In Journal of the American College of Nutrition, Vol. 13, No.
5, 429-446 (1994)
Consequences of Magnesium Deficiency on the Enhancement of
Stress Reactions; Preventive and Therapeutic Implications (A
Review)
Mildred S. Seelig, MD, MPH, Master ACN
Department of Nutrition, Schools of Public Health and
Medicine, University of North Carolina, Chapel Hill
The section headers of this paper are as follows:
Stress
intensifies release of catecholamines and corticosteroids, that
increase survival of normal animals when their lives are
threatened. When magnesium (Mg) deficiency exists, stress
paradoxically increases risk of cardiovascular damage including
hypertension, cerebrovascular and coronary constriction and
occlusion, arrhythmias and sudden cardiac death (SCD). In
affluent societies, severe dietary Mg deficiency is uncommon, but
dietary imbalances such as high intakes of fat and/or calcium
(Ca) can intensify Mg inadequacy, especially under conditions of
stress. Adrenergic stimulation of lipolysis can intensify its
deficiency by complexing Mg with liberated fatty acids (FA). A
low Mg/Ca ratio increases release of catecholamines, which lowers
tissue (i.e. myocardial) Mg levels. It also favors excess release
or formation of factors (derived both from FA metabolism and the
endothelium), that are vasoconstrictive and platelet aggregating;
a high Ca/Mg ratio also directly favors blood coagulation, which
is also favored by excess fat and its mobilization during
adrenergic lipolysis. Auto-oxidation of catecholamines yields
free radicals, which explains the enhancement of the protective
effect of Mg by anti-oxidant nutrients against cardiac damage
caused by beta-catecholamines. Thus, stress, whether physical
(i.e. exertion, heat, cold, trauma - accidental or surgical,
burns), or emotional (i.e. pain, anxiety, excitement or
depression) and dyspnea as in asthma increases need for Mg.
Genetic differences in Mg utilization may account for differences
in vulnerability to Mg deficiency and differences in body
responses to stress.
Key Teaching Points:
- Mg deficiency intensifies adverse reactions to stress that
can be lifethreatening.
- Such reactions are mediated by excess release of the stress
hormones: catecholamines and corticosteroids - which are
increased by low Mg and high Ca levels, and which further lower
tissue Mg.
- Low Mg/Ca levels favor excess release or formation of
vasoconstrictive and platelet aggregating factors (derived from
FA metabolism and endothelium).
- Low Mg/Ca levels also directly enhance intravascular blood
coagulation - in microcirculation and in large blood
vessels.
- Eclampsia is a coagulative microangiopathic disorder with
high adrenergic activity; essential hypertension is also a
stress-related disease.
- Low Mg levels are implicated in eclampsia, cardiac
arrhythmias with and without AMI, and bronchial asthma, each of
which is a stressful event that is favorably responsive to
prompt (adjunctive) pharmacologic Mg treatment.
Abbreviations
AMI acute myocardial infarction; Ca calcium; CVD
cardiovascular disease; CS corticosteroid; e.c. extracellular; FA
fatty acids; FFA free fatty acids; GCS glucocorticoid; i.c.
intracellular; IHD ischemic heart disease; i.v. intravenous; K
potassium; MCS mineralcorticoid; Mg magnesium; RDS respiratory
distress syndrome; SCD sudden cardiac death; SIDS sudden infant
death syndrome; PGI2 prostacycline; TXA thromboxane
Stress, both physical and emotional, evokes release of the
stress hormones: catecholamines and corticosteroids, which
mediate release and utilization of substrates for energy
production and for improved skeletal and cardiac muscle
performance. However, their excesses, which cause Mg loss and
inactivation can be implicated in cardiovascular disorders -
involving thrombotic events and arrhythmias, when Mg intakes from
imbalanced diets, and serum and tissue levels are sub-optimal
(Fig. 1).
Fig. 1. Stress and magnesium
Cardiac complications of stress often derive from the oxygen
debt created by arterial constriction, usually of
arteriosclerotic arteries, that reduces oxygen supply in the face
of (stress-induced) increased energy consumption. There is
suggestive evidence that Mg deficiency contributes to sudden
cardiac death (SCD). Pain of acute myocardial infarction (AMI),
angina pectoris, cancer, trauma, is stressful. In AMI especially
when there is underlying Mg deficiency as is caused by diuretics,
additional Mg loss induced by stress of pain and anxiety, might
be a factor in its morbidity and mortality. Prompt intravenous
(i.v.) pharmacologic treatment with Mg has improved AMI survival.
Mg inadequacy of pregnancy might make additional Mg need during
the stress of labor a factor in periand post-partum problems.
