Magnesium in clinical practice
Jean DURLACH
Translated by David WILSON
French edition (Le magnesium en pratique cliniques. Published
in 1985 by J. B. Baillière, Editions Médicales
Internationales, 62 rue des Mathurins, 75008 Paris, France
First English language edition published in 1988 by
John Libbey & Company Ltd, 80/84 Bondway,
London SW8 1SF, England (01) 582 5266
John Libbey Eurotest Ltd, 6 rue Blanche, 92120
Montrouge, France (1) 47 35 85 52
Excerpt. Pages 1-39.
Table of Contents
I
ELEMENTS OF MAGNESIUM BIOLOGY
1. THE PROPERTIES OF
MAGNESIUM
2. THE METABOLISM OF
MAGNESIUM
Basically, the role of magnesium in clinical practice may only
be considered in two conditions occurring with very different
frequency. On the one hand there is the major and somewhat
commonplace problem of magnesium deficits and on the other, the
much rarer condition of magnesium overload which is almost always
of iatrogenic origin.
The beginning of modern studies of the consequences of
magnesium deficit in pathology is rightly attributed only to the
demonstration of its physiologic importance in animals with the
seminal experiment of Jehan Leroy which proved
in 1926 the essential character of the ion for mice (750). One
can cite as a predecessor only J. Gaube du Gers
(492, 493, 494) who, more than a century ago, noticed in the same
animal that a diet deficient in magnesium, composed of bread
devoid of magnesium and distilled water, but also no doubt
deficient in other nutrients, caused progressive sterility.
Already magnesium appeared to him to be 'the metal of vital
activity for what is most precious and noble in life:
reproduction and sensation.' Subsequently it was the remarkable
studies of the groups of E. MacCollum and
D.M. Greenberg (281, 345) that in the Thirties
revealed many of the physiological properties of magnesium,
examining, in the rat initially the multiple effects of a lack of
magnesium in the diet on development, reproduction, neuromuscular
apparatus, and humoral balance. They then studied the specific
reversibility of such defects by oral loading of magnesium. These
studies provide as well the first experimental basis in animals
for the diagnostic test for magnesium deficiency by oral loading
with physiological doses of magnesium. Contrary to intakes of
magnesium which have non-specific pharmacologic effects, oral
physiological doses of magnesium are devoid of any activity.
Their effectiveness in a clinical context constitutes the best
proof of the existence of a developing magnesium deficiency
(332).
On the other hand, one must refrain from attributing any
compelling physiologic significance to earlier works that,
extrapolating from magnesium's various pharmacodynamic properties
(neurosedative, cardio-regulatory, vasodilating, antihemolytic,
antitoxic...), whether studied in vitro or by massive
parenteral doses, claimed to have discovered symmetrical harmful
effects in the case of magnesium deficit. Nothing could be less
conclusive: one can control a motor-stimulatory crisis or a
vascular spasm by the pharmacodynamic effects of a parenteral
injection of magnesium without in doing so providing the least
proof of a deficit of this ion as cause (332). It is pleasant
however to be able to note the predictive character of hypotheses
stated more than a century ago, and subsequently verified,
concerning the etiologic or physiopathologic role of magnesium in
certain tetanies, epilepsies, cardiovascular complaints and
hemolytic or toxic problems.
We have cited here, however, only carefully chosen examples
where modern studies have proved past extrapolations to be well
founded, and not any others. The latter have, on the contrary,
been the source of a number of unwarranted pathologic
attributions of paternity to magnesium deficit. For this reason
few ions have generated as much enthusiasm and as much
disdain.
Heated zealots like P. Delbet have seen in
magnesium a sort of panacea, the lack of which plays a major role
in the development of cancer, the spread of epidemics and even in
the frequency of suicides (340).
For the skeptics, on the other hand, magnesium has appeared as
a trace element of unclear biologic importance and physiologic
significance, existing in the diet at levels sufficient to supply
any needs, but remaining almost impossible to measure.
Between these two extremes it is today possible to find a
balance.
Magnesium, the second most abundant intracellular cation, is a
catalytic and structural element of major significance in the
physiology of the human organism. Necessary for the anatomical
and functional integrity of various subcellular organelles, it
participates in all the major metabolic pathways, i.e., those
involving carbohydrates, proteins and lipids, as well as in redox
reactions. It is involved in the regulation of ion levels,
maintaining the potassium level in the cell and exercising on the
metabolism of calcium and phosphorus vitamin D-like effects.
Integral to processes of defense, magnesium exhibits a variety
of effects: antistress, anti-allergic, anti-anaphylactic,
anti-inflammatory, antiradiation. Magnesium plays a role in
thermoregulation; it stimulates phagocytosis and the formation of
antibodies, complement and elements of the properdin system.
