magnesio

Molecular Aspects of Medicine 24 (2003) 107–136
www.elsevier.com/locate/mam
Role of magnesium in the pathogenesis

of hypertension
R.M. Touyz *
Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal,

University of Montreal, 110 Pine Avenue West, Montreal, Que., Canada H2W IR7
Abstract
Human essential hypertension is a complex, multifactorial, quantitative trait under poly-
genic control. Although the exact etiology is unknown, the fundamental hemodynamic ab-
normality in hypertension is increased peripheral resistance, due primarily to changes in
vascular structure and function. These changes include arterial wall thickening, abnormal
vascular tone and endothelial dysfunction and are due to alterations in the biology of the
cellular and non-cellular components of the arterial wall. Many of these processes are influ-
enced by magnesium. Small changes in magnesium levels may have significant effects on
cardiac excitability and on vascular tone, contractility and reactivity. Accordingly magnesium
may be important in the physiological regulation of blood pressure whereas perturbations in
cellular magnesium homeostasis could play a role in pathophysiological processes underlying
blood pressure elevation. For the most part, epidemiological and experimental studies dem-
onstrate an inverse association between magnesium and blood pressure and support a role for
magnesium in the pathogenesis of hypertension. However data from clinical studies have been
less convincing and the therapeutic value of magnesium in the prevention and management of
essential hypertension remains unclear. In view of the still ill-defined role of magnesium in
clinical hypertension, magnesium supplementation is advised in those hypertensive patients
who are receiving diuretics, who have resistant or secondary hypertension or who have frank
magnesium deficiency. A magnesium-rich diet should be encouraged in the prevention of
hypertension, particularly in predisposed communities because of the other advantages of such
a diet in prevention. The clinical aspect that has demonstrated the greatest therapeutic po-
tential for magnesium in hypertension, is in the treatment of pre-eclampsia and eclampsia. The
present review discusses the role of magnesium in the regulation of vascular function and
blood pressure and the implications in mechanisms underlying hypertension. Alterations in
magnesium regulation in experimental and clinical hypertension and the potential antihy-
pertensive therapeutic actions of magnesium will also be addressed.
Ó 2003 Elsevier Science Ltd. All rights reserved.
*
Tel.: +1-514-987-5747; fax: +1-514-987-5585.
E-mail address: touyzr@ircm.qc.ca (R.M. Touyz).
0098-2997/03/$ - see front matter Ó 2003 Elsevier Science Ltd. All rights reserved.
PII: S 0 0 9 8 - 2 9 9 7 ( 0 2 ) 0 0 0 9 4 - 8
108 R.M. Touyz / Molecular Aspects of Medicine 24 (2003) 107–136
Keywords: Cations; Vascular smooth muscle; Vascular tone; Magnesium deficiency; Blood pressure; Pre-
eclampsia
1. Introduction
Essential hypertension is a major modifiable risk factor for cardiovascular dis-

ease, such as cardiac failure, ischemic heart disease, stroke and end-stage renal
disease. It develops as a result of complex interactions between susceptibility genes
and environmental factors, which influence neural, humoral, cellular and subcellular
mechanisms that regulate blood pressure (Carretero and Oparil, 2000). The basic
hemodynamic abnormality in hypertension is increased peripheral resistance, due
mainly to decreased lumen size of resistance arteries. Since resistance (R) is inversely
proportional to the fourth power of the radius (r) (R / 1=r4 ), small changes in
arterial radius (lumen) will have significant effects on resistance. In hypertension
small arteries undergo structural and functional changes, resulting in reduced lumen
size and increased peripheral resistance. These changes include media thickening,
caused in part by increased cell growth and extracellular matrix deposition, and
altered vascular tone, due to increased contraction and/or decreased vasodilation.
Vascular smooth muscle cells are the final common pathway for many of these
dynamic changes in hypertension. Consequently, much research has focussed on
elucidating physiological mechanisms and pathophysiological events that regulate
growth and contraction of vascular smooth muscle cells in health and cardiovas-
cular disease. Of the many factors implicated in these processes, magnesium may
play a key role.
Magnesium is an essential element that has numerous biological functions in the
cardiovascular system. At the subcellular level, magnesium regulates contractile
proteins, modulates transmembrane transport of calcium, sodium and potassium,
acts as an essential cofactor in the activation of ATPase, controls metabolic re-
gulation of energy-dependent cytoplasmic and mitochondrial pathways, regulates
oxidative-phosphorylation processes and influences DNA and protein synthesis
(Cowna, 2000; Grubbs and Maguire, 1987). Small changes in extracellular Mg2þ
levels ([Mg2þ ]e ) and/or intracellular free Mg2þ concentration ([Mg2þ ]i ) have major
effects on cardiac excitability and on vascular tone, contractility and reactivity
(Altura and Altura, 1995; Altura et al., 1991). Decreased magnesium levels enhance
reactivity of arteries to vasoconstrictor agents, attenuate responses to vasodilators,
promote vasoconstriction and increase peripheral resistance, leading to increased
blood pressure. Elevated magnesium levels have opposite effects leading to vasodi-
lation, reduced vascular tone and decreased blood pressure. Thus magnesium may
be physiologically important in blood pressure regulation whereas changes in
magnesium levels could contribute to pathological processes underlying hyperten-
sion. Epidemiological and experimental studies support a role for magnesium de-
ficiency in the pathogenesis of hypertension, with reports demonstrating inverse
correlations between magnesium levels and blood pressure, hypotensive actions of
R.M. Touyz / Molecular Aspects of Medicine 24 (2003) 107–136 109
dietary magnesium supplementation and hypertensive effects of magnesium defi-

ciency (Touyz et al., 1987; Resnick et al., 1997; Kesteloot and Joossens, 1988;
Kisters et al., 1998; Kawano et al., 1998; Touyz et al., 1992; Geleinjoise et al., 1996;
Sasaki et al., 2000; Sanjuliani et al., 1996). However the therapeutic value of mag-
nesium in the management of essential hypertension is unclear, with results from
clinical trials being heterogeneous and inconsistent. There is also much controversy
regarding the clinical importance of modestly decreased or elevated serum levels
of magnesium. Furthermore, although intracellular magnesium deficiency has been
implicated in hypertension, the current data are conflicting. The present re-
view discusses the role of magnesium in the regulation of vascular function and the
implications in hypertension. In addition, alterations in magnesium homeostasis in
the pathogenesis of hypertension and the putative role of magnesium as an anti-
hypertensive modality in the therapeutic management of hypertension will be con-
sidered. Magnesium influences functions of many systems, however the present
review focuses specifically on the cardiovascular system and implications in hyper-
tension.
2. Magnesium homeostasis in cardiovascular cells
For magnesium to significantly modulate cellular events, magnesium itself

