ET-1 concentration in
eclamptic, preeclamptic, hypertensive, normotensive pregnant,
hypertensive, and normotensive nonpregnant women are summarized in
Table 2. Platelet count significantly
decreased, ET-1 level markedly increased, and severe hemoconcentration
was observed in eclamptic (P<0.0001) and preeclamptic
(P<0.0001) patients compared with normotensive pregnant
women. Fewer significant changes in platelet count, hematocrit
level, and ET-1 concentration were found in hypertensive pregnant,
hypertensive, and normotensive nonpregnant women than in normotensive
pregnant patients.
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Table 2. Clinical Parameters of Eclamptic,
Preeclamptic, Hypertensive, Normotensive Pregnant, Hypertensive, and
Normotensive Nonpregnant Women
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The correlation between NE concentration in the cultured sympathetic
nerve after stimulation with eclamptic and preeclamptic plasma and ET-1
level in the plasma of the corresponding patients is shown in Figure 3. A significant positive correlation
between NE concentration and ET-1 levels was observed in both cases.
The correlation coefficient and probability values were
r=0.677, P<0.0001 and r=0.583,
P<0.0001, respectively.
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Figure 3. Correlation between NE concentration in the
cultured sympathetic nerve (after stimulation with eclamptic and
preeclamptic plasma) and ET-1 level in the respective plasma is shown.
NE concentration was significantly correlated with ET-1 level in
eclamptic (r=0.677, P<0.0001) and
preeclamptic (r=0.583, P<0.0001)
plasma.
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The cultured explants of the chick sympathetic nerve consisted of
neural and nonneural cells. The electron micrographs of nerve cell
histology are shown in Figure 4. The
histology of nerve, stimulated by plasma from eclamptic and
preeclamptic women, shows that nerve cells were enlarged and irregular
in shape (4A and 4B). The perikarya of nerve cells were in close
contact with each other and with the nerve cell processes. The nerve
fibers were in tightly arranged fascicles between the cells, compared
with the control and sham control histology (4C and 4D). Demyelination
of the cell membranes and irregular shapes were found in
bupivacaine-treated nerve (4E).
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Figure 4. A and B, Preeclamptic and eclamptic
plasma–stimulated nerve cells are enlarged and irregular in shape.
Perikarya are in close contact with each other and with the nerve cell
processes (arrows). C and D, Control and sham control cells are normal
in size and shape. E, Bupivacaine-stimulated neuron cells are irregular
in shape, and the cell membranes are demyelinated (arrows).
Original magnification x2700.
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Discussion
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The major findings of the present study are that the NE
contents in sympathetic neurons were markedly enhanced when they were
stimulated with plasma from eclamptic and preeclamptic women compared
with plasma from normotensive pregnant women. It is likely that plasma
from eclamptic and preeclamptic women contains various factors that
exert a trophic influence on the sympathetic neurons to increase their
noradrenergic properties. Complicated pregnancies, such
as those involving eclampsia, show marked changes in stimulation of the
sympathetic nervous system in the production of
NE.1 An earlier report demonstrated that the
postganglionic action potential in sympathetic nerve fibers was
increased in preeclampsia.7 Recently, we
suggested that sympathetic nerve stimulation is responsible for
vasospasm and endothelial injury resulting in
preeclampsia-like phenomena.8 18 19 In our
present experiment, stimulation with plasma from eclamptic patients
showed higher values than plasma from preeclamptic patients. Eclampsia
produces more acute stress than preeclampsia, resulting in an abnormal
stimulation of the sympathetic nervous system. The seizures in the
eclamptic condition might accelerate the production of factors
that are responsible for increased secretion of NE. The mechanism by
which NE secretion is increased is not clearly known. There may be two
possibilities: (1) increases in the synthesis of NE in the nerve cell
and (2) increases in neuronal release of NE from storage sites.
Stimulation of the sympathetic nervous system in eclampsia and
preeclampsia may also be a secondary phenomenon.
Previous observations demonstrated that biosynthesis of NE was
accelerated by application of biopterin, a cofactor for tyrosine
hydroxylase also known as catecholamine biosynthetic
enzyme.20 21 Kessler22
found that the membrane depolarization in cultures stimulates the
development of noradrenergic traits, such as tyrosine
hydroxylase, and increases catecholamine synthesis in
sympathetic neurons. It is well known that plasma of eclamptic and
preeclamptic women contains high levels of ET-1, insulin, and
thrombin.11 23 24 ET-1 and insulin were found to
stimulate the sympathetic nerve,13 25 and the
existence of thrombin receptor in the nerve cells was
demonstrated.26 Although the exact factors
responsible for sympathetic nerve stimulation in this study are not
clearly understood, such mediators might be candidates. The
depolarization effects of ET-1 on peripheral postganglionic
sympathetic neurons have been suggested.13 A
significant correlation between the NE and ET-1 concentrations exists
in both eclamptic and preeclamptic patients. NE (a neurohormone) and
ET-1 (a marker of endothelial injury) are important
parameters to determine the status of this disease.