Present in many tissues, it is active in the physiology of
many systems, not only neuromuscular, osteo-articulatory, and
dental, but also respiratory, endocrine, reproductive, ocular,
digestive, hepatic, pancreatic, renal, cardiovascular and
hematologic.
Dietary magnesium in many regions and particularly in France
appears to be insufficient to satisfy any daily need that is
markedly high with respect to body stores. Thanks in particular
to atomic absorption spectrophotometry, magnesium can now be
measured analytically with ease and accuracy. If its essentially
intracellular distribution still makes it difficult to evaluate,
the "deterring factors" which have previously prevented the
systematic study of its pathology have been permanently removed.
It has become quite easy to identify the various clinical
manifestations of magnesium deficits. But one must not approach
both primary and secondary deficits in the same fashion. A
primary magnesium deficit only allows one to observe a more or
less specific, strictly magnesium-dependent symptomatology while
the signs of a secondary magnesium deficit must be distinguished
from among the consequences of the causative illness. Moreover, a
primary magnesium deficit clearly constitutes the only indication
where corrective magnesium therapy represents the principal and
specific form of therapeutic intervention. Such a possibility
occurs with great frequency since it corresponds to the majority
of cases previously described without their magnesium dependency
having been seen at the time, for example normocalcemic latent
tetany, hyperventilation syndrome, or idiopathic
Barlow's disease (332, 345, 363, 371, 372, 375).
A secondary magnesium deficit on the contrary presents as but one
of the elements of a complaint. One must determine the etiologic
factors that cause such a secondary deficit and then evaluate its
relative importance according to the physiopathology of the
illness that causes it. The correcting of a secondary magnesium
deficit must always depend initially on treatment of the
causative illness. It must invariably take into account the whole
picture, ionic deficit included. Specific therapeutic measures
that seek to correct a secondary magnesium deficit are therefore
justified only if etiologic treatment of the responsible illness
is either impossible or ineffective. Such measures then are no
more than adjunct treatments, justified only by the ultimate
importance of secondary magnesium deficits in the physiopathology
of the original illness. They are valid only in as much as it is
possible to correct the problems causing the deficit.
We intend successively to:
• At first, as a necessary preliminary to the study of
the role of magnesium in pathology, recall some of the basic
elements of the biology of magnesium:
— its properties
— its metabolism
— methods of analysis
• Then devote the largest part of this clinical study to
the question of primary magnesium deficits and
especially to their best known forms:
— Neuromuscular hyperexcitability: the typical example
will be latent tetany in the adult. The practical approach to
this strictly magnesium pathology will be described: clinical and
paraclinical symptomatology, pathogenic etiology,
physiopathology, development, clinical variability and diagnostic
problems.
— Other primary magnesium deficits: endocrine-humoral,
osteo-articulatory, allergic, cardiovascular.
• Secondary magnesium deficits will be categorized as
deficits secondary to a "spontaneous" pathology or as deficits of
"iatrogenic" origin, classifying them in both cases according to
the principal mechanisms that cause them.
— Problems of intake or absorption
— Neuroendocrine and metabolic dysfunctions
— Renal hyperexcretion
• We will examine magnesium excess more briefly, taking
as the typical example massive parenteral overload.
• Finally, we will consider the problems of therapy,
stressing in particular:
— The treatment of magnesium deficits, contrasting
treatment of simple "deficiency" forms, where it is sufficient to
increase intake, with the treatment of severe "depletion" forms
where only an ever increasing knowledge of the control mechanisms
of magnesium metabolism will allow correction of the problem.
— Treatment of magnesium overload.
I
ELEMENTS OF MAGNESIUM BIOLOGY
1. The properties of
magnesium
Magnesium has an atomic number of 12 and an electronic
structure with complete K and L shells that have 2 and 8
electrons respectively, while the outer M shell has only two
electrons (Fig.
1) . This outer shell determines the reactive capacity
of magnesium.
Its atomic weight is 24.3. It has an atomic radius of 0.66
Å in non-aqueous medium and 5.9 Å in aqueous medium.
The three naturally occurring stable isotopes of magnesium are
24Mg (79%), 25Mg (10%) and 26Mg
(11%). The two principal radioisotopes are 27Mg and
28Mg with half lives respectively of 9.5 minutes and
21.3 hours.
Magnesium belongs to group II of the third period of the
Periodic Table of elements, a group that includes only two other
physiologically important elements: calcium and zinc.
We will outline briefly the main biologic properties of
magnesium, going from the biochemical level to the cellular and
finally to the level of physiologic function.
