Magnesium Inhibits Norepinephrine Release by Blocking
N-Type Calcium Channels at Peripheral Sympathetic
Nerve Endings
Tatsuo Shimosawa, Koji Takano, Katsuyuki Ando, Toshiro Fujita
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Abstract—Although Mg2⫹ contributes to blood pressure regulation partly in terms of vasodilator action, its sympatholytic
effect may also play an important role to control blood pressure. Thus, in the present study, we investigated the effect
of Mg2⫹ on sympathetic tone and blood pressure. We studied its actions on the blood pressure response to hydralazine,
a direct vasodilator, in conscious spontaneously hypertensive rats (SHRs), and to electrical stimulation in the pithed
Sprague–Dawley rat; catecholamine release by peripheral sympathetic nerve endings; and the N-type Ca2⫹ channels of
cultured neural cells. Intravenous Mg2⫹ infusion (MgSO4: 3⫻10⫺6 mol/kg body weight/min) induced the greater
hypotensive response to hydralazine with attenuated reflex tachycardia in SHRs. In pithed rats, Mg2⫹ infusion
significantly attenuated the blood pressure elevation (2⫾2 mm Hg versus 27⫾6 mm Hg, P⬍0.01) in response to spinal
electrical stimulation. In the perfused mesenteric arteries system, norepinephrine release was significantly attenuated
(51⫾2%, P⬍0.01) by high Mg2⫹ concentration solution (4.8 mmol/L) compared with normal Mg2⫹ solution
(1.2 mmol/L). When we applied the perforated whole-cell patch clamp method to nerve growth factor-treated PC12
cells, Mg2⫹ blocked voltage-gated Ca2⫹ currents in a concentration-dependent manner. The majority of the voltage-gated
Ca2⫹ currents were carried through N-type channels, followed by L-type channels. Mg2⫹ blocked both of these channels.
These findings suggest that Mg2⫹ blocks mainly N-type Ca2⫹ channels at nerve endings, and thus inhibits norepinephrine
release, which decreases blood pressure independent of its direct vasodilating action. (Hypertension. 2004;44:897-902.)
Key Words: hypertension 䡲 catecholamines 䡲 ion channels 䡲 cocaine
gated the in vitro effect of extracellular Mg2⫹ concentrations
on the voltage-gated Ca2⫹ current of nerve growth factor
(NGF)-differentiated PC12 cells, which have characteristics
in common to peripheral sympathetic nerves.12,13
T
he second most plentiful cation in intracellular fluid and
an essential element for the activity of many enzymes is
Mg2⫹.1 In addition to these biochemical actions, magnesium
salts have been shown to lower blood pressure.2,3 The
hypotensive effect of Mg2⫹ has been found to be mediated by
nonspecific antagonism of the Ca2⫹ channels in vascular
smooth muscle cells.4,5 On the contrary, Mg2⫹ deficiency
results in a high catecholamine level, altered barofunction,
and hypertension.6,7 Sympathoactivation and catecholamine
elevation induce tachycardia, glucose intolerance, and abnormal fat metabolism, as well as direct cardiotoxicity.8,9 At the
same time, recent clinical studies revealed that Mg2⫹ protects
brain from ischemic damages.10,11 The mechanism for neuroprotection of Mg2⫹ is not fully elucidated; however, similar
to Mg2⫹ effect on vasculature, it is speculated that Mg2⫹induced decrease in intracellular Ca2⫹ plays an important role.
It can be hypothesized that Mg2⫹ effect on Ca2⫹ homeostasis
in neural cells may be a common mechanism between
sympathoinhibitory and neuroprotective action of Mg2⫹.
In the present study, we performed in vivo and ex vivo
experiments to investigate the effect of Mg2⫹ on circulatory
control by modulating sympathetic tone. Also, we investi-
Methods
For a detailed Methods section, please see http://hyper.hypertensionaha.org.