must be regulated within the cell. Despite the fact that magnesium is the most
abundant cytosolic divalent cation, little is known about intracellular magnesium
homeostasis and transport and mechanisms controlling [Mg2þ ]i are poorly under-
stood (Murphy, 2000). Magnesium is not a static ion. It moves between compart-
ments and across membranes (Fig. 1). Magnesium enters cells along a concentration
gradient (Flatman, 1991) and is extruded from cells via an active efflux mecha-
nism (Murphy, 2000; Flatman, 1991; Murphy et al., 1991) Influx/efflux are under
hormonal control and intracellular Mg2þ ions are buffered by ATP, actin and
other proteins and can be taken up by intracellular organelles, such as mito-
chondria and endoplasmic/sarcoplasmic reticulum (Romani and Scarpa, 1990;
Smith and Maguire, 1998; Beyenbach, 1990; Luthi et al., 1999; Romani and Scarpa,
2000b).
Mechanisms whereby magnesium enters cells are unclear, but a channel and/or a
carrier system may be important (Romani and Scarpa, 2000b; McGuigan et al.,
2002). Magnesium channels have been demonstrated in renal cells and magnesium
has been shown to pass through glutamate receptor-coupled cation channels in
neurons (McGuigan et al., 2002; Freire et al., 1996; Stout et al., 1996). Recently, a
Mg ATP-regulated divalent cation channel, LTRPC7, was cloned from human
haemopoietic cells (Nadler et al., 2001). Whether these channels are functionally
present in vascular cells is still unknown. Various extrusion mechanisms have been
suggested for magnesium (Flatman, 1984; Murphy et al., 1991; McGuigan and
Elder, 2000). Although it is still unclear which transporter/s is/are responsible for
magnesium efflux in cardiovascular cells, a functionally active Naþ /Mg2þ antiporter
has been demonstrated in both cardiac and vascular smooth muscle cells (Murphy
Mg2+ influx
Na+/Mg2+
exchanger Mg2+-buffers
Na+ Mg2+ + ATP = Mg-ATP2-
Mg2+ [Mg2+]i Mg2+ + protein = Mg2+-protein
SR/ER
uptake/release
Mitochondria
uptake/release
Unknown
Mg2+ efflux
mechanisms
Fig. 1. Scheme demonstrating possible mechanisms regulating magnesium influx and efflux in vascular
smooth muscle cells. Cytoplasmic Mg2þ is modulated by plasma membrane and organelle transport and
by intracellular buffering. Although it is unclear how Mg2þ enters cells, channels or carriers may be im-
portant. Mg2þ is extruded from cells via a Naþ -dependent Mg2þ exchanger and possibly through other, as
yet undetermined, pathways. SR ¼ sarcoplasmic reticulum; ER ¼ endoplasmic reticulum; [Mg2þ ]i ¼
intracellular free Mg2þ concentration.
et al., 1991; McGuigan and Elder, 2000; Romani et al., 2000a; Touyz and Schiffrin,
1996; Quamme and Rabkin, 1990; Touyz et al., 1998). The Naþ –Mg2þ exchanger
was first demonstrated in the squid giant axon where sodium moving into the cell
down its electrochemical gradient is coupled to magnesium moving out of the cell.
Sodium-dependent magnesium transport is inhibited by amiloride, quinidine, imi-
pramine and manganese and it may be linked to protein kinase C, the Naþ –Hþ
antiporter and the Naþ /Ca2þ exchanger (Murphy et al., 1991; McGuigan and Elder,
2000; Zhang and Melvin, 1996; Di Francesco et al., 1998; Gunther et al., 1992;
Romani et al., 1993a). Within cells, magnesium is compartmentalized in nuclei,
mitochondria and endoplasmic/sarcoplasmic reticulum (Bond et al., 1987; Romani
et al., 1993b) and is highly regulated by intracellular buffering processes as well as by
various hormones and vasoactive agents (Table 1). Phorbol esters, isoproterenol,
glutathione and endothelin-1 (ET-1) increase intracellular magnesium concentra-
tions (Barbagallo et al., 1999; Okada et al., 1992; Quamme et al., 1993) whereas
angiotensin II (Ang II), vasopressin, aldosterone, norepinephrine and epinephrine
stimulate magnesium efflux and decrease [Mg2þ ]i (Touyz and Schiffrin, 1996;
Quamme et al., 1993; Delva et al., 2000). Intracellular magnesium is tightly regu-
lated and because magnesium is a critical component in multiple biochemical re-
actions, even small changes in vascular smooth muscle cell [Mg2þ ]i can have
significant effects on intracellular signaling pathways that regulate vascular func-
tion.
Table 1
Hormones and vasoactive agents that influence intracellular magnesium levels in cardiovascular cells
Hormone/agent Effect Reference
Vascular smooth muscle cells
ET-1 " Okada et al. (1992)
Ang II # Touyz and Schiffrin (1996)
Vasopressin "=# Touyz and Schiffrin (1996), Touyz et al. (1998) and Okada
et al. (1992)
Cardiomyocytes
Norepinephrine # Romani and Scarpa (2000b), McGuigan et al. (2002) and
Romani et al. (1993a)
Carbachol " Romani and Scarpa (2000b), McGuigan et al. (2002) and
Romani et al. (1993a)
Insulin " Romani et al. (2000a) and Romani et al. (1993a)
Isoproterenol # Quamme and Rabkin (1990)
"¼ increase; #¼ decrease.
3. Vascular changes in hypertension––role of magnesium
Hypertension is due primarily to increased peripheral vascular resistance that is