-
1.1 The biochemical
functions of magnesium
The biochemical properties of magnesium can be deduced
from three principal modes of action (12, 13, 14, 191, 328,
337, 361, 364, 398, 409, 546, 690, 1147, 1327, 1337):
— the synthesis and utilization of energy-rich
compounds
— the synthesis of electron and proton
transporters
— the synthesis and activity of numerous enzymes
-
-
1.11 Synthesis
and utilization of energy-rich compounds
The energy necessary for the functioning of the
machinery of the cell must be stored in the form of
potential chemical energy or energy-rich bonds.
Magnesium is necessary for the synthesis of
various compounds that have energy-rich bonds of any
type: the phosphoric anhydride bond that is found
mainly in ATP or adenosine triphosphate, "the main fuel
of life" (13), but also in GTP (guanosine triphosphate)
as well as in other nucleoside triphosphates such as UTP
(uridine triphosphate), CTP (cytosine triphosphate) and
ITP (inosine triphosphate). It is also found in the
phosphoamide bond of phosphocreatine, the phosphoenol
bond of phosphoenolpyruvic acid, the mixed anhydride bond
of 1,3-diphosphoglyceric acid and in the bond between an
acid and a thiol group as in acyl coenzyme A or succinyl
coenzyme A.
The permanent reconstitution of these compounds from
the products of their own degradation is accomplished by
phosphorylation coupled to redox reactions and magnesium
is essential for the coupling of the phosphorylating and
redox reactions (12, 13, 14). It thus allows cellular
respiration to be used to store energy in the form of
high energy phosphates, that is to say, in the form of
phosphorylated compounds that contain energy-rich
bonds.
Moreover, magnesium has also been established as
necessary for the utilization of energy-rich bonds
whether this occurs by transfer or by hydrolysis.
Magnesium activates in effect all reactions that transfer
the phosphorylated radical (1327): reactions involving
phosphoryltransferases whether reversible (adenylate
kinase or myokinase, creatine kinase, carbamate kinase,
phosphoglycerate kinase, pyruvate kinase) or
non-reversible (glucokinase, hexokinase,
phosphofructokinase, adenylate cyclases that catalyze the
conversion of ATP to cAMP, adenosine triphosphatases,
i.e., normally membrane-bound polyphophatases that
degrade ATP).
The formation and subsequent utilization of
energy-rich bonds, processes that both require
Mg2+, constitute the necessary basis for all
synthetic reactions and for all cellular activities. This
alone would be sufficient to establish the critical
biologic importance of magnesium.
-
1.12 Synthesis of
proton and electron transporters
Proton and electron transporters represent other basic
compounds necessary for the redox coupled reactions.
Magnesium is essential for their synthesis. It is
involved in the formation of phosphopyridine nucleotides,
DPN (diphosphopyridine nucleotide or NADH2 and
TPN (triphosphopyridine nucleotide or NADPH2;
in the formation of flavin nucleotides, FMN (flavin
mononucleotide) and FAD (flavin adenine dinucleotide);
and finally in that of coenzyme A.
-
1.13 Synthesis
and activity of enzymes
Magnesium activates a very large number of enzymes
(approximately 300). In some cases Mg2+ is
linked to the substrate through chelation. The Mg-ATP
complex represents a typical linking of compounds that
becomes the true substrate of the enzyme. This kind of
activation occurs for example with hexokinase and
phosphoglycerate kinase. In other cases, Mg2+
is first bound to the enzyme, causing it thus to assume
its active conformation which is able to act on the
substrate. This is the case, for example, with enolase,
pyruvate kinase and pyrophosphatase. These two mechanisms
are not moreover incompatible. A single Mg2+
may initially form a Mg-ATP complex that represents the
real substrate of an ATPase which will only act on this
substrate when activated by a second Mg2+
(546).
All ATP-dependent enzyme reactions exhibit an absolute
need for Mg2+ (12).
We will list some of the principal enzymes that are
involved in the major metabolic pathways:
• Enzymes of
carbohydrate metabolism (336, 396): glucokinase,
hexokinase, galactokinase, phosphorylase phosphatase,
phosphorylase kinase, phosphoglucomutase,
6-phosphofructokinase aldolase, triokinase,
fructose-1,6-bisphosphatase, glucose-6-phosphatase,
glucose-6-phosphate dehydrogenase, transketolase,
phosphoglycerate kinase, phosphoryl glycerylmutase,
enolase, pyruvate kinase, thiamine-pyrophosphate kinase,
pyruvate decarboxylase, glycerokinase,
glycerophosphatase, various pentoside kinases that
activate B vitamins....