Elevated NE and ET-1 levels might increase parallel to the progression
of this disease. Hemoconcentration is another confirming factor in
eclampsia and preeclampsia.27 28 Increased
hematocrit concentration and decreased platelet count in eclamptic
and preeclamptic women reflect hemoconcentration and intravascular
coagulation. One of the early pathophysiological
changes in eclampsia and preeclampsia is endothelial
cell disorder leading to vasoconstriction, thus enhancing capillary
permeability and intravascular coagulation.12 The
increase in plasma factors such as ET-1 and hemoconcentration found in
our experiment might be responsible for depolarization of sympathetic
neurons and thus acceleration of NE secretion. Electron microscopic
findings also support the membrane depolarization phenomenon. Clearly,
elucidation of the factors of sustained axoplasmic membrane
depolarization and the mechanism of NE increment awaits further
studies.
A concentration-dependent effect was found after stimulation with
plasma from preeclamptic and eclamptic women, with the increment of NE
concentration being greater with 50% than with 10% plasma. Moreover,
1% plasma from eclamptic and preeclamptic women and various
concentrations of plasma from normotensive pregnant patients could not
induce NE secretion. This implies that the increased concentration of
NE in the preeclamptic and eclamptic condition is closely related to
the severity of the disease. The failure of plasma from hypertensive
pregnant women without superimposed preeclampsia demonstrates that
effects of plasma from preeclamptic and eclamptic women relate to the
disease and not just to the hypertension. Recently, we reported that
plasma catecholamine levels are closely correlated to the
degree of eclampsia.4 This result seems to be
compatible with the findings of our present experiment.
Stimulation of the sympathetic nerve with a mixture of
bupivacaine and eclamptic or preeclamptic plasma blunted the increased
NE levels that have been seen in stimulation with plasma from eclamptic
or preeclamptic patients only. Bupivacaine is thought to hamper the
effect of plasma from eclamptic and preeclamptic women through the
blockade of sympathetic stimulation. We also observed that incubation
of cultured sympathetic neurons with bupivacaine significantly
decreased NE secretion. The catecholamine transport system
across the axoplasmic membrane is Na+-dependent
and is blocked selectively by a number of drugs, such as bupivacaine.
Local anesthetics block the conduction of nerve impulses by decreasing
the permeability of excitable membranes to Na+,
which produces a slight depolarization of the
membrane.29 The blockade of depolarization
affects the normal development of tyrosine hydroxylase activity and
thus hampers NE secretion.30 Electron microscopic
studies of bupivacaine-treated nerve cells showed demyelination of the
nerve cells, and the myelin sheath appeared to be more sensitive. The
demyelination of nerve cells implies the blockade of depolarization
effects. Additional support for this hypothesis is derived from reports
that lumbar epidural anesthesia blocks sympathetic nerve
activities and thus improves the symptoms and biochemical
parameters in preeclampsia.14 31 32
The results of the present study are compatible with those of
previous reports, since our data show that stimulation with bupivacaine
impaired NE secretion more than stimulation with eclamptic plasma,
suggesting that hyperstimulation of the sympathetic nervous system in
the eclamptic condition improves with bupivacaine treatment.
In conclusion, plasma from eclamptic and preeclamptic women has a
potent depolarizing effect on the sympathetic nerve. Depression of the
sympathetic nervous system may be an important treatment of
preeclampsia.
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Selected Abbreviations and Acronyms
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|---|
| EIA |
= |
enzyme immunoassay |
| ET-1 |
= |
endothelin-1 |
| HPLC |
= |
high-performance liquid chromatography |
| NE |
= |
norepinephrine |
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Acknowledgments
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This study was supported by a grant from the Japanese Ministry
of Education and Science (No. 08457439) and the Adeza Biomedical grant
(USA). We are indebted to Dr Sultana Jahan, Department of Obstetrics
and Gynecology, and Dr Faruque A. Azim, Department of Pathology, Dhaka
Medical College and Hospital, Bangladesh, for their contribution to the
collection of blood samples and clinical details in Bangladesh. Yoko
Kumakiri, Central Laboratory of Electron Microscopy, Hamamatsu
University School of Medicine, Japan, is sincerely thanked for her
expert technical assistance in the electron microscopic
investigations.
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Footnotes
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Reprint requests to Selina Khatun, MBBS, Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, 3600 Handa-cho, Hamamatsu City, Shizuoka, 431–31, Japan.
Received November 5, 1997;
first decision November 25, 1997;
accepted January 19, 1998.
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Abstract
Introduction