associated with functional, structural and mechanical alterations in the peripheral
vasculature (Korner et al., 1989; Folkow, 1990; Mulvany and Aalkjaer, 1990) (Fig.
2). Functional alterations that increase peripheral resistance, include enhanced
vascular reactivity to vasoconstrictor agents or impaired vasodilation and reflect
changes in excitation–contraction coupling and/or electrical properties of cells
(Dominiczak and Bohr, 1989; Schiffrin et al., 1993; Touyz et al., 1994; Feldman and
Gros, 1998). Magnesium plays an important role in these processes. Increased
concentrations of extracellular magnesium cause vasodilation and attenuate agonist-
induced vasoconstriction, whereas decreased concentrations cause contraction and
potentiate agonist evoked vasoconstriction (Folkow, 1990; Laurant et al., 1997a;
Tirittilli, 1998). The exact cellular basis for the molecular contractile action of
magnesium is unknown, but magnesium probably influences [Ca2þ ]i , which is a
major determinant of vascular smooth muscle contraction. In vascular smooth
muscle cells, magnesium acts extracellularly by inhibiting transmembrane calcium
transport and calcium entry and decreasing contractile actions of vasoactive agents
or intracellularly as a calcium antagonist thereby modulating the vasoconstrictor
actions of increased [Ca2þ ]i (Nakajima et al., 1997; Yoshimura et al., 1997; Iseri and
French, 1984; Zhang et al., 1992; Nakajima et al., 1997; McHugh and Beech, 1996).
The influence of magnesium on vascular tone and reactivity could also be due to
effects on Naþ /Kþ ATPase activity, which regulates Naþ and Kþ transport, and
to formation of cyclic AMP and cyclic GMP, important factors modulating va-
sodilation (Touyz et al., 1991; Ishiguro et al., 1997). Since [Mg2þ ]i influences many
enzymes in signal transduction pathways involved in vascular contraction, low
Fig. 2. Diagram demonstrates role of Mg2þ in the regulation of vascular function. Elevated levels of Mg2þ
compete with influx of Ca2þ and stimulate Ca2þ -ATPase-mediated Ca2þ efflux, resulting in decreased
intracellular free Ca2þ concentration ([Ca2þ ]i ) and consequent reduced vascular contractility. Magnesium
also increases production of endothelial-derived relaxant factors, which promote vasodilation. Increased
Mg2þ is associated with reduced bioavailability of reactive oxygen species and decreased oxidative stress,
which further contribute to maintaining vascular integrity and function. Decreased levels of Mg2þ have
opposite effects. "¼ increase, #¼ decrease, þ ¼ stimulation, ¼ inhibition, VSMC ¼ vascular smooth
muscle cell, cGMP ¼ cyclic guanosine monophosphate.
[Mg2þ ]i could have important effects in vascular smooth muscle cell function in
hypertension. Indeed many studies demonstrated that vascular magnesium levels
are reduced in hypertension (Touyz et al., 1991; Ishiguro et al., 1997; Resnick,
1992; Picado et al., 1994; Touyz and Schiffrin, 1999; Ng et al., 1992). Underlying
mechanisms for cellular magnesium depletion in hypertension are unclear, but
magnesium-deficient states, decreased membrane permeability, altered Naþ –Mg2þ
exchange, defective membrane binding as well as altered cellular responsiveness
have been suggested (Ishiguro et al., 1997; Picado et al., 1994; Touyz and Schiffrin,
1999).
Major vascular structural changes associated with hypertension include reduced
vessel lumen diameter and media thickening (vascular remodeling) (Mulvany et al.,
1996; Schiffrin, 1992; Laurant et al., 1997b; Rizzoni et al., 1998; Intengan et al., 1999;
Mulvany et al., 1985). At the cellular level, there is hyperplasia, hypertrophy,
elongation of vascular smooth muscle cells and/or reorganization of cells around the
lumen of the artery (Mulvany et al., 1985; Lee, 1987; Lee and Dickhout, 1998;
Gibbons et al., 1992; Tsoporis et al., 1998). These growth processes are associated
with apoptosis, which regulates fine-tuning of the cell population in the vessel wall.
Emerging evidence suggests that Mg2þ regulates cell growth and differentiation
(Wolf and Cittadini, 1999), processes that could contribute to vascular remodeling in
hypertension. In many cell types Mg2þ is a positive modulator of cell growth (Wolf
and Cittadini, 1999). Proliferating cells have more Mg2þ than non-proliferating cells
and high extracellular Mg2þ stimulates DNA and protein synthesis and energy
metabolism (Wolf and Cittadini, 1999; Cameron and Smith, 1989). Exposure of fi-
broblasts, endothelial and epithelial cells to reduced extracellular Mg2þ , inhibits cell
proliferation whereas replacing Mg2þ in the culture medium stimulates cell growth
(Rubin and Berbie, 1978; Banai et al., 1990; Zhou and Kummerow, 1995). However,
this postive correlation between Mg2þ availability and degree of proliferation is not
a homogeneous phenomenon. In some conditions Mg2þ depletion paradoxically
increases cell growth (Wolf and Cittadini, 1999; Maguire, 1988). A chronic Mg2þ -
deficient diet induced tumorigenic effects in Sprague Dawley rats (Hass et al., 1989).
In cultured cell lines, Mg2þ -poor culture medium significantly increased growth rate
and protein synthesis (Maguire, 1988). Magnesium influences cell proliferation and
differentiation at several levels. It stabilizes DNA structure, promotes DNA repli-
cation and transcription, influences RNA translation, induces ribosomal assembly
and regulates the opening/closing of ion channels, which accounts for pH and Ca2þ
changes preceding cell division (Wolf and Cittadini, 1999; Walker, 1995; Vernon,
1998; Aikawa, 1981). Mg2þ also regulates cell growth through its effects on activa-
tion of tyrosine kinases (including Src), PI3K, Rho/Rho kinase and mitogen-acti-
vated protein kinases (Zheng et al., 2001; Yang et al., 2000a,b; Zhang et al., 2000),
which we and others have found to be altered in vascular smooth muscle cells in
hypertension (Bodin et al., 1993; Touyz et al., 1999; Fukuda, 1997; Touyz and
Schiffrin, 2000).
Most of the above studies were performed in non-vascular cells. Recent studies
demonstrated that altered magnesium metabolism in genetically hypertensive rats is
associated with vascular smooth muscle cell hyperplasia and hypertrophy (Touyz
and Yao, 2002). In addition, magnesium-deficient spontaneously hypertensive rats
(SHR), which develop severe hypertension, exhibit significant media thickening in
mesenteric resistance arteries (Touyz et al., in press). These data, suggest that al-
terations in magnesium status not only influence vascular contractility, but also
vascular smooth muscle cell growth, an important factor associated with vascular
structural changes in hypertension (Mulvany et al., 1985; Lee, 1987; Lee and
Dickhout, 1998; Gibbons et al., 1992; Tsoporis et al., 1998).
4. Regulation of vascular tone and reactivity by magnesium
It has long been recognized that the concentration of extracellular magnesium