• Enzymes of nucleic
acid and protein metabolism (188, 328, 684, 690, 732,
1149, 1327): RNA polymerase which allows the synthesis of
RNA and especially that of messenger RNA which,
associated with post-ribosomal factors of initiation and
elongation and with polyamines, codes for amino acids to
produce specific proteins; DNA polymerase which allows
the reconstitution and recombination of DNA, ornithine
carbamyl transferase, glutamine synthetase, carbamate
kinase, argininosuccinate synthetase, creatine kinase,
insulinase, leucine aminopeptidase which appears to be
similar to hypertensinase....
• Enzymes of lipid
metabolism (328, 732, 1065, 1067): acetylcoenzyme A
synthetase, acylco A synthetase, beta-ketothiolase,
diglyceride kinase, phosphatidate phosphatase, mevalonate
kinase, phosphomevalonate kinase,
lecithin-cholesterol-acyl transferase (LCAT).
• Finally, various
other enzymes: alkaline phosphatase, cholinesterase,
anti-hyaluronidase.
Enzyme activation is not however the only action of
magnesium on these proteins.
• It can sometimes on
the contrary inhibit them: this is the case for example
with the ATPase activity of myosin and with most of the
guanylate cyclases.
• It participates above
all in their synthesis, not only as a constituent of a
magnesium metalloenzyme such as alkaline phosphatase, but
especially by its role in protein synthesis in general
and therefore in that of enzymes in particular. The
reduced levels of serum alkaline phosphatase and of
erythrocyte glucose-6-phosphate dehydrogenase (G6PDH) in
the case of magnesium deficiency in the calf (729, 730)
or those of lymphocyte elongation factors 1 and 2 during
magnesium deficit in the rat (473) are two examples.
Thus, Mg2+ which is necessary for the
synthesis of energy-rich compounds, electron transporters
and enzymes and controls their effects appears to be a
major cellular component. One can understand that it
constitutes the fundamental regulator of the cell cycle
(1333). Compartmentalization of Mg2+ in the
cell permits it to play a key role in the coordination of
metabolic pathways where the limiting steps are
represented by phosphorylation reactions (550, 550a,
1105, 1106, 1107, 1108, 1129, 1317).
-
1.2 The cellular
properties of magnesium (12, 13, 14, 328, 337, 546, 549, 550,
550a, 617, 847, 1286, 1336, 1337)
The cytologic properties of magnesium deserve the very
special attention due an ion that is almost totally
intracellular. They are determined by the extreme
heterogeneity of both its physicochemical and its anatomical
distribution.
Even though its different concentrations clearly vary
according to the cell type being studied as a function of the
physiologic activities of various tissues, these
concentrations present certain common characteristics.
-
-
1.21
Physicochemical heterogeneity
The cellular distribution of magnesium corresponds to
a broad compartmentalization that is essentially a
function of the tendency of this metal to form chelates
with different cellular constituents, very often in
competition with calcium. (12, 13, 14, 546, 549,
550).
• Phospholipids form
complexes with magnesium as well as with calcium, which
explains why magnesium is an integral part of the
structure of many membranes, cellular or subcellular,
plasma or mitochondrial, reticular, and sarcoplasmic.
• Nucleic acids form
complexes with magnesium that have a much greater
flexibility than those formed with calcium. They add to
the high levels in ribosomes as well as in the
nucleus.
• By virtue of the law
of mass action, these different bound magnesium compounds
(corresponding to about 70% of intracellular magnesium)
are in equilibrium with a pool of free magnesium (i.e.,
about 30% of cellular magnesium).
• Heterogeneity may be
observed not only among different substructures of the
cell — one can, for example, contrast the richness
of mitochondria and microsomes in magnesium with the more
modest magnesium levels of the cytosol — but also
within a given subcellular organelle. In a mitochondrion
the intermembrane compartment is much richer than the
inner or outer membranes. Similarly, in the cytosol,
magnesium is not uniformly distributed. Its highest
levels are found near negatively charged membranes or on
the surface of polyanions. Buffered at a level of pMg 3
(pMg = -log [Mg2+]), intracellular
Mg2+, whatever its site, is found in
equilibrium with bound magnesium and in an optimal
concentration for the exercise of its metabolic effects
(546).
Thus, magnesium, distributed in the cell in a very
heterogeneous manner, is found at high levels in all
cellular and subcellular membranes, in mitochondria,
microsomes, and the nucleus, always remaining in an
equilibrium between bound and free forms that is optimal
for the exercise of its effects, the most notable of
which is its stabilizing capacity.
-
1.22 The cellular
and subcellular stabilizing effects of
magnesium
Magnesium appears to have a stabilizing effect not
only for the cell membrane but also for various
subcellular organelles.
• One of the major
properties of magnesium is that of stabilizing membranes.
This depends mainly on its structural role. The
complexing of magnesium with phospholipids reduces
membrane fluidity and lowers membrane permeability with
parallel polarizing electrostatic effects.
