Cellular-Free Magnesium Depletion in Brain and Muscle of
Normal and Preeclamptic Pregnancy
A Nuclear Magnetic Resonance Spectroscopic Study
Lawrence M. Resnick, Mario Barbagallo, Mordechai Bardicef, Orit Bardicef, Yoram Sorokin,
Jeffrey Evelhoch, Ligia J. Dominguez, Brian A. Mason, David B. Cotton
Abstract—Preeclampsia is a pregnancy disorder of unknown origin, characterized by vasospasm, elevated blood pressure,
and increased neuromuscular irritability, features common to syndromes of magnesium deficiency. Evidence of serum
and ionized magnesium metabolism disturbances have been observed in women with preeclampsia. This and the
therapeutic utility of magnesium in preeclampsia led us to investigate the extent to which an endogenous tissue
magnesium deficiency might be present in and contribute to its pathophysiology. We used 31P nuclear magnetic
resonance spectroscopy to noninvasively measure in situ intracellular-free magnesium levels in brain and skeletal
muscle of fasting nonpregnant women (n⫽12), and of third trimester women with uncomplicated pregnancies (n⫽11)
and preeclampsia (n⫽7). Compared with nonpregnant controls (brain 519⫾59 ␮mol/L; muscle 604⫾34 ␮mol/L), brain
and skeletal muscle intracellular magnesium levels were significantly lower in both normal pregnant (brain
342⫾23 ␮mol/L; muscle 482⫾40 ␮mol/L; P⫽0.05 for both tissues) and preeclamptic women (brain 229⫾17 ␮mol/L;
muscle 433⫾46 ␮mol/L; P⫽0.05 for both tissues). Brain intracellular magnesium was further reduced in preeclamptics
compared with normal pregnant subjects (P⫽0.05). For all pregnant subjects, blood pressure was significantly and
inversely related to the concomitantly measured intracellular magnesium level in brain (systolic, r⫽⫺0.59, P⫽0.01;
diastolic, r⫽⫺0.52, P⫽0.02) but not in muscle. Cellular magnesium depletion is characteristic of normal pregnancy and
may be one factor contributing to the pathophysiology of preeclampsia. Furthermore, the influence of central nervous
system factors on blood pressure may be mediated, at least in part, by ambient intracellular magnesium levels.
(Hypertension. 2004;44:1-5.)
Key Words: preeclampsia 䡲 magnesium 䡲 metabolism 䡲 ions 䡲 pregnancy
H
ypertension is the most common medical disorder during pregnancy.1 The exact incidence of gestational
hypertension–preeclampsia in the United States is unknown.
Estimates indicates that 5% to 8% of all pregnant women will
have preeclampsia, defined as hypertension and proteinuria
beginning during the second half of gestation.1 Preeclampsia
may also be associated with increased neuromuscular irritability and seizures.2 Interestingly neuromuscular excitability,
vasoconstriction, elevated blood pressure (BP), and increased
vascular sensitivity to pressor agents are also characteristic of
magnesium (Mg) depletion.3,4
The therapeutic use of intravenous Mg sulfate is universal,
at least in the United States, for women with mild preeclampsia to prevent eclampsia seizures,5,6 and its effectiveness has
been confirmed in a recent metaanalysis showing that parental Mg more than halves the risk of eclampsia.7 However, a
clear role of Mg deficiency in the pathophysiology of
preeclampsia has not been clearly established,1,8,9 and dietary
Mg supplementation does not seem to prevent the subsequent
incidence of preeclampsia.10
Our group has developed the use of 31P nuclear magnetic
resonance (NMR) spectroscopic techniques to noninvasively
measure intracellular-free magnesium (Mgi) content in a
variety of clinical disease states, such as hypertension, where
Mgi levels were closely and inversely related to the height of
BP.4 We have extended these NMR techniques to include the
analysis of Mgi in situ in intact tissues such as brain and
skeletal muscle tissues, where brain Mgi was also closely
related to BP.11
Therefore, to investigate cellular Mg metabolism in hypertensive disorders of pregnancy, we measured brain and
skeletal muscle Mgi concentrations in situ in nonpregnant and
pregnant women with and without the diagnosis of preeclampsia. Our present results document that tissue Mg
Received February 14, 2004; first decision March 1, 2004; revision accepted June 22, 2004.