influences blood flow, vascular reactivity and blood pressure in mammals. Processes
by which magnesium influences hemodynamics leading to increased blood pressure
are shown in Fig. 3. Hazard and Wurmser demonstrated in 1932 that increased
serum magnesium produces significant vasodilation and hypotension (Hazard and
Wurmser, 1932), whereas hypomagnesemia is associated with vasoconstriction and
elevated blood pressure. The direct vascular effect of magnesium was originally
suggested by Blackfan and Hamilton when it was observed in clinical studies that
magnesium salt infusion lowers blood pressure via a reduction in peripheral vascu-
lar resistance (Blackfan and Hamilton, 1925). Experimental studies support these
clinical findings and confirm that acute magnesium administration leads to hypoten-
sion through vasodilatory actions (Resnick et al., 1994; Ji et al., 1983; Altura et al.,
1993; Nishio et al., 1988). Vasorelaxation and increased blood flow induced by mag-
nesium have been observed in various vascular beds (Nishio et al., 1988; Fujita et al.,
1990; Perales et al., 1991, 1997). Increased extracellular magnesium concentration
improves blood flow, decreases vascular resistance and increases capacitance func-
tion of the peripheral, renal, coronary and cerebral blood vessels while decreasing the
extracellular magnesium concentration exerts opposite effects (Perales et al., 1991,
1997; Altura et al., 1987; Kimura et al., 1989; Kemp et al., 1993; Fullerton et al.,
1996) (Table 2). At the microcirculatory level, increased extracellular magnesium
produces dose-dependent dilation of arterioles and venules in the splanchnic, skeletal
muscle and cerebral vasculatures (Altura et al., 1992). Hypermagnesemia inhibits the
spontaneous tone of arteries, veins, arterioles and venules, both in vitro and in intact
Fig. 3. Vascular mechanisms whereby decreased intracellular magnesium concentration influences he-
modynamic processes underlying pathogenesis of hypertension. "¼ increase; #¼ decrease.
Table 2
Effects of magnesium on vascular function
Vascular effects of low magnesium concentrations
Increased endothelial permeability
Decreased endothelium-dependent vasodilation
Enhanced vascular reactivity to vasoconstrictor agents
Increased vascular tone
Increased production of vasoactive agents and cytokines (eg. ET-1, catecholamines)
Decreased production of endothelial-derived vasodilators (eg. prostacyclin)
Increased oxidative stress
Vascular effects of high magnesium concentrations
Increased responsiveness to vasodilators
Decreased reactivity to vasoconstrictor agents
Increased vasorelaxation
Decreased vascular contractility
animals, and reduces arterial resistance to blood flow (Altura and Altura, 1981;
Altura and Turlapaty, 1982).
Mechanisms whereby elevations in extracellular magnesium concentration de-
crease vascular resistance are not fully understood, but magnesium-elicited vasore-
laxation occurs rapidly in a dose-dependent manner indicating that vascular effects
of magnesium probably occur via direct actions on the vasculature (Zhang et al.,
1992; Nishio et al., 1988; Somlyo and Somlyo, 1994; Fleckenstein-Grun et al., 1997).
In vitro studies demonstrated that the increase in extracellular magnesium concen-
tration inhibits calcium-induced contraction of isolated vessels in calcium-free, high
potassium physiological salt solution, indicating that external magnesium may block
calcium influx. Reducing basal vascular tone and spontaneous mechanical activity
by raising the extracellular magnesium concentration is reversed by a concentration-
dependent elevation in extracellular calcium. When extracellular magnesium con-
centration is below the physiological level, the elevation in mechanical activity and
tone is reduced as extracellular calcium is lowered. These findings suggest that
magnesium regulates the activity of vascular smooth muscle cells by competing with
calcium and modulating the level of intracellular total and free calcium (Gilbert
DÕAngelo et al., 1992; Zhang et al., 1993; Morales et al., 1996; Levine and Coburn,
1984; Yamaoka and Seyama, 1996).
Magnesium also influences vascular tone by altering responsiveness to vasocon-
strictor and vasodilator agents. An increase in the extracellular magnesium con-
centration above basal levels of 1.2 mmol/l attenuates the vasoconstrictor actions
and potentiates the vasorelaxant properties of many vasoactive agents (Nishio et al.,
1988). These effects may be related to altered binding of agonists to their specific cell
membrane receptors and/or to modulation of [Ca2þ ]i . Magnesium modulates pro-
duction of certain vasoactive agents such as ET-1 and catecholamines (Weglicki
et al., 1992; Ohtsuka et al., 2002). In magnesium-deficient rats, plasma ET-1 levels are
elevated, whereas in magnesium supplemented rats, plasma ET-1 levels are reduced
(Weglicki et al., 1992; Laurant and Berthelot , 1996). These changes could influence
vascular tone as the vasoconstrictor activity and sensitivity to ET-1 are modulated
depending on extracellular magnesium concentration. Increased magnesium atten-
uates ET-1-induced contraction whereas reduced magnesium levels augment ET-1-
stimulated contractile responses (Laurant and Berthelot, 1996). Magnesium also
influences production and release of vasodilators. Elevation of extracellular mag-
nesium levels stimulates endothelial release of PGI2 from human umbilical arteries
and from cultured umbilical vein endothelial cells (Briel et al., 1985). These effects
may be particularly important in MgSO4 treatment of eclampsia and pre-eclampsia
(Watson et al., 1986; Sipes et al., 1994).
Another possible mechanism whereby magnesium regulates vascular function and
contractility is via its antioxidant actions (Weglicki et al., 1996). There is increasing
evidence that the vasculature is a rich source of reactive oxygen species, which di-
rectly influences vascular smooth muscle cell contraction and growth (Touyz and
Schiffrin, 1999; Griendling et al., 2000). Magnesium has antioxidant properties that
could attenuate deterimental effects of oxidative stress on the vasculature, thereby
preventing increased vascular tone and contractility. These effects may be particu-
larly important in hypertension, where generation of reactive oxygen species is in-
creased and [Mg2þ ]i is reduced (Touyz, 2000).
5. Magnesium and endothelial function
In addition to direct actions on vascular smooth muscle, magnesium modulates

endothelial function (Altura and Altura, 1987). The vascular endothelium plays a
fundamental role in the regulation of vasomotor tone by releasing nitric oxide (NO),
ET-1, cyclo-oxygenase-derived prostanoid(s) such as prostacyclin (PGI2 ), and en-
dothelial-derived hyperpolarizing factor. Intraarterial magnesium infusion increases
endothelial-dependent vasodilation in human forearm (Haenni et al., 2002). These
effects have been linked to nitric oxide-cyclic guanosine monophosphate and cy-
clooxygenase systems (Longo et al., 2001; Yang et al., 2000). Magnesium also dilates
epicardial and resistance coronary arteries in humans, but these effects appear to be
independent of nitric oxide (Teragawa et al., 2001). Shechter et al. (2000), demon-
strated that oral magnesium therapy improves endothelial function in patients with
coronary artery disease. Experimental studies also demonstrated an important role
of magnesium in endothelial function. Magnesium produces endothelium dependent
and endothelium-independent relaxations in rat aorta in a concentration-dependent
manner. These relaxant actions of magnesium on intact aortic rings, but not on
denuded rings, were suppressed by nitric oxide synthase inhibitors, indicating the
important role of nitric oxide in magnesium-mediated dilation (Yang et al., 2000).
An acute reduction of extracellular magnesium leads to a transient vasodilation
followed by a sustained contraction. In the presence of endothelial damage, low
magnesium induces a sustained contraction without the transient vasorelaxation
phase (Ann and Ku, 1986; Ku and Ann, 1991; Gold et al., 1990; Szabo et al., 1991,
1992; Pearson et al., 1998). These findings suggest that magnesium has a dual effect
in the regulation of vascular reactivity, depending on the integrity of the endothe-
lium. An intact endothelium prevents against the detrimental effects of acute hyp-
omagnesemia, whereas in the presence of an injured endothelium, as is the case in
many cardiovascular diseases, the compensatory vasodilatory effect is absent and
low Mg2þ has a direct constrictor effect on vascular smooth muscle. This was further
confirmed by Miyagawa et al. (2000) who showed that magnesium removal impairs
inhibitory functions of the endothelium against norepinephrine-induced contraction,
without affecting endothelium-dependent relaxation in normotenive rats, whereas
the effect of magnesium removal was not apparent in SHR. The fact that after re-
moval of magnesium the contraction in endothelium-intact arteries was identical in
WKY and SHR, suggested that a normotensive artery with magnesium deficiency
mimics a hypertensive artery through endothelial impairment.
6. Magnesium and experimental hypertension
6.1. Hypomagnesemia in experimental hypertension
Hypomagnesemia and decreased tissue content of magnesium have been dem-