Thus in magnesium deficit the permeability of plasma
membranes increases. Cells become loaded with
Ca2+ and Na+ and lose K+
and phosphorus. At the same time, the cell membrane
depolarizes (70). The direct structural effects of
magnesium on the membrane are of fundamental importance.
They may be re-inforced by comparable effects on the
ATP-dependent pumps that regulate the active transport of
Na+, K+, and Ca2+. It is
particularly necessary to stress the potentiating effect
of magnesium on Na+/K+-adenosine
triphosphatase (Na+/K+-ATPase) that
controls the "active sodium pump." When activated, it
removes sodium from the cell and thus allows potassium to
remain. In this fashion, a lack of magnesium induces
changes in cellular ion levels which in turn cause
various ionic interactions. Increasing cytosolic
Na+, for example, alters the distribution of
the calcium load. The level of cytosolic Ca2+
which has already been increased by the hyperpermeability
of the plasma membrane is increased even more by a flux
of calcium from the mitochondrion into the cytosol that
is caused by changes in the mitochondrial membrane (546).
Calcium remains even more tightly bound in the cytosol
because magnesium deficit increases the affinity of its
binding sites for it (293).
Magnesium's stabilizing role is not limited to the
plasma membrane: Mg2+ is necessary for the
anatomical and functional integrity of a variety of
subcellular organelles.
• Magnesium maintains a
"strongly coupled" state in the mitochondrion, that is, a
state where oxidative phosphorylation, the fundamental
element of energy reactions, is highly efficient. The
primary function of all mitochondria is to keep
phosphorylation coupled to oxidation and to produce ATP,
the basic fuel of life. With magnesium deficit, cellular
respiration accelerates while phosphorylation slows down
and one observes a reduction of the P/O ratio. In
conjunction with this uncoupling, the mitochondria swell
because of the increase in the permeability of their
membranes. This membrane hyperpermeability during
magnesium deficiency depends again less on the changes in
ATPase activity than on the direct effect of the increase
in membrane permeability. The uncoupling of oxidation and
phosphorylation seems to be a function of an increase in
the permeability of the inner mitochondrial membrane to
the influx of protons, while ATPase activity remains
normal (571).
• Ribosomes require
magnesium in order to maintain their physical stability:
their aggregation into polysomes which can form peptide
chains is possible only in the presence of
Mg2+. During magnesium deficiency they
dissociate into small particles. The almost exclusive
function of ribosomes is the biosynthesis of proteins.
The stabilizing activity of magnesium on polysomes
maintains the structure of RNA complexes, allowing, with
the help of elongation factors (188, 473) and polyamines
(1149), the formation of polypeptides and ultimately the
most stable conformation of the protein (12, 13, 14, 323,
546, 549, 1327).
• Magnesium also
appears to protect lysosomes. Magnesium deficit in the
rat, for example, is accompanied by a degranulation of
mast cells that may be compared to the degranulation of
polynuclear basophils in man. This is not the result of a
degranulating factor in serum, but rather of a direct
cellular effect of magnesium deficit, perhaps a reduction
in the level of cAMP (343). Thus a diet deficient in
magnesium, like any other degranulating factor, can be
classified among the conditioning agents that increase
susceptibility to necrosis (918). Above all, magnesium
deficit in the rat along with excessive blood levels of
histamine and serotonin due to mast cell degranulation
offers an experimental model approximating the clinical
expression of an immediate type hypersensitivity. The
binding of reagins to mast cells or their circulating
equivalents, polynuclear basophils, allows these
homocytotropic antibodies to bring about the same events
(1038).
• In the nucleus more
than half the magnesium is closely associated with
nucleic acids and mononucleotides. Magnesium is necessary
for the physical integrity of the double helix of DNA
which carries genetic information and the code for
specific proteins (1340). Its excess favors, at least
in vitro, the formation of the Z form of DNA
which is antigenic (367, 719, 1261). It likewise
facilitates the formation of messenger RNA which
transmits to ribosomes information about the sequence of
specific amino acids. Finally, nuclear magnesium appears
necessary for the structural integrity of chromosomes
(115, 620, 621). Magnesium deficiency in female rats
causes chromosomal anomalies in both mother and
fetus.
Magnesium thus acts as a major cellular and
subcellular stabilizing agent which is necessary for the
stability of plasma membranes, for the integrity of
mitochondria, lysosomes, polysomes, and chromosomes as
well as for the integrity of the helix of DNA and of
messenger RNA and of RNA complexes. One can understand,
therefore, its use as a cell protecting agent for organ
transplants (1349) or during open heart surgery (1151,
1330, 1389) as well as its indispensable character for
major biochemical functions: activation of the major
metabolic pathways for carbohydrates, proteins and
lipids, redox reactions, acid-base equilibrium, ion
metabolism.... Necessary for cellular integrity and
distributed throughout the organism, magnesium clearly
must participate in the principal physiologic
functions.