From the Weill Medical College of Cornell University (L.M.R., O.B.) New York, NY; the Department of Obstetrics and Gynecology (M.B., Y.S.,
B.A.M., D.B.C.), Magnetic Resonance Center (J.E.), Wayne State University of Medicine, Detroit, Mich; and the Geriatric Unit (M.B., L.J.D.), University
of Palermo, Italy.
Correspondence to Mario Barbagallo, MD, PhD, Chair of Geriatrics, University of Palermo, Via F Scaduto 6/c, 90144 Palermo, Italy. E-mail
mabar@unipa.it
© 2004 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000137592.76535.8c
1
2
Hypertension
September 2004
Figure 1. 31P NMR spectra obtained
from brain (left) and skeletal muscle
(right) of a study nonpregnant control.
PME indicates phosphomonoesters; Pi,
inorganic phosphate; PDE, phosphodiesters; PCr, phosphocreatinine; ␥, ␣,
␤-NTP, ␥, ␣, and ␤ nucleoside triphosphate (predominantly adenosine triphosphate) phosphoryl resonances.
depletion is a characteristic feature of normal pregnancy,
especially those complicated by preeclampsia. Furthermore,
the quantitative relation of cellular-free Mg content to concomitant BP levels also suggests a role for cellular Mg
deficiency in the pathophysiology of preeclampsia.
Methods
Three groups of patients were studied: (1) nonpregnant women of
reproductive age (n⫽12), (2) unmedicated third trimester women
with uncomplicated pregnancies (n⫽11), and (3) unmedicated third
trimester pregnant women with preeclampsia (n⫽7). Diagnosis of
preeclampsia was based on the following criteria1: increased BP
accompanied by proteinuria, edema, or both. Hypertension was
defined as a diastolic BP ⱖ90 mm Hg, a systolic BP ⱖ140 mm Hg,
a rise in the former of ⱖ15 mm Hg, or in the latter of 30 mm Hg.
These altered BP readings were obtained on at least 2 separate
occasions 6 hours or more apart. Patients taking medication, with
other existing medical problems, or both were excluded, as were all
patients with any contraindication for MR. The study was approved
by the Human Investigation Committee of Wayne State University.
Written informed consent was obtained from all patients, and the
procedures followed were in accordance with institutional guidelines. All women were clinically evaluated in the morning after an
overnight fast. BP measurements were taken with the patient relaxed
in a sitting position in a quiet room at a comfortable temperature after a
short period of rest, and, if stable, patients were transferred to the MR
center for brain and skeletal muscle NMR spectroscopy determination.
NMR Evaluation
10.0 minutes for muscle). This provided 31P NMR spectra from
contiguous 1.25-cm-thick 8- or 9-cm-diameter slices within the
sensitive volume of the surface coil. 31P CSI data set was processed
on the Siemens VAX 4000. A 1 to 5 Hz Lorentzian filter was applied
and the CSI data were Fourier transformed in 2 dimensions (1 spatial
and 1 chemical shift). For further analysis, a single spectrum was
selected from each CSI data set on the basis of resolution, sensitivity,
and, in the case of brain, phosphocreatinine and phosphomonoesters
levels consistent with brain 31P spectra. The baseline roll caused by
the acquisition delay was removed by fitting and subtracting a cubic
spline function to each spectrum. Peak positions were estimated from
the spectra of interest using Siemens software.
Calculation of Mgi and pHi
For the selected brain and muscle spectra, Mgi levels were calculated
from the observed difference between the chemical shift difference
of the ␣- and ␤-phosphoryl resonances of ATP, as previously
described in detail.4,13 pHi values were also calculated from the same
31
P NMR spectra, as previously described.13
Statistical Analysis
Analysis of the data was performed using statistical software on a
Macintosh personal computer (Stat View 4.01 and Super Anova,
Abacus Concepts). To compare differences in variables among the
diagnostic groups, 1-factor ANOVA was used with post-hoc testing
(Bonferroni) for significance. Comparison between muscle and brain
values for both Mgi and pHi in each group used paired Student t test
analysis. Relationships between BP and Mgi levels used linear
regression analysis with Pearson correlation coefficients. All values
are reported as mean⫾SEM.