Complications of bronchial asthma and of its drug treatment with
Mg-wasters: beta-adrenergic agonists, corticosteroids (CS), and
theophylline, resemble signs of Mg deficiency that can culminate
in arrhythmia and sudden death. Providing i.v. Mg in doses
comparable to that effective in eclampsia, is valuable adjunctive
therapy in management of intractable bronchial asthma. Mg
supplements have improved endurance and reduced cramps and
fatigue in athletics; might they also protect against SCD of
athletes?
New findings on interactions of prostanoids with Mg provide
insight into how intravascular coagulation is involved in the
pathogenesis of thrombotic arterial lesions that increase
vulnerability to acute changes caused by stress. The mutual
enhancement by the anti-oxidant, vitamin E and by Mg, of their
protective effects against stress-induced myocardial damage, that
is intensified by Mg deficiency, is interrelated with
catecholamine-release of free radicals, as well as with loss of
tissue Mg.
MECHANISMS OF
INTERACTIONS OF STRESS, STRESS HORMONES AND MAGNESIUM
Stimulation by Stress of Secretion of Catecholamines
and Corticosteroids
Classic studies of activation of the sympathetic system by
emotional or sensory stimuli showed that pain, hunger, fear and
rage increased epinephrine urinary excretion (1). During
aggressive and violent action, norepinephrine release
predominates (2). Isolation or overcrowding, forced exercise,
cold or hot environments, noise, light flashes, electric shocks,
or other anxiety-evoking stimuli, including frustration in access
to food, or listening to recordings of fights involving the
species under study - have increased secretion and/or release of
catecholamines by the adrenal medulla, nerves and ganglia. The
heart also synthesizes, stores and releases norepinephrine (2-5);
almost immediately after a coronary occlusion, catecholamines are
released from granules within the heart (5,6).
Elevation of plasma CS and increased urinary excretion of CS
and its metabolites have been reported in monkeys subjected to
anxiety or aggression (7), and in humans under emotional and
physical stresses (2,8-10).
Stress Reactions as Affected by Magnesium and
Calcium
Interrelations among Catecholamines, Magnesium and
Calcium. Catecholamine-secreting granules from adrenal
medulla or nerve endings, suspended in low Mg/high Ca or high
Mg/low Ca solutions, release more catecholamine in low Mg and
less in high Mg media; Ca has reciprocal effects(11-15). (Figure
2) The effect of verapamil, a Ca channel-blocker, on
catecholamine release has been compared to that of Mg, a
physiologic Ca-blocker (16).
Hypomagnesemia occurs in patients with elevated blood
catecholamines: in AMI, cardiac surgery and insulin-induced
hypoglycemia stress tests (17). Epinephrine infused into healthy
volunteers, with and without prior treatment with Ca-blocking
agents, lowered both serum Mg and K (18). Infusion of
pathophysiologic amounts of epinephrine, or a therapeutic dose of
salbutamol (a beta 2-catecholamine agonist) lowered plasma Mg
levels in normal subjects. Epinephrine, but not norepinephrine,
significantly reduced plasma Mg in healthy men (19). Infused
beta-blockers had no significant effect on plasma Mg in 15
sedentary, healthy young men when maximally exercised (20).
Mg infusion (MgSO4, 60 mg/kg, i.v.) improved management of
patients with pheochromocytoma prior to and during surgery to
remove the catecholamine secreting tumor (21), and inhibited
release of catecholamine produced by the stress of tracheal
intubation (22). Experimental and clinical hyperadrenalemia
caused elevated blood Mg levels, that fell to within normal
limits after extirpation of an adrenal gland (23,24). The high
erythrocyte (rbc) Mg (24) may be to the increased rbc Mg levels
of most athletes, whose release of catecholamines increases
during strenuous training (infra vide).
Corticosteroids during Stress; Interrelations with
Magnesium
Prolonged isolation and other emotional, but not physical,
stress has increased serum CS in rats (25). Runners exhibited
increased excretion of both catecholamines and CS; Mg supplements
significantly decreased their CS excretion (9). A marathon
runner, whose CS levels gradually increased during a race,
attained twice pre-race values at the end of the race (26). A
mixed CS, with glucocorticosteroid (GCS) and
mineralocorticosteroid (MCS) activity, caused negative Mg balance
in normal volunteers, mostly by interfering with intestinal Mg
absorption (27).
MCS hormones: aldosterone and desoxyycortosterone acetate
(DOCA) affect Mg metabolism and are influenced by the Mg status.