-
1.3 The physiologic
properties of magnesium
Our enumeration of these characteristics will constitute a
logical introduction to clinical practice, but it will be
brief enough to allow further discussion when we reach the
subject of physiopathologic analysis.
It is necessary to avoid any confusion between the
pharmacodynamic properties of magnesium and its physiologic
properties. Pharmacodynamic properties are established either
in vitro or in isolated organs or sometimes in cells
of species quite removed from humans and for variations in
magnesium intake that are incompatible with life. Physiologic
properties correspond to those observed in vivo
preferably in man or the whole animal, thus maintaining the
possibility of general or local reactions. The best proof of
a physiologic action of magnesium is to reveal its role in a
deficiency by administering a dose to correct the deficiency.
Similarly, its role may be revealed when an overload is
corrected by ceasing magnesium intake.
-
-
1.31
Neuromuscular physiology (191, 222, 223, 224, 268, 332,
337, 345, 346, 348, 359, 363, 364, 370, 380, 466, 728,
749, 860, 1012, 1014, 1015, 1016, 1091)
The magnesium ion has a sedative effect on the nervous
system. Thus, magnesium deficit provokes a diffuse
neuromuscular hyperexcitability that has effects on both
the central and the peripheral nervous systems. These
effects act on cortex and subcortex, on the extra-dural
neurons and on the neuromuscular junction (curare effect)
and on both the voluntary and involuntary nervous
systems. In regard to effects on the autonomic nervous
system, it is of interest that magnesium accomplishes its
sedative functions by stimulating their inhibitory
effects and depressing their stimulatory activity (860).
It acts especially as a ganglioplegic. Experimental
deficiency may sometimes induce organic nervous
lesions.
Magnesium's effects on muscles occur most often in a
manner similar to those affecting nerve excitability: it
achieves its neuro-sedative effects by lowering the
excitability of the muscular fiber, either striated
(muscle relaxing effect) or smooth (musculotropic
effect). Experimental magnesium deficiency occasionally
causes the lesions of myopathy.
On the other hand, magnesium increases muscular
efficiency when storing actin molecules, using them in
energy requiring reactions or synthesizing them.
-
1.32 The
cardiovascular system and the formed elements of the
blood
Magnesium acts on the containing system, the heart and
the vessels, as well as on what it contains, the
circulating formed elements and humoral risk factors.
-
-
1.321
Magnesium, the heart and the vascular system (28, 29,
32, 33, 457, 1165)
With the myocardium, magnesium acts as a calcium
antagonist. It reduces conductivity and irritability.
It exercises an energy enhancing effect. It exhibits
cardio-protective effects, both anti-hypoxic and
anti-ischemic. Magnesium deficiency may, conversely,
induce cardiomyopathy.
Magnesium protects the vessel wall by reducing the
possibility of calcium overload and of connective
tissue disturbances and by direct vasodilating
effects and indirect antispasmodic effects on the
muscles. Conversely again, experimental magnesium
deficiency may cause vascular lesions.
-
1.322
Magnesium and vasopathogenic blood
factors
Magnesium plays a physiologic antithrombotic role.
(323, 324, 325, 346, 353, 359, 1239, 1240). This
effect depends on its platelet-stabilizing capacity.
Magnesium deficiency in man and in the rat causes a
magnesium curable hyperaggregation of platelets. This
effect is due to a reduction in the plasma factor
that degrades ADP, thus slowing the breakdown of
serum aggregating activity. (323, 325, 1240). A
direct action on membranes is also possible (421).
This may also be linked to the erythrocyte
stabilizing capacity of magnesium. Magnesium deficit
reduces the deformability of red cells with a
parallel decrease in erythrocyte ATP and 2,3-DPG
(962) as well as structural alterations in membranes
(421, 422, 423, 757).
The effects of magnesium on leucocytes —
enhancing phagocytosis and the production of
lymphocytes and their transformation into blast cells
while moderating the inflammatory reaction (342, 349)
— are less important in the analysis of the
effects of magnesium deficit on the formed elements
of the blood as a vascular risk factor than are its
stabilizing effects on platelets and
erythrocytes.
Magnesium deficit, on the other hand, favors
vascular disease by its effects on the metabolism of
phosphorus and calcium in calcinosis, on the
metabolism of proteins, carbohydrates and
glycoproteins in alterations analogous to connective
tissue changes due to aging and finally on the
metabolism of lipids and lipoproteins by enhancing
atherogenic dyslipidemias (32, 33, 57, 146, 343, 396,
727, 1057, 1061, 1064, 1065, 1067, 1161).