31
P NMR spectra was obtained from the brain and gastrocnemius
muscle using 1D chemical shift imaging (CSI)12 (Figure 1). For brain
CSI, subjects were placed in the magnet on their side with a 9-cm
surface coil placed over the temporal parietal region. For muscle
CSI, subjects were placed in the magnet on their side (pregnant
subjects) or prone (normal subjects) with an 8-cm surface coil placed
over the gastrocnemius muscle. The water 1H signal was used to
optimize the magnetic field homogeneity (ie, shim so that the water
line width was 10 to 15 Hz). One-dimensional CSI data sets were
acquired with a repetition time of 3 seconds, 60° adiabatic pulse
(roughly the optimum flip angle for the ATP peaks), 0.5-ms
triangular phase encoding gradients, 0.5-ms acquisition delay, 1024
data points with a 512-ms acquisition time (4000 Hz spectral width),
and 12 (brain) or 6 (muscle) acquisitions for each of 32-phase
encoding steps (total acquisition time was 19.6 minutes for brain and
Results
The clinical characteristics of all patients are presented in
Table 1. All 3 patient groups were equivalent in age, and
among pregnant subjects, in gestational age at the time of
NMR-based intracellular ion measurements. Systolic and
diastolic blood pressures were significantly higher in the
preeclamptic patients compared with both nonpregnant and
normal pregnant subjects (P⬍0.0001 and P⫽0.0007, respectively). Four preeclamptic women had mild preeclampsia, 2
had severe preeclampsia, and 1 had preeclampsia superimposed on prior ongoing chronic hypertension. All preeclamptic women were induced, and 5 of them delivered prema-
TABLE 1. Clinical Characteristics of Nonpregnant, Pregnant, and
Preeclamptic Women
Age (y)
Systolic Blood
Pressure (mm Hg)
Diastolic Blood
Pressure (mm Hg)
Nonpregnant (n⫽12)
28.2⫾1.2
118⫾3
71⫾3
Pregnant (n⫽11)
23.8⫾1.8
110⫾4
71⫾3
35.2⫾0.8
Preeclampsia (n⫽7)
24.8⫾2
150⫾6*
91⫾4*
34.1⫾1.2
Study Group
*P⬍0.001 vs both nonpregnant and normal pregnant subjects.
Gestational
Age (wk)
Resnick et al
Intracellular Magnesium in Preeclampsia
3
TABLE 2. Brain and Skeletal Muscle Intracellular-Free Magnesium and pH
Levels in Nonpregnant, Pregnant, and Preeclamptic Subjects
Study Group
Brain Mgi
(␮mol/L)
Muscle Mgi
(␮mol/L)
Brain pHi/TD
Muscle pHi
Nonpregnant (n⫽12)
519⫾59
604⫾34
7.03⫾0.017
7.08⫾0.005
Pregnant (n⫽11)
342⫾23*
483⫾41*
7.07⫾0.012
7.09⫾0.008
Preeclampsia (n⫽7)
229⫾17*†
433⫾46*
7.06⫾0.012
7.10⫾0.011
Mgi indicates intracellular-free magnesium; pHi, intracellular pH.
*P⫽0.0005 (ANOVA), P⫽0.05 vs nonpregnant.
†P⫽0.01 (ANOVA), P⫽0.05 vs pregnant.
turely. The gestational age at the time of delivery (35.8⫾1.1
versus 39.4⫾0.5 weeks, P⫽0.008) and the birth weights
(2480⫾323 versus 3243⫾177 g, P⫽0.04) were lower among
the preeclamptic group versus controls. Two preeclamptic
women were delivered by caesarean section (1 for fetal
distress and 1 for intrauterine growth retardation and fetal
distress).
The values of Mgi and pHi in brain and skeletal muscle are
displayed in Table 2. Both pregnant and preeclamptic individuals had significantly lower brain and muscle Mgi levels
than nonpregnant patients (ANOVA; brain, P⫽0.0005; muscle, P⫽0.01; P⫽0.05 for both versus nonpregnant). In addition, brain Mgi levels in women with preeclampsia were
significantly further suppressed compared with pregnant patients themselves (P⫽0.05; Figure 2).
For all pregnant subjects, a significant inverse relation was
observed between both systolic and diastolic BP and the
concomitant measured cellular-free Mgi levels in brain (systolic blood pressure, r⫽⫺0.59, P⫽0.01; diastolic blood
pressure, r⫽⫺0.52, P⫽0.02; Figure 3). No significant relations were observed between BP and muscle Mgi levels. No
relation was also present between the length of pregnancy and
the occurrence of low brain Mgi concentrations.