Each interferes with Mg absorption and increases urinary Mg
excretion in experimental animals (28,29) and in humans with
adrenal tumor-induced aldosteronism (30,31). Mg deficiency has
increased MCS secretion in experimental animals, through induced
juxtaglomerular hypertrophy (32,33). Anti-aldosterone agents
reverse Mg deficiency of cardiac patients on long-term use of
Mg-wasting diuretics, as reflected by restoration of depressed
tissue Mg levels (34,35).
There is substantial experimental evidence (2,26,36-49) that
cardiac damage - induced by stress or exogenous catecholaminesis
intensified by CS, beta-adrenergic agonists, and by Mg
deficiency. The myocardial lesions are characterized by necrosis
and Ca deposition; Mg administration is protective.
Catecholamines, Fatty Acid Release, Coagulation, and
Prostanoids
Fatty Acid release of Stress; Interrelations with Mg.
Free fatty acids (FFA), an energy source during stress, are
mobilized through lipolysis induced by beta-catecholamines
(50,51). However, they bind and inactivate Mg in blood and heart,
intensifying functional Mg deficiency. The stress of alcohol
withdrawal increased serum FFA and lowered serum Mg (in dogs
[52]). AMI increases catecholamine release and increases FFA
levels (53,54), that is associated with a decline in serum Mg
(55). Hyperexcitable (Type A) subjects, who are more vulnerable
than Type B subjects to AMI, exhibit greater adrenergic release,
have increased serum FFA and slight increase in plasma Mg and a
small but significant decrease in rbc Mg (56).
Among five marathon racers, four were well trained; an
untrained racer had been taking a Mg supplement (370 mg/day) for
a week before the run (57). Blood samples drawn 6 times during
the race showed steady increase in mean FFA that peaked at 26
miles, and that was associated with a steady fall in serum Mg in
the trained runners, but not in the untrained, Mg supplemented
man.
Fat and Magnesium/Calcium Ratios in Coagulation.
Diets rich in saturated fats are implicated in hyperlipidemia and
atherosclerosis, and increase thrombogenesis. Mg deficiency
worsened both fat-induced intravascular hyper- coagulation
(58-61) and atherogenesis; Mg was protective (42,46,59). It has
prevented platelet aggregation on experimentally damaged
endothelium (60,61), and has protected against spontaneous MI of
rats, dogs and cocks on nutritionally imbalanced diets that
caused Mg deficiency (42,62,63). Increased platelet aggregability
increases myocardial vulnerability to ischemic injury in Mg
deficient hamsters (64). The reciprocal effects of Ca and Mg on
coagulation are considered elsewhere, re the need for Mg
supplements of post-menopausal women taking both estrogen and Ca
to slow osteoporosis (65), and in eclampsia, premenstrual
syndrome, and migraine (66).
Platelet Aggregation and the Prostanoids, Affected by Mg
and Ca. Prostacycline (PGI2) and thromboxane (TXA or TXB2)
also participate in platelet aggregation, PGI2 inhibiting
aggregation; TXA enhancing it. PGI2 is also a potent vasodilator;
TXA is a vasoconstrictor. Guenther et al have reported that
increased prostanoid synthesis is linked to translocation of Ca
into cells (67). Mg deficiency (which causes hypercalcemia in
rats) caused increased levels of PGI2 and its metabolite PGF1,
but to a far lesser extent than it increased TXA synthesis and
release. Studies by Nadler et al (68-70) in normal men have shown
that Mg infusion significantly increased excretion of the PGI2
metabolite 6-keto-PGF1a, without altering urinary output of PGI2,
and reduced TXB2 synthesis. Franz et al (26) found that physical
stress of marathon racing increased TXB2 levels, inversely
related to serum Mg levels. Early in the race TXB2 fell slightly,
but it rose 9-fold by the end of the race, in association with a
fall in serum Mg. PGI2 mediates, at least in part, the
hemodynamic (vasodilator) effects of infused Mg (71). Altura et
al (72) showed that, in its absence, PGI2-induced relaxation in
isolated rat aortic strips is prevented. PGI2 and Mg infusions
elicit similar hemodynamic effects (73), and in vitro exposure of
(umbilical) vascular endothelial cells to vasodilating
concentrations of Mg stimulates release of PGI2 (74,75).
Catecholamines, Free Radicals, Magnesium and
Antioxidants. Recent work in the laboratories of Weglicki
and Bloom (76-83) indicates that oxidative stress, induced by the
beta-agonist isoproterenol, causes membrane damage of myocardium,
endothelium, and erythrocytes in which release of free radicals
participates. Mg deficiency and catecholamines each causes tissue
Ca overload. Both beta-blockers and Ca-channel blockers cause
degrees of membrane lipid anti-peroxidative activity (76-81).