onstrated in various experimental models of hypertension (Laurant and Berthelot,
1992; Laurant and Berthelot, 1994; Mahboob et al., 1996; Berthelot et al., 1987;
Laurant et al., 1995; Jones et al., 1988). The intracellular concentration of free
magnesium is lower in isolated cardiomyocytes, striated and vascular smooth muscle
cells from SHR, as well as in circulating cells from SHR, deoxycorticosterone acetate
(DOCA)-salt hypertensive rats and nitric oxide synthase blockade-induced hyper-
tensive rats compared to normotensive controls (Jones et al., 1988; Wells and
Agrawal, 1992; Jelicks and Gupta, 1991; Adachi et al., 1993; Saito et al., 1995;
Senturk et al., 2000; Kisters et al., 2001; Ameen et al., 1991). In experimental models
of severe hypertension, [Mg2þ ]i is negatively and [Ca2þ ]i is positively correlated to
systolic blood pressure, while [Mg2þ ]i and [Ca2þ ]i are inversely associated (Touyz
et al., 1991; Saito et al., 1995) suggesting that magnesium could be involved in blood
pressure regulation by competing with calcium. Processes contributing to hypo-
magnesemia in experimental hypertension may relate to reduced magnesium ab-
sorption and to increased urinary magnesium output (Berthelot et al., 1987; Wells
and Agrawal, 1992; Gilles-Baillien and Cogneau, 1992). Another possibility for al-
tered magnesium metabolism is a structural change of the plasma membrane so that
the apparent permeability to magnesium is decreased (Altura and Altura, 1987;
Haenni et al., 2002).
6.2. Vascular changes in magnesium-deficient hypertensive animals
Long-term magnesium deficiency in rats potentiates responses to vasoconstrictor

agents, attenuates responses to vasodilator agents, increases vascular tone and ele-
vates blood pressure (Fig. 2) (Wolf et al., 1987; Wu et al., 1999; Makynen et al.,
1995). Some of these actions may be associated with endothelial dysfunction
(Laurant and Berthelot, 1992, 1994; Moncada, 1994; Laurant et al., 1992). Although
chronic dietary magnesium deprivation elevates blood pressure in rats (Laurant

et al., 1999a,b), an initial transitory hypotensive phase has been observed, which may
be due to the stimulated release of vasodilator substances such as histamine and
cyclooxygenase-derived prostanoids (Laurant et al., 1999a, b; Luthringer et al., 1988;
Rayssiguier et al., 1992). Magnesium deficiency is also associated with vascular
morphological changes, including decreased lumen diameter, increased intima-media
thickness, cross-sectional area, and media-to-lumen ratio (Laurant et al., 1999a),
which are indicative of medial hypertrophy and vascular remodeling, characteristic
features of arterial structural changes in hypertension (Ng et al., 1992; Mulvany et al.,
1996; Schiffrin, 1992; Laurant et al., 1997b; Rizzoni et al., 1998; Intengan et al., 1999;
Mulvany et al., 1985). Magnesium deficiency alters the viscoelastic properties of
arteries by increasing wall stiffness and accelerating the age-related decrease in dis-
tensibility (Laurant et al., 1999b). Furthermore, magnesium depletion is associated
with oxidative stress, an important factor contributing to hypertensive vascular
damage (Griendling et al., 2000; Touyz, 2000).
6.3. Magnesium supplementation in experimental hypertension
In DOCA-salt hypertension and in cyclosporin-induced hypertension, magnesium

supplementation attenuates the development of hypertension (Kisters et al., 2001;
Mervaala et al., 1997; Kh et al., 2000) whereas in adult SHR with established hy-
pertension, magnesium supplementation has only modest blood pressure-lowering
effects (Evans and Weaver, 1989; Laurant et al., 1996). Dietary manipulation of
magnesium during the prehypertensive and the developing stages of hypertension in
SHR prevents the rise in blood pressure (Berthelot and Esposito, 1983; Touyz and
Milne, 1999). These data suggest that oral magnesium may be beneficial in pre-
venting further blood pressure elevation if magnesium is given at a critical stage
during the development of hypertension (4–10 weeks of age). In the prehypertensive
period, a physiological mechanism underlying blood pressure regulation may be
magnesium dependent. During this phase, intracellular free calcium concentration
progressively increases in SHR, but not in age-matched WKY (Touyz and Milne,
1999; Laurant and Berthelot, 1998). Considering the competitive nature of magne-
sium on calcium it may be possible that exposure of vascular smooth muscle cells to
high magnesium levels limits the elevation of [Ca2þ ]i during the developing stage of
hypertension, thereby attenuating the rise of vascular tone and thus opposing blood
pressure elevation. Although it is still unclear exactly how magnesium treatment
modulates vascular tone and reactivity Mg2þ -associated changes in intracellular
signaling pathways, altered cellular Mg2þ /Ca2þ interactions in vascular smooth
muscle cells and improved endothelial function may be important (Altura and Al-
tura, 1995; Altura et al., 1991; Nakajima et al., 1997; Zhang et al., 1992; Levine and
Coburn, 1984). Another possibility whereby magnesium influences blood pressure
regulation could be at the central level. Recent studies demonstrated that pressor
responses evoked by N-methyl-D -aspartate and activation of metabotropic gluta-
mate receptors in the rostral ventrolateral medulla of rats were attenuated by
magnesium chloride and magnesium sulphate microinjection (Kagiyama et al.,