Pregnancy was associated with an altered relationship
between brain and muscle Mgi values. In nonpregnant controls, brain and muscle Mgi levels were equivalent. However,
in both pregnant groups, brain Mgi levels were significantly
lower than levels in muscle (pregnant controls, P⫽0.01;
preeclampsia, P⫽0.004) because of the greater fall in brain
Mgi values during pregnancy (Figure 4). Altogether, for all
subjects, despite these effects related to pregnancy, brain and
muscle Mgi values were significantly and positively related
(r⫽0.55, P⬍0.002). pHi values in brain and muscle did not
differ significantly among any of the diagnostic groups
(Table 2).
Figure 2. Mgi in nonpregnant, pregnant, and preeclamptic
women. NP indicates nonpregnant; P, pregnant; PE,
preeclampsia.
Figure 3. Relation of brain Mgi levels and blood pressure in
pregnancy. SBP indicates systolic blood pressure; DBP, diastolic blood pressure.
Discussion
Applying NMR spectroscopic techniques to noninvasively
measure Mgi levels in pregnancy, we have observed in this
study: (1) that pregnancy itself is characterized by lower Mgi
values both in brain and muscle tissue; (2) that brain Mgi
levels are further suppressed in preeclamptic compared with
normal pregnant and nonpregnant women; (3) that both
systolic and diastolic blood pressures are quantitatively and
inversely related to brain Mgi values; and lastly, (4) Mg
depletion in pregnancy appears to be differentially expressed
in brain vis a vis muscle, Mgi concentrations being equivalent
in the nonpregnant state, but, with pregnancy, decreasing in
brain to a greater extent than in muscle.
Mg functions intracellularly as a necessary cofactor of
⬎300 enzyme systems, and a decrease in cellular Mg would
result in partial membrane depolarization and decreased
repolarization in association with cellular calcium accumulation and potentiated calcium-dependent cell actions including, in smooth muscle, vasoconstriction14 –17; in neural tissue,
enhanced sympathetic activity18,19; and in skeletal muscle and
fat tissue, insulin resistance.20,21 These alterations have indeed been reported in cellular Mg– deficient states, such as
essential hypertension4 and noninsulin-dependent diabetes
mellitus.16 Furthermore, these same defects can be induced
4
Hypertension
September 2004
Figure 4. Brain versus muscle Mgi levels in nonpregnant, pregnant, and preeclamptic women.
experimentally by dietary Mg depletion,22,23 directly causing
vasoconstriction or vascular spasm in various vascular beds
including cerebral, coronary, and placental vessels as well as
elevated BP, increased neuromuscular irritability, and frank
tetany.24 –25
Historically consistent with the above, it was the ability of
Mg to suppress neural irritability that first led investigators
more than 70 years ago to use Mg therapeutically in preeclamptic pregnancy,26 and Mg sulfate remains a standard
therapeutic maneuver and the drug of choice to prevent
convulsions in women with preeclampsia, although the exact
mechanism of action of Mg remains unknown.1,2,5,6 Two
recent randomized trials have documented that Mg sulfate is
superior to a placebo for prevention of convulsions in women
with severe preeclampsia.27,28 Among all women enrolled in
the large Magpie trial, 1 of the largest randomized trials to
date that enrolled 10 141 women with preeclampsia in 33
nations, the rate of eclampsia was significantly lower in those
assigned to Mg sulfate (0.8% versus 1.9%; relative risk, 0.42;
95% confidence interval, 0.29, 0.60).27 A recent Cochrane
systematic review has shown that Mg sulfate is superior to
other regimens for preventing eclamptic seizures, more than
halving the risk, and may reduce the risk of maternal death,
although not improving the outcome for the baby.7 However,
despite the long-standing therapeutic use of intravenous Mg
sulfate in preeclampsia, oral magnesium supplementation
does not seem to influence the incidence of preeclampsia.10
Clinically, Mg deficiency and preeclampsia share many
features, including placental vasospasm, elevated BP, and
increased neuromuscular irritability. This and our previous
findings of cellular Mg deficiency in essential hypertension,4,16 made it seem reasonable to investigate the possibility
that an endogenous-tissue Mg depletion might underlie or
predispose to at least some pathophysiological aspects of
preeclampsia. Surprisingly, although this hypothesis has been
suggested,25 it is virtually absent from discussions of the
cause of preeclampsia in current textbooks of obstetrics.8,9
Our present findings suggest a role for cellular Mg depletion,
especially in the central nervous system, in predisposing to or
directly participating in the pathophysiology of preeclampsia.