All protocols in this study were approved by the ethics committee
of our institution, and rats were handled in our accredited facility in
accordance with the institutional animal care policies of the University of Tokyo. All research protocols conformed to the guiding
principles for animal experimentation as enunciated by the Ethics
Committee on Animal Research of the University of Tokyo, Faculty
of Medicine.
Protocol 1: Sympatholytic Effect of Mg2ⴙ and
Blood Pressure Changes In Vivo
Male spontaneously hypertensive rats were used in this experiment.
The rats were divided into 2 groups: Mg2⫹ group (n⫽8) and a control
group (n⫽7). In the Mg2⫹ group, MgSO4 (3⫻10⫺6 mol/kg body
weight/min) was infused, and in the control group saline was infused.
Responses to hydralazine (1, 3, and 6⫻10⫺5 g/kg body weight) were
observed. A 100 ␮L blood sample was drawn before and after saline
or MgSO4 infusion to measure the serum Mg level. The nadir mean
Received March 8, 2004; first decision March 30, 2004; revision accepted September 21, 2004.
From the Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Correspondence to Toshiro Fujita, MD, Department of Internal Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo, 113-8655, Japan. E-mail [email protected]
© 2004 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000146536.68208.84
897
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Hypertension
December 2004
Figure 1. BP and heart rate (HR)
responses to hydralazine in control and
Mg2⫹ infused groups. a, Decreases in
MAP of the Mg2⫹ group (F) were significantly larger than those of the control
group (f). b, Increases in HR of the
Mg2⫹ group (F) were significantly smaller
than those of the control group (f). Data
are presented as means⫾SEM. P⬍0.01
by ANOVA and Sheffe method.
Downloaded from http://hyper.ahajournals.org/ by guest on June 17, 2017
arterial pressure (MAP) and peak heart rate (HR) in 2 groups were
compared.
Male Sprague–Dawley rats were pithed as described elsewhere.14
Briefly, rats were pithed by inserting a steel rod covered with enamel
except at its tip (5 mm), and its end was positioned at the level of the
7th to 10th thoracic vertebrae. The rats were divided into 2 groups as
described. After infusion for 20 minutes, we stimulated at 0.5 Hz for
1 minute with an electrical stimulator between the pithing rod and the
indifferent electrode. Each stimulus was 50 V and 1 millisecond.
Blood pressure and HR changes were observed. To confirm quality
of pithing, the rats were injected with 1 mg/kg hexamethonium, and
responses to electrical stimulation were observed after the aforementioned experiments.
Protocol 2: Effect of Mg2ⴙ on Norepinephrine
Release by Peripheral Sympathetic Nerve Ending
The superior mesenteric artery from Sprague–Dawley rats was
prepared by a modification of Castellucci method.15 The preparations were perfused with a Krebs–Henselit solution with 1.2 mmol/L
of Mg2⫹. Low-Mg2⫹ buffer was prepared by reducing the MgSO4
concentration to 0.3 mmol/L substitution with Na2SO4, and highMg2⫹ buffer with a magnesium concentration of 3.6 mmol/L was
prepared by replacing NaCl with MgCl2 iso-osmotically.
A platinum electrode was placed around the periarterial plexus of
the mesenteric artery, and every 15 minutes we stimulated at 8 Hz for
1 minute. Each stimulus was 10 V and 1 millisecond. The perfusate
through the mesenteric vascular preparation was collected for measurement of norepinephrine (NE) by high-performance liquid chromatography.15 NE overflow was defined as NE content of perfusates
per wet mesenteric artery weight. To identify component of NE
overflow that was affected by Mg2⫹, we applied cocaine, a specific
blocker of NE reuptake by nerve tissue,16 or deoxycorticosterone, a
blocker of NE uptake by non-neuronal tissue.17
Protocol 3: Effect of Extracellular Mg2ⴙ on
Voltage-Gated Ca2ⴙ Channels
The PC12 cells were cultured in Dulbecco modified eagle medium
containing 10% fetal calf serum and 2.5 S NGF (10 ng/mL) for 7
days. We selected cells with neurite outgrowth for the electrophysiology experiments.