2001).
7. Magnesium and human hypertension
7.1. Epidemiological studies
Epidemiological studies have linked hypertension and hypertensive heart diseases,

as well as ischemic heart diseases, with Ôsoft waterÕ, low in Mg2þ , and protection
against cardiovascular disease with Ôhard waterÕ, high in Mg2þ (Elwood and Pic-
kering, 2002). The best epidemiological evidence linking magnesium and blood
pressure comes from the Honolulu Heart study (Joffres et al., 1987), in which the
relationships of various dietary variables with blood pressure were examined. Of all
the nutrients, dietary magnesium intake had the strongest relationship with blood
pressure. This was manifested with both dietary intake and with the use of magne-
sium supplements. Men with the highest magnesium intakes had systolic and dia-
stolic blood pressures that were significantly lower than men who had the lowest
magnesium intakes. Many subsequent epidemiological and clinical investigations
further supported the notion that increased magnesium intake contributes to pre-
vention of hypertension and cardiovascular disease (Whelton and Klag, 1989; Van
Leer et al., 1995; Simons-Morton et al., 1997; Ascherio et al., 1992; Mizushima et al.,
1998). A large prospective study among nurses in the USA demonstrated that the
risk of developing hypertension is reduced by 23% in women with a magnesium
intake of more than 300 mg/day compared with a magnesium intake of less than 200
mg/day (Suter, 1999). In the Dietary Intervention Study in children who had elevated
low-density lipoprotein cholesterol, an increased magnesium intake of 65 mg per day
was associated with a reduction of systolic blood pressure and diastolic blood
pressure by 0.91 and 0.72 mmHg respectively (Simons-Morton et al., 1997). Joffres
et al. (1987) analyzed 61 dietary variables in a group of 615 men free of cardio-
vascular disease and found that total magnesium intake was the variable with the
greatest inverse association with blood pressure. Dietary potassium, phosphorous
and fiber were also negatively correlated with blood pressure. These findings sug-
gested that the high magnesium content of vegetables, whole grains and fruits may
be responsible for the low blood pressure seen in vegetarians. In support of these
data are those from the Dietary Approaches to Stop Hypertension (DASH) clinical
trial, which demonstrated that hypertensive patients on a magnesium-rich diet of
fruit, vegetable and low fat improved, blood pressure by 11.4/5.5 mmHg (Harsha
et al., 1999; Appel et al., 1997; Davis and Jones, 2002; Milan et al., 2002). Data from
recent well-conducted, large, prospective studies on nutrition and blood pressure in
US and Dutch populations, have also reported that magnesium-rich diets may re-
duce blood pressure levels, especially in older individuals (Geleinjoise et al., 1996;
Ascherio et al., 1996). It is possible that dietary magnesium could be acting as a
surrogate for other nutrients. This is especially relevant regarding fruits and vege-
tables, which are protective against cardiovascular disease. In the average diet in the
United Kingdom, 25% of total magnesium derives from fruit and another 25% from
vegetables (Elwood et al., 1996). A large retrospective study which assessed mag-
nesium and calcium content in drinking water in subjects who died from hyperten-
sion compared with those who died from other causes demonstrated that magnesium
levels in drinking water were inversely related to the risk of death from hypertension
(Yang and Chiu, 1999). Data from the recent Vanguard study, in which physio-
logical factors affecting blood pressure responses to nonpharmacological factors was
assessed, demonstrated that independently of weight reduction, diet-induced changes
in systolic blood pressure were significantly related to changes in urinary excretion of
magnesium, potassium and calcium relative to sodium (Resnick et al., 2000). These
epidemiological studies together with experimental evidence support an inverse re-
lationship between Mg2þ and blood pressure.
7.2. Magnesium status in human hypertension
Clinical studies have shown, for the most part, some form of hypomagnesemia
(serum and/or tissue) in hypertensive patients, with significant negative correlations
between magnesium concentration and blood pressure (Touyz et al., 1987; Resnick
et al., 1997; Kesteloot and Joossens, 1988; Kisters et al., 1998; Kawano et al., 1998;
Touyz et al., 1992). A relationship has also been described between the renin-
angiotensin system, magnesium and blood pressure. High renin hypertensive patients
have lower serum magnesium levels than normotensive subjects (Resnick et al., 2000;
Resnick et al., 1987) and serum magnesium is inversely associated with plasma renin
activity (PRA). Since increased PRA indicates activation of the renin-angiotensin
system, it may be possible that Ang II-dependent hypertension is associated, at least
in part, with vascular and cardiac effects of hypomagnesemia. Recent studies have
also reported a negative dependency between [Mg2þ ]i and arterial compliance in
humans, the lower the [Mg2þ ]i , the stiffer the blood vessels and the greater the blood
pressure (Resnick et al., 1997). In earlier investigations, total Mg2þ levels were de-
termined which may not necessarily reflect the free component, the physiologically
active from of magnesium. Today, with the availability of selective fluorescent Mg2þ
probes and Mg2þ -specific ion-selective electrodes, which accurately measures of
[Mg2þ ]i in living cells, it is evident that many cell types from hypertensive patients
have significantly lower [Mg2þ ]i than cells from normotensive subjects, even if total
Mg2þ levels are within the normal range (Touyz and Schiffrin, 1993).
Underlying causes for altered magnesium metabolism in hypertension are unclear,
but genetic, dietary, hormonal factors or drugs could play a role. Inadequate dietary
intake of magnesium or errors in magnesium metabolism lead to dyslipidemias,
insulin resistance, vasospasm and endothelial damage, characteristic features of
small arteries in hypertension. At the cellular level, aberrant regulation of magne-
sium is important. Changes in magnesium buffering, influx, mobilization or efflux all
contribute to reduced [Mg2þ ]i . Recent studies reported that activity of the Naþ –
Mg2þ exchanger, which induces magnesium efflux, is increased in erythrocytes from
essential hypertensive patients, in lymphocytes from patients with hyperaldostero-
nism and in vascular smooth muscle cells from SHR, suggesting that this transporter
Table 3
Subgroups of hypertensive patients who benefit from magnesium supplementation
Blacks
Elderly
Patients who have insulin resistance
Patients on diuretics
Hypomagnesemic patients
Patients resistant to treatment
Severe or malignant hypertension
Pre-eclampsia
may be pivotal in abnormal intracellular magnesium status in hypertension (Flat-

man, 1984; Resnick, 1992; Picado et al., 1994; Touyz and Schiffrin, 1993; Touyz and
Milne, 1995; Rubenowitz et al., 1998).
Not all clinical investigations reported magnesium depletion in hypertension.
Some studies found no differences in serum magnesium levels or in [Mg2þ ]i in hy-
pertensive patients (Cappuccio et al., 1985; Ferrara et al., 1992), while others re-
ported increased erythrocyte [Mg2þ ]i in patients with essential hypertension (Hiraga
et al., 1998). Furthermore, a few epidemiological studies failed to show an associ-
ation between magnesium intake and blood pressure (Whelton and Klag, 1989). It is
evident that not all hypertensive patients are hypomagnesaemic, and not all patients
with magnesium deficiency are hypertensive. Despite the inconsistencies in the lit-
erature regarding magnesium status in hypertension, there are subgroups of hyper-
tensive patients who consistently demonstrate altered magnesium metabolism (Table
3). These include, blacks, obese patients, those with insulin resistance, patients with
hypertriglyceridemia and patients with severe or malignant forms of hypertension
(Kawano et al., 1998; Sanjuliani et al., 1996; Luthringer et al., 1988; Bardicef et al.,
1995; Delva et al., 1996, 1998; Touyz et al., 1995; Fox et al., 1999).
7.3. Putative mechanisms whereby magnesium influences hypertension in humans
Despite the fact that there is strong clinical evidence implicating magnesium in the
pathogenesis of hypertension, the exact role of this cation is still unclear. Three
major mechanisms have been suggested, (1) ionic hypothesis mechanism, (2) Mg2þ -
dependent, Ca2þ -mediated mechanisms and (3) Mg2þ -dependent, Naþ -mediated
mechanisms. Resnick and colleagues demonstrated that [Mg2þ ]i is inversely related
to blood pressure and to the insulinemic responses to glucose loading, and proposed
the ionic hypothesis, in which these cellular abnormalities are manifestations of a
common underlying defect in many pathological conditions (Resnick, 1993; Do-
minguez et al., 1998; Barbagallo et al., 2001). Abnormal cellular ion handling is
characterized by decreased [Mg2þ ]i and associated reduced [Kþ ]i , increased [Ca2þ ]i
and [Naþ ]i and insulin resistance and is present not only in hypertension, but also in
obesity, ischemic heart diseases, hyperinsulinemia and non insulin-dependent dia-
betes (NIDDM) (Resnick, 1993; Dominguez et al., 1998; Barbagallo et al., 2001;
Tosiello, 1998). Magnesium deficiency may be the link between the insulin resistance
of hypertension, obesity and NIDDM, as its function in regulating cellular pumps,