Furthermore, catecholamine auto-oxidation leads to generation of
cytotoxic free radicals (84). That the cardiomyopathy of Mg
deficiency, alone, also involves free radicals is indicated by
the protective effects of vitamin E and anti-oxidant drugs in
Mg-deficient hamsters (80-83). This is pertinent to the
observation that high intakes of anti-oxidant nutrients, as well
as of Mg, were cardioprotective in a large series of Indian
cardiac patients (Singh et al [85,86]) .
Cardiac Synthesis and Release of Catecholamines;
Cardiac Complications with Excess Catecholamines
Raab first reported very high catecholamine content in the
myocardium of a young athlete who died in his sleep after a
stressful event (3). The inotropic response to increased demands
caused by stress increases the force of cardiac contraction and
oxygen utilization (4). Resulting oxygen debt causes relative
myocardial hypoxia that can contribute to a shift of Mg out of
cells to the extracellular space and plasma, as occurs with local
ischemia of skeletal muscle (87) and in infants with asphyxia
(88). The inward shift of Ca, stimulated by catecholamines is
important in cardiac contractility, but when excessive, as in
patients with ischemic heart disease (IHD) - the chronotropic
responses to catecholamines predominate, and there is increased
risk of arrhythmia and myocardial damage (89). Even in normal
subjects, especially if low in Mg, the chronotropic effect of
stress-induced excessive catecholamines may cause arrhythmia and
sudden cardiac death (SCD). The increase in FFA caused by stress
plays an important role in reducing availability of myocardial
Mg. Focal myocarditis and congestive heart failure (CHF), common
in patients with pheochromocytoma (90), is the clinical
counterpart of the focal myocardial lesions seen in rats given
high dosage norepinephrine (91), and in those caused by injection
of a beta-adrenergic agonist (isoproterenol), at a dose just
sufficient to cause multifocal micronecrosis (40,92). Mg loss is
the earliest electrolyte derangement, preceding loss of K and
gain of Na and Ca.
Functional stress tests, to which IHD patients are subjected,
evoked significantly higher epinephrine and aldosterone levels in
cardiac patients than in healthy controls (93). Pre-stress serum
Mg levels were 1.6 mEq/L, and fell further at the test end.
Influence of Personality on Cardiovascular Responses to
Stress and Magnesium
Emotion/anxiety, as well as ischemia, interfere with
myocardial oxygen economy (2). Emotion evokes outpouring of
catecholamines and CS, which deplete myocardial Mg, as the
central cardio-damaging factor of stress, leading to tachycardia,
arrhythmia, cardiomyopathy and even SCD. Nervous, emotional
individuals who are most prone to cardiovascular disease (Type A)
have far less stress tolerance than do Type B persons (94).
Exposure to noise and mental stress results in excretion of more
catecholamines by Type A than by Type B subjects, who have higher
blood Mg (most marked in erythrocytes) than do Type A subjects
(56,95). Henrotte et al have found that 70% of variance in rbc Mg
levels is familial (56,95,96). Type A students, given a
standardized test, had a statistically greater fall in rbc Mg
than did Type B students, similarly stressed (56). The
self-sustained stress and exaggerated response to external
stresses of Type A persons might lead to subnormal Mg status.
Patients with latent tetany of Mg deficiency, who have
psychoneurotic complaints (97,98), may also be especially
vulnerable to mitral valve prolapse (97,99,100). Children with
"nervous" complaints related to psychosocial and school stresses
are also prone to hypomagnesemia (101). Durlach (97) suggests
that whether Mg deficiency is acute or marginal and chronic (as
with long-term suboptimal Mg intake, genetic Mg malabsorption,
renal-wasting, or maldistribution), it increases vulnerability to
stress, and increases its harmful effects.
Hypertensive Responses to Emotional Stress; Mg/Ca
Effects
Emotional stress is a factor in hypertension (2,102). Whether
clinical hypertension is associated with low or high plasma renin
activity (PRA), free i.c. Mg is low (103-107); there is negative
correlation of PRA with serum Mg levels (103). In low PRA
patients, whose blood pressure was reduced by Ca supplements, and
high PRA patients who respond to Mg, free i.c. Mg was inversely
correlated with degree of hypertension (104). Low free i.c.Mg was
also seen in rats made hypertensive whether by MCS and salt
loading, by nephrectomy or renal ischemia (107). Low i.c. free
rbc Mg was found in thin and obese hypertensive patients, in
hypertensive obese patients with or without diabetes mellitus,
and in diabetics (106).