The perforated whole-cell clamp technique18 was used to avoid the
run-down of voltage-gated Ca2⫹ currents. Ba2⫹ ion was used as a
charge carrier through the voltage-gated Ca2⫹ channels. The standard
patch electrode solution contained 1.2 mmol/L of Mg2⫹. Low-Mg2⫹
and the high-Mg2⫹ extracellular solutions were prepared as described
in protocol 2. Extracellular solutions containing different concentrations of Mg2⫹ were applied by changing the perfusion solution. All
the data were corrected for the liquid junction potential (⫺4 to ⫺2
mV). Amphotericin B (200 ␮g/mL) was used for the perforated
whole-cell clamp experiments.
An L-type Ca2⫹ channel blocker, nitrendipine (NIT) (5 ␮mol/L),
and an N-type Ca2⫹ channel blocker, ␻-conotoxin GVIA (␻-CgTX)
(1 ␮mol/L), were used to identify the type of voltage-gated Ca2⫹
current.
Statistical Analysis
In protocol 2, the average of the control responses of NE overflow to
electrical stimulation and the following 2 responses in the different
Mg2⫹ concentration buffers or in the presence of drugs were
calculated. The results are expressed as total NE overflow standardized by tissue weight and the percent change from the averaged NE
overflow in control buffer.
Data are shown as means⫾SEM in protocols 1 and 2 and as
means⫾SD in protocol 3. The statistical analysis in protocol 2 was
performed by the paired and unpaired Student t test, and in protocols
1 and 3 by analysis of variance (ANOVA). P⬍0.05 was considered
indicative of statistical significance.
Results
Protocol 1: Sympatholytic Effect of Mg2ⴙ and
Blood Pressure Changes In Vivo
The body weight of the rats infused with Mg2⫹ (Mg2⫹ group)
was 241⫾2g, their baseline MAP was 175⫾5 mm Hg, and
their HR was 453⫾9 bpm, which were not affected by the
Mg2⫹ infusion (MAP, 170⫾4 mm Hg; HR, 440⫾7 bpm). The
serum Mg level significantly increased from 2.5⫾0.05 mg/dL
to 3.5⫾0.11 mg/dL after Mg2⫹ infusion (P⬍0.01). The body
weight of the rats in the control group was 245⫾4g, their
baseline MAP was 173⫾3 mm Hg, and their HR was
442⫾12 bpm. None of those parameters changed much after
saline infusion in the control group (MAP, 174⫾5 mm Hg;
HR, 444⫾10 bpm; serum magnesium from 2.5⫾0.05 mg/dL
to 2.5⫾0.06 mg/dL). Hydralazine decreased MAP dosedependently and the decrease was more prominent in the
Mg2⫹ group than control group (Figure 1a), whereas HR
increased more in the control group than in the Mg2⫹ group
(Figure 1b).
Blood Pressure Response to Electrical Stimulation
in Pithed Sprague–Dawley Rats
The body weight of the rats infused with Mg2⫹ (Mg2⫹ group)
was 271⫾10g, their baseline MAP after pithing was
55⫾11 mm Hg, and their HR was 206⫾25 bpm. The body
weight of the rats in the control group was 275⫾16g, their
baseline MAP after pithing was 53⫾10 mm Hg, and their HR
was 208⫾22 bpm. Electrical stimulation significantly increased both MAP and HR, but the extent of the increase was
greater in the control group than in the Mg2⫹ group (Figure 2).
Mg2ⴙ and Calcium Channel
Shimosawa et al
899
Figure 2. Blood pressure responses to
electrical stimulation in pithed rat. a,
Representative traces of blood pressure
changes by electrical stimulation from
control (right panel) and Mg2⫹ group (left
panel). Increases in MAP (b) and HR (c)
were significantly attenuated in the Mg2⫹
group compared with the control group
(P⬍0.01 and P⬍0.05 by ANOVA and
Dunnet method). Data are presented as
means ⫾ SEM.