such as Naþ /Kþ ATPase and Ca2þ -ATPase necessary for regulating peripheral
vascular tone, would be reduced. The magnesium dependent, calcium-mediated
mechanism suggests that intracellular magnesium deficiency leads to intracellular
calcium overload, a primary mediator of increased vascular smooth muscle con-
tractility, peripheral resistance and blood pressure, rather than magnesium depletion
itself (Sanders et al., 1999; Saris et al., 2000). Altered membrane calcium/magnesium
content could be important. Kosch et al. reported increased calcium/magnesium
ratio in erythrocyte membranes from essential hypertensive patients compared with
normotensive controls (Kosch et al., 2001). The third mechanism suggests that in-
tracellular sodium is the most important ion for hypertension, and that hypomag-
nesemia-dependent increases in intracellular sodium cause increased vascular
resistance and hypertension (Sanders et al., 1999). Thus while magnesium is a key
modulator of many cellular processes important in the regulation of vascular tone
and resistance, magnesium does not act alone, and it is probably the interaction of
many factors including magnesium deficiency, that contributes to the pathogenesis
of hypertension.
7.4. The therapeutic role of magnesium in hypertension
The therapeutic value of magnesium in the treatment of clinical hypertension was

suggested in 1925 when magnesium infusion was found to improve malignant hy-
pertension (Blackfan and Hamilton, 1925). Since then many investigations have
supported a putative role for magnesium in the treatment of hypertension. Con-
sidering the inexpensive nature of the agent, and the fact that it is easy to handle,
magnesium is theoretically, an excellent contender for a place in the routine man-
agement of hypertension. However, this is not so in clinical practice. In general, data
from clinical trials of magnesium therapy in hypertension have been disappointing.
Some studies reported significant blood pressure-lowering effects of oral or intra-
venous magnesium treatment (Suter, 1999; Corica et al., 1999; Widman et al., 1993;
Itoh et al., 1997; Motoyama et al., 1989; Kawasaki et al., 1998; Dyckner and Wester,
1983) and magnesium supplementation to patients already receiving diuretics or
other antihypertensive agents appears to reduce blood pressure further (Katz et al.,
1999; Pastori et al., 1999). However other trials failed to demonstrate any hypo-
tensive action of magnesium supplementation (Resnick, 1993; Dominguez et al.,
1998) and results from the Trial of Hypertension Prevention (TOHP) showed no
benefit of magnesium therapy in 698 patients followed for six months (Yamamoto
et al., 1995). The inconsistency in results may be due to the number of studies that
were small or of short duration, differing treatment protocols, variable forms of
magnesium salts used, different concentrations of magnesium supplemented and the
heterogeneity of the population of hypertensives investigated. Studies that have
consistently shown a beneficial effect of magnesium treatment were performed in
black patients, those with established hypomagnesemia, those with diuretic-associ-
ated hypertension, and in patients where magnesium was supplemented long term
(Table 3) (Ford, 1998; Lind et al., 1991). Also, in secondary hypertension as well as
in pre-eclampsia, magnesium is therapeutically effective in lowering blood pressure

(Jurcovicova et al., 1998; Mason et al., 1996). Thus, although this cation may not be
a universally effective antihypertensive agent, it does seem to benefit a subgroup of
hypertensive patients. Taken together, these data suggest magnesium is at best
weakly hypotensive. The use of magnesium supplementation with diuretics, espe-
cially thiazide diuretics, is advisable to prevent intracellular magnesium and potas-
sium depletion (Stuhlinger, 2002).
Before making definitive therapeutic recommendations on the use of magnesium
in the management of hypertension, well-controlled, long-term therapeutic trials, in
carefully characterized hypertensive patients are need. However, the potential ben-
efits of magnesium are currently recognized and the Sixth Report of the Joint Na-
tional Committee on Prevention, Detection, Evaluation and Treatment of High
Blood Pressure (JNC VI) has included maintenance of adequate dietary magnesium
intake as a recommendation for life-style modifications for hypertension prevention
management (Joint National Committee on Detection, Evaluation and Treatment of
High Blood Pressure, 1997).
8. Magnesium and pre-eclampsia/eclampsia
Pre-eclampsia, defined as hypertension after 20 weeks of gestation, with pro-