From our data we cannot determine the mechanism of the
more pronounced suppression of Mg levels found in the brain
tissue (Table 2) and whether these tissue specific alterations
are related to the increased predisposition to neuromuscular
irritability and seizures of preeclampsia as it is suggested.
This should be the goal of future studies.
However, we believe the present observations add significantly to previous studies in pregnancy, which have been
few, that have usually measured total rather than free Mg
concentrations and have focused on circulating blood cells.
Kisters et al observed significantly lower erythrocyte total
cellular and membrane Mg content29 but not altered plasma
total Mg levels in preeclampsia versus normal pregnant
women, suggesting the presence of a disturbance in the
transmembrane Mg distribution in preeclampsia. In contrast,
Ryzen et al, measuring total Mg per mg cell protein in
circulating mononuclear cells of preeclamptic versus normal
pregnant subjects, did not detect lower total cellular Mg
levels.30 Interestingly, compared with nonpregnant subjects,
both normal pregnant and preeclamptic subjects had lower
extracellular total Mg levels in this study. Using recently
developed ion-specific Mg electrode techniques, we and
others have also observed a deficit in biologically active
ionized Mg in pregnant and preeclamptic women, which in
itself could be responsible for the presently observed lower
Mgi values in brain and muscle tissue.31,32 Similar to our
findings in muscle, circulating Mg levels in preeclamptic
subjects were no further suppressed than those in normal
pregnancies.31,32 Altogether, these previous studies may be
limited by the fact that plasma, erythrocyte, and white blood
cell total Mg content may poorly reflect total body Mg status,
and that metabolically active cellular-free Mg activity represents only 10% to 20% of total cellular Mg.
Despite the suggestion emerging from this study of a role
for Mg, especially in the central nervous system, in the
regulation of BP in pregnancy and preeclampsia, certain
caveats need to be considered. First, longitudinal data obtained serially during pregnancy are required to ascertain
whether or not the development of Mg depletion necessarily
corresponds with BP throughout pregnancy and thus in
particular, whether preeclamptic pregnancies can be distinguished before the onset of clinical signs and symptoms.
However, at least in experimental animals, Schooley et al
have recently shown that a moderate dietary Mg deficiency
during pregnancy in rats leads to significantly increased BP.33
Second, the mechanism by which cellular Mg depletion
follows pregnancy, and how especially in the central nervous
system this ionic lesion is linked to preeclampsia, has not
been addressed in this study and is unknown. One would
presume that if the suppression of Mgi levels characteristic of
normal and preeclamptic pregnancy were nutritional in origin, or the result of decreased extracellular availability of Mg
to the cell, then oral Mg supplementation during pregnancy
might significantly influence the subsequent incidence of
preeclampsia. This has not been the case, however, in the few
reported trials published thus far,10 although the numbers of
subjects studied may not have been sufficiently large. Reversal of the cellular Mg deficit may therefore not be easily
amenable to dietary maneuvers.
Perspectives
Our present results document that normal pregnancy is
associated with a cellular Mg depletion both in brain and in
Resnick et al
muscle tissue. A further suppression of cellular brain Mg is
present only in preeclamptic women, suggesting that the
greater fall in brain Mgi may be 1 factor contributing to the
pathophysiology of preeclampsia. The quantitative relation of
cellular-free Mg content to concomitant BP levels further
suggests a role for cellular Mg deficiency in the pathophysiology of preeclampsia. The relation of insulin to Mg metabolism is well established.16,17,20,21,24 Future studies are needed
to support any relationship between insulin and insulin
sensitivity and the alterations of magnesium metabolism in
brain and in muscle shown in this article. Future studies
should also determine the mechanism of the more pronounced suppression of Mg levels found in the brain tissue
and whether these tissue specific alterations are related to the
increased predisposition to neuromuscular irritability and
seizures of preeclampsia.
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