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The pressor responses to electrical stimulation were completely abolished (n⫽3; MAP, 55⫾8 to 53⫾4 mm Hg; HR,
205⫾10 to 204⫾8 bpm) by 1 mg/kg hexamethonium, suggesting that the pressor response reflects peripheral sympathetic stimulation.
Protocol 2: Effect of Mg2ⴙ on NE Release From
Peripheral Sympathetic Nerve Endings
NE overflow at 1.2 mmol/L Mg2⫹ was 0.266⫾0.032 ng/g
tissue weight, and percent change of NE overflow with each
buffer is shown in the Table. High-Mg2⫹ buffer significantly
suppressed NE overflow.
In the presence of cocaine or deoxycorticosterone, the
high-Mg2⫹ buffer significantly attenuated NE overflow, and
the Mg2⫹-induced changes were not significantly altered.
Protocol 3: Effect of Extracellular Mg2ⴙ on the
Voltage-Gated Ca2ⴙ Currents
To determine the effect of extracellular Mg2⫹ on NE release,
we investigated the effect of extracellular Mg2⫹ on the
voltage-gated Ca2⫹ currents of PC12 cells differentiated by
NGF. Figure 3A shows the Ba2⫹ currents through voltagegated Ca2⫹ channels recorded under the voltage clamp from a
PC12 cell at 3 different extracellular Mg2⫹ concentrations.
The holding potential was ⫺74 mV, and a test pulse step to
6 mV was applied. The Ba2⫹ current exhibited a clear
inactivation process, but the steady current persisted. The
Ba2⫹ current first appeared at a potential step to ⫺34 mV. As
the depolarizing steps became greater, the amplitude of the
Ba2⫹ current increased. When the extracellular Mg2⫹ concentration was changed sequentially, the amplitude of the peak
current was largest in the 0.3 mmol/L Mg2⫹ solution, smaller
in the standard extracellular solution (1.2 mmol/L Mg), and
smallest in the 4.8 mmol/L Mg2⫹ solution. Increases in the
extracellular Mg2⫹ concentration inhibited the voltage-gated
Ca2⫹ current, and the inhibition was reversible when the
extracellular solution was changed to the 0.3 mmol/L Mg2⫹
solution (0.3 mmol/L Mg2⫹ recover).
The current–potential relationships of the Ba2⫹ current in
the extracellular solutions containing 3 different Mg2⫹ concentrations are shown in Figure 3B. Increased extracellular
Mg2⫹ induced a decrease in amplitude of the Ba2⫹ current at
all potentials, indicating that inhibition of the Ba2⫹ current
was not voltage-dependent. Figure 3C summarizes the amplitude of the Ba2⫹ current at the 3 Mg2⫹ concentrations. The
amplitude of the peak Ba2⫹ current in the standard extracellular solution was normalized as 100% in each record.
Extracellular Mg 2⫹ inhibited the Ba 2⫹ current in a
concentration-dependent manner when analyzed by repeated
measures ANOVA with post-test for linear trend. We could
observe significant linear trend (P⬍0.0001).
Figure 4A shows the sequential effect of NIT (5 ␮mol/L)
and 4.8 mmol/L Mg2⫹ on the Ba2⫹ current. Application of
NIT decreased the current by ⬇17% of the control, and
Percent Change of Norepinephrine Overflow From Peripheral Nerve Endings
Low Mg2⫹ (0.3 mmol/L Mg2⫹)
High Mg2⫹ (4.8 mmol/L Mg2⫹)
Control
Cocaine
Deoxycorticosterone
113⫾5% (n⫽10)
115⫾8% (n⫽5)
108⫾7% (n⫽5)
51⫾2% (n⫽10)*
53⫾4% (n⫽5)*
49⫾5% (n⫽5)*
2⫹
Norepinephrine overflows were calculated as percent changes from 1.2 mmol/L Mg
Data are presented as means⫾SEM.