teinuria (Shear et al., 1999), has been treated with magnesium salts since the turn of
the century. During pre-eclampsia, both cardiac output and plasma volume are re-
duced whereas systemic vascular resistance is increased (Shear et al., 1999; Robert
and Redman, 1993). These changes result in reduced perfusion of the placenta,
kidney, liver and brain, leading to maternal and foetal morbidity and mortality
(Robert and Redman, 1993). The cause of pre-eclampsia remains elusive but it is
thought that endothelial dysfunction or damage may be important (Roberts et al.,
1989). Magnesium has been shown to improve endothelial function in pre-eclampsia.
This may be due to the direct vasodilatory properties of magnesium and/or to the
ability of magnesium to stimulate release of the endothelial vasodilator prostacyclin,
which induces vasodilation as well as inhibits platelet adherence and aggregation
(Shear et al., 1999; Nadler et al., 1987).
Acute magnesium sulfate administration elicits a rapid fall in systemic vascular
resistance, a rise in cardiac index and a transient decrease in blood pressure (Belfort
and Moise, 1992; Cotton et al., 1984; Scardo et al., 1995). Magnesium sulfate in-
fusion also increases renal blood flow and stimulates production and release of
prostacyclin in pre-eclampsia, but not in preterm labour (Sipes et al., 1994; Nadler
et al., 1987). In healthy nonpregnant women these effects are inhibited by indo-
methacin (cyclooxygenase inhibitor) suggesting that the fall in blood pressure is
mediated by magnesium-induced prostacyclin release (Nadler et al., 1987).
Data relating to magnesium concentrations in pre-eclampsia are conflicting, with
some studies failing to demonstrate any differences between pre-eclampsia and un-
complicated pregnancy and others reporting decreased serum and intracellular
magnesium (Handwerker et al., 1995; Standley et al., 1997; Sanders et al., 1998;
Frenkel et al., 1994; Seydoux et al., 1992). Some studies found total magnesium
levels to be higher in pre-eclamptic women (Kisters et al., 1990). Reasons for these
differences are unclear, but heterogeneity of populations studied may be important.
Although the exact role of magnesium in the pathogenesis of pre-eclampsia remains
obscure, it has been suggested that magnesium can be used as a predictive tool for
pre-eclampsia. Standley et al. (1997) studied the magnesium levels at different ges-
tational ages. They found that magnesium decreases in both pre-eclamptic and un-
complicated pregnancies, but that the magnesium concentration was lowered earlier
in women with pre-eclampsia. This difference has been proposed as a marker of
severity of the condition. It has also been suggested that alterations in the Naþ /Mg2þ
exchanger in trophoblast cells may be important (Standley and Standley, 2002).
Magnesium sulfate remains the most frequently used treatment in the manage-
ment of pre-eclampsia and eclampsia in USA (Lucas et al., 1995). The Collaborative
Eclampsia Trial provides level I evidence of the superiority of magnesium sulfate for
the treatment of eclampsia. Magnesium sulfate had a 52% lower risk of recurrent
convulsions versus diazepam and a 67% lower risk of recurrent convulsions versus
phenytoin (The Eclampsia Collaborative Group, 1995). Use of magnesium sulfate
for prophylactic treatment in women with pre-eclampsia is more controversial. A
recent large trial among severe pre-eclamptic women compared magnesium sulfate
with placebo. The trial was terminated prematurely after finding a significant re-
duction in the development of eclampsia with magnesium sulfate (0.3% vs. 3.2%)
(Coetzee et al., 1998). The largest clinical trial comparing magnesium sulfate with
phenytoin in hypertensive pregnancies also reported that eclampsia was significantly
reduced in women taking magnesium sulfate compared to those on phenytoin (Lucas
et al., 1995; Duley et al., 1992). The Magpie trial, which involved 10,141 women with
pre-eclampsia in 175 hospitals in 33 countries recently showed that magnesium
sulphate significantly reduces the risks of eclampsia among women with pre-
eclampsia (The Magpie trial collaborative group, 2002). These data clearly demon-
strate that magnesium sulphate has a very important role in preventing as well as
controlling eclampsia, and the available evidence suggests that it is tolerably safe.
Although the use of magnesium sulphate for eclampsia is well substantiated there is
little evidence supporting the routine use of magnesium sulphate in cases of gesta-
tional hypertension. Shear et al. (1999) suggest that magnesium sulphate should be
used liberally in women with severe pre-eclampsia and in those who are at risk for
becoming pre-eclamptic. In patients with proteinuria or with mild pre-eclampsia,
magnesium sulphate treatment should be individualized according to specific clinical
needs.
9. Conclusions
The major hemodynamic abnormality in hypertension is increased peripheral

resistance, due to changes in vascular structure and function. These changes include
arterial wall thickening, altered vascular tone and impaired endothelial function and
are influenced by multiple factors, including magnesium. At the cellular level there is
increased vascular smooth muscle cell growth, increased extracellular matrix depo-
sition, increased contractility and decreased dilation. Perturbations in magnesium
status may play a key role in these processes, since magnesium regulates contractile
proteins, modulates transmembrane transport of ions, acts as an essential cofactor
in the activation of ATPase, controls metabolic regulation of energy-dependent
pathways, regulates oxidative-phosphorylation processes and influences DNA and
protein synthesis. Minor changes in magnesium levels have major effects on cardiac
excitability and on vascular tone. Hence magnesium may be important in the
pathophysiological processes underlying blood pressure elevation. Most epidemio-
logical and experimental studies demonstrate a negative relationship between mag-
nesium and blood pressure and support a role for magnesium in the pathogenesis of
hypertension. With the development of new technologies to assess magnesium status,
research has increased our understanding of cellular magnesium transport and
regulation and has allowed for the improved detection of intracellular magnesium
status in both experimental animals and in humans. It is now timely for experimental
magnesium research to extend to the clinical milieu where the exact role of mag-
nesium in the pathophysiology of cardiovascular diseases, such as hypertension, can
be further studied in humans. The biological importance of magnesium, the ease and
safe handling of magnesium, as well as the low treatment costs justifies the increasing
interest in magnesium for scientific research and clinical use in hypertension.
Acknowledgements
The authorÕs work cited in the review was supported by the Canadian Institutes of
Health Research, Heart and Stroke Foundation of Canada, Canadian Hypertension
Society and the fonds de la recherche en sante du Quebec.
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Molecular Aspects of Medicine 24 (2003) 107–136

Role of magnesium in the pathogenesis

Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal,

Essential hypertension is a major modiﬁable risk factor for cardiovascular dis-

dietary magnesium supplementation and hypertensive eﬀects of magnesium deﬁ-

2. Magnesium homeostasis in cardiovascular cells

For magnesium to signiﬁcantly modulate cellular events, magnesium itself

3. Vascular changes in hypertension––role of magnesium

Hypertension is due primarily to increased peripheral vascular resistance that is

4. Regulation of vascular tone and reactivity by magnesium

It has long been recognized that the concentration of extracellular magnesium

5. Magnesium and endothelial function

In addition to direct actions on vascular smooth muscle, magnesium modulates

6. Magnesium and experimental hypertension

6.1. Hypomagnesemia in experimental hypertension

Hypomagnesemia and decreased tissue content of magnesium have been dem-

6.2. Vascular changes in magnesium-deﬁcient hypertensive animals

Long-term magnesium deﬁciency in rats potentiates responses to vasoconstrictor

chronic dietary magnesium deprivation elevates blood pressure in rats (Laurant

6.3. Magnesium supplementation in experimental hypertension

In DOCA-salt hypertension and in cyclosporin-induced hypertension, magnesium

magnesium chloride and magnesium sulphate microinjection (Kagiyama et al.,

7. Magnesium and human hypertension

7.1. Epidemiological studies

Epidemiological studies have linked hypertension and hypertensive heart diseases,

7.2. Magnesium status in human hypertension

may be pivotal in abnormal intracellular magnesium status in hypertension (Flat-

7.3. Putative mechanisms whereby magnesium inﬂuences hypertension in humans

of hypertension, obesity and NIDDM, as its function in regulating cellular pumps,

7.4. The therapeutic role of magnesium in hypertension

The therapeutic value of magnesium in the treatment of clinical hypertension was

in pre-eclampsia, magnesium is therapeutically eﬀective in lowering blood pressure

8. Magnesium and pre-eclampsia/eclampsia

Pre-eclampsia, deﬁned as hypertension after 20 weeks of gestation, with pro-

The major hemodynamic abnormality in hypertension is increased peripheral

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