-
1.323
Magnesium and other systems
Magnesium is necessary for the growth and
mineralization of bone (338, 570, 902). It is
involved in the synthesis and activation of alkaline
phosphatases, pyrophosphatases and ATPase and in the
formation of collagen and sulfated
mucopolysaccharides (with induction of the synthesis
of magnesium- and ATP-dependent phosphoadenosine
phosphosulfate or PAPS, which is the key to sulfur
activation). In this manner, magnesium encourages
ossification, acting on the protein matrix of bone as
well as on its mineralization and activating both
osteoblasts and osteoclasts. On the other hand,
magnesium may behave like a "poison" in the formation
of crystals of apatite (323). Magnesium deficiency
produces a true "aging" of bone with a slowed
turnover of bone cells and a reduced receptivity to
the hormone-like D vitamins as well as to parathyroid
hormone. Magnesium deficiency affects the teeth
before affecting skeletal bones (338, 694, 902,
1292).
Magnesium is involved in renal physiology. It has
common reabsorption sites with calcium and is
apparently necessary for the conservation of
phosphorus and potassium as well as for that of amino
acids, especially taurine. It also appears to be
necessary for responsiveness to ADH and for the
secretion of acid by the kidneys through its action
on the carbonic anhydrase system and on ammonia
production (1032, 1281).
Magnesium is involved as well in reproductive
functions. Magnesium plays a role in the gametes'
transmission of genetic information and activates the
motility of the spermatozoa. It shows a "tocolytic"
action on uterine muscle, i.e. decreases gravid
myometrial contractility (389, 1228) and assures
proper fetal trophicity (199, 389, 619, 621, 622,
624, 715a, 715b, 1326, 1411, 1412).
Magnesium participates in the synthesis of enzymes
and of the mucins in digestive juices as well as in
the synthesis of the digestive polypeptides e.g.
CCK-PZ (cholecystokinin-pancreomyzin). It stimulates
various hepatic functions: glycogenic, lipotropic and
detoxifying.... Magnesium deficiency may bring on
changes in gastric, intestinal or hepatic function.
Also, while the exocrine pancreas may not be affected
(383, 1265), the functioning of the endocrine
pancreas may be altered by a severe and prolonged
magnesium deficit (396).
In the lungs, magnesium participates in the
synthesis of surfactant (1100).
Magnesium exhibits a number of interactions with
hormones (732, 889, 1334). It may be necessary for
their synthesis (insulin), their storage
(catecholamines) or their release (PTH). It may act
on their peripheral receptors, most often in a
favorable way (PTH, oxytocin, ADH, vasopressin,
insulin, beta adrenoreceptor), but sometimes as an
antagonist (alpha-adrenoreceptor, thyroxin). Several
mechanisms may explain the action of magnesium on the
endocrine glands: effects on cyclic nucleotides.
permeability of the plasma membrane, activation of
genes and the synthesis of messenger RNA, the pentose
phosphate pathway, mitochondrial coupling of
oxidative phosphorylation (141, 328, 361, 398, 490,
732, 1383).
Magnesium is involved in active membrane
mechanisms that prevent hyperhydration of the
crystalline substance of the lens and its becoming
opaque (339, 706, 799, 1226). It is active in the
physiology of the retina in association with high
levels of phosphorus, ATPase, carbohydrates and
taurine (336, 397). It is also involved in olfaction
and hearing (481, 658).
Finally, magnesium is involved in a number of
defense processes. It exhibits a variety of
"antistress" functions: antihypoxic, anti-allergic,
anti-anaphylactic, anti-inflammatory. These effects
also include stimulation of phagocytosis, a role in
activating the complement system (fixing of
C2 on C4 in the classic
pathway, but also activation of the alternate
pathway), regulation of acid-base equilibrium, redox
reactions and homeothermia. These antistress
functions also include antitoxic effects as for
example in the cases of cardiotonic glycosides (234,
260, 905, 1165, 1262), vitamin D (1165), lead (540)
and acetaldehyde (390).
Found in many tissues, magnesium is thus involved
in almost all of the physiologic functions of the
organism. We must therefore now discuss its
metabolism in detail.
2. The metabolism of
magnesium
Magnesium is absorbed, stored and excreted. In the case of
marginal deficit or load, there is no symptomatology. In the case
of severe deficit or overload, the symptoms become apparent. It
is necessary thus, with a disturbance of magnesium metabolism, to
analyze the mechanisms which permit the latency of marginal
disturbances. To this end, one must contrast the direct cellular
effects of the metabolic disturbance with the general responses
that it evokes. Then it is necessary to determine from among the
latter those that are useful, serving to maintain the constancy
of the internal environment, i.e., distinguish the homeostatic
responses from the harmful ones.