*P⬍0.01 compared to 1.2 mmol/L Mg2⫹ buffer by paired t test.
condition.
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December 2004
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Figure 3. Effect of extracellular Mg2⫹ on voltage-gated Ca2⫹ current. Currents were recorded under voltage-clamp with the perforated
whole-cell clamp technique from a PC12 cell differentiated by NGF. A, Ba2⫹ currents were evoked by a pulse step to 6 mV from the
holding potential of ⫺74 in extracellular solutions containing 0.3 mmol/L Mg2⫹, 1.2 mmol/L Mg2⫹, 4.8 mmol/L Mg2⫹, and again in
0.3 mmol/L Mg2⫹ to examine the recovery. B, The current–potential relationship of the Ba2⫹ current in each Mg2⫹ level (F, 0.3 mmol/L;
E, 1.2 mmol/L; ‚, 4.8 mmol/L) are plotted. The ordinate indicates the peak amplitude of the Ba2⫹ current in pA and the abscissa indicates test potential in mV. C, Concentration dependency of the effect of Mg2⫹ on the Ba2⫹ current. The amplitude of the peak Ba2⫹ current in the 1.2 mmol/L Mg2⫹ solution was normalized as 100% in each record. The mean amplitude of the current in 1.2 mmol/L Mg2⫹
solution was 124⫾44 pA. Means and standard deviations of the currents in 0.3 mmol/L, 3.6 mmol/L, 2.4 mmol/L, and 4.8 mmol/L Mg2⫹
normalized to that in 1.2 mmol/L Mg2⫹ were 124⫾19%, 83⫾10%, 75⫾7%, and 68⫾15%, respectively. *Statistical significance (P⬍0.05)
using 1-way ANOVA with Tukey multiple comparison test.
additional application of high-Mg2⫹ solution inhibited the
current by an additional 21% of the control. Figure 4B shows
the sequential effect of ␻-CgTX (1 ␮mol/L) and 4.8 mmol/L
Mg2⫹ on the Ba2⫹ current, and application of ␻-CgTX
decreased the current by ⬇78% of the control. Additional
application of 4.8 mmol/L Mg2⫹ solution inhibited the current
by only an additional 5% of the control.
Figure 4C summarizes the data obtained in these experiments. Application of NIT inhibited the Ba2⫹ current to
83.5⫾5.6% (n⫽15) of the control, and additional application of 4.8 mmol/L Mg2⫹ inhibited it to 59.4⫾7.5% (n⫽15)
of the control. There was a significant difference (P⬍0.001
by paired t test) between the current after NIT and after
NIT plus 4.8 mmol/L Mg2⫹. Application of ␻-CgTX
inhibited the Ba2⫹ current to 13.1⫾2.6% (n⫽15) of the
control, and additional application of 4.8 mmol/L Mg2⫹
inhibited it to 7.7⫾1.3% (n⫽15) of the control. There was
a significant difference (P⬍0.001 by paired t test) between
the current after ␻ -CgTX and after ␻ -CgTX plus
4.8 mmol/L Mg2⫹. The current–potential relationships of
the non–L-type currents and non–N-type currents before
and after high Mg2⫹ (4.8 mmol/L) application are shown in
Figure 5A and B, respectively. Both non–L-type and
non–N-type currents were inhibited by high Mg2⫹. These
results indicated that the Ba2⫹ current in NGF-treated PC12
cells was mainly carried through N-type Ca2⫹ channels and
Figure 4. Inhibition of N-type Ca2⫹ current by high Mg2⫹. A, Effect of L-type Ca2⫹ channel blocker, nitrendipine (NIT), and high Mg2⫹ on
the Ba2⫹ current. The Ba2⫹ current was evoked by the pulse step to 6 mV from the holding potential of ⫺74 mV. The amplitude of the
peak current was measured every 10 seconds. The ordinate indicates percentage of the Ba2⫹ current as compared with the control
(before application of NIT in 1.2 mmol/L Mg2⫹) and the abscissa the time course of the application of 5 ␮mol/L NIT and 4.8 mmol/L
Mg2⫹. After NIT attained its maximal effect, 4.8 mmol/L Mg2⫹ solution with NIT was applied. B, Effect of N-type Ca2⫹ channel blocker,
␻-conotoxin GVIA (CgTX), and 4.8 mmol/L Mg2⫹ on the Ba2⫹ current. The Ba2⫹ current was recorded by the same method as in (A).
The ordinate indicates percentage of the Ba2⫹ current as compared with the control (before application of CgTX in 1.2 mmol/L Mg2⫹)
and the abscissa, and the time course of the application of 1 ␮mol/L CgTX and 4.8 mmol/L Mg2⫹. After CgTX attained its maximal
effect, 4.8 mmol/L Mg2⫹ solution with CgTX was applied. C, Summary of the experiments. The ordinate indicates the mean and standard deviation of the normalized Ba2⫹ current as compared with the control (before application of channel blocker in 1.2 mmol/L Mg2⫹).
High Mg2⫹ indicates application of 4.8 mmol/L Mg2⫹ solution.
Shimosawa et al
Mg2ⴙ and Calcium Channel
901
Figure 5. Effect of 4.8 mmol/L Mg2⫹ on the
current–potential relationship of non–L-type
(mostly N-type) and non–N-type (mostly
N-type) currents. A, The current–potential
relationship of the Ba2⫹ current in extracellular solutions containing 5 ␮mol/L nitrendipine in 2 Mg2⫹ levels (F, 1.2 mmol/L; E,
4.8 mmol/L) are plotted. B, The current–
potential relationship of the Ba2⫹ current in
extracellular solutions containing 1 ␮mol/L
␻-conotoxin GVIA in 2 Mg2⫹ levels (F,
1.2 mmol/L; E, 4.8 mmol/L) are plotted.
The ordinate indicates the peak amplitude
of the Ba2⫹ current in pA and the abscissa
indicates test potential in mV.
the majority of the remaining current was L-type Ca2⫹
channels, and that both of these currents are inhibited by
high Mg2⫹.
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Discussion
Mg2⫹ is reported to modulate cardiac function and vasomotor
control by nonspecific antagonism of the Ca2⫹ channels.4,5,7,19 –21 Mg2⫹ also modulates neuronal activity6,7 but the
precise mechanisms are still unknown. In the present study,
we showed an Mg2⫹ effect on sympathetic tone both in in
vivo and in vitro studies. Firstly, using both conscious
spontaneously hypertensive rats and pithed rats, we showed
that Mg2⫹ possesses sympatholytic effects and reduces blood
pressure. Secondary, using perfused mesenteric artery preparation, we revealed that Mg2⫹ reduces norepinephrine release. Finally, Mg2⫹ inhibits N-type Ca2⫹ channels in differentiated PC12 cells. The results of the present study indicate
that Mg2⫹ attenuated sympathetic tone mainly by inhibiting
N-type Ca2⫹ channels.