Magnesium deficiency produces low magnesium levels in the
extra-cellular compartment and a reduction of levels in the cell
along with hyperpermeability of the cell membrane. This
depolarisation finally causes a lowered level of cellular
potassium and a calcium overload (increase of intracellular Ca),
in conjunction with a lowering of phosphorus levels and an
increase in intracellular Na+. The increased influx of
calcium into the cell produces lower blood levels of calcium and
the release of potassium from the cell raises blood levels of
potassium. Moreover, if the deficiency is prolonged, the cellular
calcium overload may cause calcinosis, due to mixed apatite
crystals which combine Ca, P and Mg. These salts that have no
physiologic value increase the cellular levels of P and,
paradoxically, those of Mg during prolonged severe MD (146).
Severe magnesium deficit may thus be accompanied in tissues by
calcinosis and low cellular potassium levels (with sodium
retention) while one can observe in blood low calcium, phosphorus
and potassium levels and in urine low calcium and high phosphorus
and potassium levels (361). It is therefore necessary to
elucidate the regulatory mechanisms that cause the least severe
magnesium deficits, both in experimental animals and in man, to
remain latent and notably "normohumoral," that is to say,
magnesium levels appear normal as do levels of calcium,
phosphorus, potassium and sodium (Table 1).
Circulating levels of phosphorus-calcium and potassium-sodium
are subject to well-defined endocrine regulation. Parathyroid
hormone (PTH, calcitonin (CT) and 1,25-dihydroxycholecalciferol
(1,25-(OH)2-D) are the major regulatory elements for
phosphorus and calcium metabolism, renin, aldosterone and insulin
for potassium and sodium metabolism. It is thus logical to assume
that the compensatory mechanisms for disturbances of calcium and
potassium metabolism in magnesium deficit can bring into play the
parathyroid and medullary-thyroid glands and hormone-like vitamin
D in the kidney to control the calcium disturbance and renin,
aldosterone and insulin to control the potassium problem.
Thus it is the whole of the endocrine system that one must
consider as entering into the regulation of magnesium homeostasis
(732, 1334). It will be necessary in the study of hormonal
modifications of magnesium homeostasis to distinguish between
harmful and useful manifestations, between harmful endocrine
responses that must be treated and homeostatic endocrine
responses that must be respected. Vitamin D is hardly involved at
all since it is not generally modified in vivo in
magnesium deficit (16, 902, 903, 1062, 1371) while the
renin-aldosterone system can exercise only harmful effects (732).
With magnesium deficit there exists, in effect, a hyperfunction
of the juxtaglomerular apparatus and an excessive production of
aldosterone (189, 190) which can only aggravate any potassium
problems (360). Therefore only the positive effects of other
endocrine changes will be analyzed.
Magnesium overload is only roughly a mirror image of magnesium
deficit. It is important to note that, as with magnesium deficit,
the moderate forms remain latent and are clearly without
consequence for calcium and potassium metabolism. Large overloads
generally occur in conjunction with calcium problems but very
rarely with disturbances of potassium metabolism (916).
The direct membrane effects of magnesium excess normally cause
a release of calcium (and sodium) from the cell with subsequent
hypercalcemia and an increased influx of potassium (and
magnesium) with the resulting cellular excess of potassium and
hypokalemia.
In fact, the compensatory mechanisms operate so vigorously
that large magnesium overloads are, on the contrary, accompanied
by hypocalcemia (with hypercalciuria) and problems with blood
levels of potassium are unusual: there are rare cases of
hypokalemia with hyperkaluria.
Therefore, in order to define the essentials of magnesium
metabolism and of its control mechanisms, we must,
-
review how absorption,
storage, and secretion of magnesium occur.
-
then analyze in order the
regulatory mechanisms of this metabolism, studying them
from four different points of view:
-
the regulation of magnesemia,
and its remarkable stability which needs to be explained
(14, 361, 380, 398, 583, 770, 1314, 1327),
-
the regulation of the
principal ionic consequences (calcium and potassium) of
magnesium disturbances (361, 398).
-
the regulation of cellular
magnesium, since it is necessary to understand the
relatively constant levels of intracellular Mg (75,
146,168, 591, 1313).
-
the regulation of the cellular
consequences of magnesium problems, mainly those that
concern cyclic nucleotide second messengers, but also the
principal cellular ionic effects, stressing at each step
the failure of these controls and contrasting their
homeostatic value in the latent forms with their
ineffectiveness in symptomatic decompensated forms (361,
398).
This page was first uploaded to The Magnesium Web Site on July
13, 2002
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Healthy Water
Association--USA