Mg2⫹ augmented the antihypertensive effect of hydralazine
and attenuated the reflex tachycardia. It suggests that Mg2⫹
exerts an inhibitory effect on sympathetic tone and enhances
the vasodilator effect of hydralazine. To further investigate
roles of peripheral sympathetic nerves on blood pressure
regulation, we applied the mechanically pithed preparation in
which central nervous activities are fully destroyed and also
we can avoid pharmacological interference. Electrical stimuli
were applied at the level of 7th to 10th thoracic vertebrae to
direct stimulation of cardiac sympathetic nerve be possible.14
Mg2⫹ attenuated blood pressure elevation evoked by sympathetic nerve stimulation. Norepinephrine is a main factor that
is released by electrical stimulation and regulates blood
pressure in the pithed model; however, other circulatory
factors could be released. Thus, we applied ex vivo model to
investigate effect of Mg2⫹ on norepinephrine release. We
measured NE overflow from the periarterial plexus of the
mesenteric artery. There are 2 components to NE overflow:
NE release from nerve endings and NE reuptake into nerve
terminals and other tissue. We showed that Mg2⫹ affects NE
release but not uptake by using uptake blockers such as
cocaine16 and deoxycorticosterone.17
To specify Mg2⫹ effect on Ca2⫹ channels that play a pivotal
role in sympathetic activity, we used NGF-treated PC12 cells.
NGF-treated PC12 cells exhibited neurite outgrowth. Ap-
proximately 90% of the voltage-gated Ca2⫹ channel currents
were composed of ␻-CgTX-sensitive N-type Ca2⫹ currents.
An L-type Ca2⫹ channel blocker, NIT, reduced Ca2⫹ influx to
a smaller extent than ␻-CgTX. These characteristics are
consistent with those of differentiated PC12 cells, which have
characteristics similar to those of noradrenergic sympathetic
neurons, including the development of N-type Ca2⫹ channels.12,13,22 In the present study, Mg2⫹ further inhibited the
Ba2⫹ current after treatment with NIT but not after ␻-CgTX,
suggesting that Mg2⫹ inhibits N-type Ca2⫹ channels. The high
Mg2⫹-induced inhibition of N-type Ca2⫹ channels observed in
the present study was similar to the effect of proadrenomedullin N-terminal 20 peptide on the N-type current
in NGF-treated PC 12 cells.18 This inhibition of the N-type
Ca2⫹ current plays a role in the inhibition of Ca2⫹ influx
through voltage-gated Ca2⫹ channels and as a result reduces
the intracellular Ca2⫹ concentration.
Based on these results, extracellular Mg2⫹ blocks N-type
and partly L-type Ca2⫹ channels, and thus inhibits NE release,
and these effects play an important role in regulating sympathetic tone and blood pressure.
Perspectives
Recent large clinical studies have shown that the lower the
blood pressure obtained by treatment, the more successful in
preventing hypertensive patients from cardiovascular
events.23–25 Although dihydropyridine Ca2⫹ channel blockers
are potent antihypertensive agents, short-acting Ca2⫹ channel
blockers have been shown to be unfavorable for the treatment
of hypertension.26 This may be partly caused by reflex
sympathoactivation and catecholamine release, which induce
unfavorable effects.8,9 Several epidemiological studies have
supported tachycardia, an indicator of sympathetic tone, as an
independent risk factor for cardiovascular death in elderly
men.27 Because all vasodilators induce reflex sympathoactivation in hypertensive patients, treatment that aims to reduce
sympathoactivation can achieve a greater therapeutic effect.
Because Mg2⫹ decreases NE release from nerve endings by
inhibiting voltage-gated N-type Ca2⫹ currents, Mg2⫹ may be
beneficial in preventing organ damage by inhibiting reflex
sympathoactivation. In fact, some studies have shown that
Mg2⫹ supplementation improves the outcome of cardiovascular diseases.11,28 However, the antihypertensive action of
Mg2⫹ is very weak.29 It led us to the speculation that Ca2⫹
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Hypertension
December 2004
channel blockers with the inhibitory action of both an L-type
and N-type Ca2⫹ channels such as cilnidipine30 –32 might be
efficacious for the treatment of hypertension.
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Magnesium Inhibits Norepinephrine Release by Blocking N-Type Calcium Channels at
Peripheral Sympathetic Nerve Endings
Tatsuo Shimosawa, Koji Takano, Katsuyuki Ando and Toshiro Fujita
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Hypertension. 2004;44:897-902; originally published online October 11, 2004;
doi: 10.1161/01.HYP.0000146536.68208.84
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