In a study of total rbc Mg levels (a less sensitive parameter
than the free rbc Mg) of middle-aged patients with labile
hypertension, only those with low total rbc Mg had a blood
pressure-lowering response to three months of Mg supplements
(108). Workers in a high noise environment, and students
preparing for their final examination experienced a rise in blood
pressure during the work or study period (109) on diets providing
about 5 mg/kg/day, which is above the current official American
Recommended Dietary Allowance (RDA) (110). There was no rise in
blood pressure in workers, or in students, given Mg
supplementation that increased daily Mg intake to 6-7 mg/kg/day
(109).
TOXEMIAS OF PREGNANCY,
POSTPARTUM CARDIOMYOPATHY AND SIDS
Magnesium, Platelet Aggregation and Prostanoids of
Toxemias of Pregnancy
Although only indirectly related to acute stress, aside from
labor - which can intensify damage associated with toxemias of
pregnancy, hypertension, that responds to Mg treatment, is
characteristic of pre-eclampsia, as is greater than normal
increase of blood pressure following catecholamine injection
(111). Increased urinary epinephrine has been found in most
patients with convulsive eclampsia (112).
Elucidation of interrelations of Mg on PGI2, TXA and
endothelial-derived factors provides insight into the
hypertension and hypercoagulability of blood of toxemic
pregnancy, and draws parallels to that of cardiovascular disease
and diabetes mellitus (113). The reversal of increased blood
coagulability of women, with toxemias of pregnancy, by infusions
of Mg was demonstrated first by Weaver (114), His pregnant ewes
on Mg-low diets had hypertension, renal glomerular endotheliosis,
and placental infarcts (115,116).
The increased Mg requirements of pregnancy, and the favorable
response of complications of pregnancy to Mg treatment are well
known (59). Mg deficiency during complicated pregnancy might be
contributory to microvascular thromboses of severe toxemias. Pain
from labor, as a stress factor that further increases Mg needs
might be a factor in peripartal cardiomyopathy. It is provocative
that Woods' rationale for extension of trials of Mg in AMI
patients (71) derived partially from its efficacy in eclampsia,
and from studies of Mg/PGI2 relations in pregnancy (74,75).
Vascular endothelial damage (reflected by elevated fibronectin
levels in preeclampsia), is associated with hyper-aggregability
of platelets, and linked with prostanoid disturbances and
microvascular thrombi in more severe toxemias (75,117). Watson et
al (75) found that eclamptic patients have depressed PGI2 levels,
whereas serum from MgSO4-treated eclamptic patients increased
release of PGI2 by cultured (human umbilical vein) endothelial
cells, and that it overcame thrombin induced- platelet adhesion
to endothelium. Calvin et al (118) found that plasma fibronectin
(released from damaged endothelium) was higher in 18 preeclamptic
women than in 19 normal pregnant controls. However, the
metabolite of PGI2 (6-keto-PGF1x: which they suggested is
possibly a poor index of PGI2 at the microvascular level) was
also higher. In vitro studies of the effect of Mg on platelet
aggregation in umbilical cord vessel showed that elevated Mg
levels increased PGI2 release from the vessels, and increased the
anti-aggregating response of platelets to PGI2 (75).
Relationships of Perinatal Mg Deficiency to Infantile
Reactions to Stress
Low birth weight (LBW) infants are more commonly born after
complicated pregnancies, that are associated with Mg loss, and to
Mg deficient mothers than after Mg-replete pregnancies (59). Not
only are such infants more prone to early infantile
complications, they are subject to serious reactions to stress.
Dietary Mg deficiency of ruminants has caused birth of low birth
weight young (115,116). Rats born to Mg deficient dams are less
tolerant of stress, even after infancy (119). Pregnant Mg
deficient cows and ewes exhibited 3-fold more clumping of
platelets than did controls, and six of 18 lambs, that died in
tetany after being fed low Mg diet for 2-12 months, had heart and
lung lesions very similar to those produced by
collagen-activation of platelets (120). Miller et al (120)
suggest that abnormal blood platelet activation may be a
significant mortality risk factor in severe gestational and
infantile Mg deficit, and draw a parallel between the pathologic
findings in Mg deficient lambs with those in the sudden infant
death syndrome (SIDS). Caddell proposes that neonatal and
postneonatal apnea and respiratory distress syndrome (RDS) are
premonitory findings in infants who are later victims of SIDS,
and advises Mg treatment in doses low enough not to constitute a
risk (0.4 -1 mEq/kg/d for about 2 weeks) in RDS infants with
immature kidneys (121-123). Infants with RDS are most commonly
born to mothers subject to hypomagnesemia (59,124). SIDS has
pathogenic features analogous to sudden cardiac death (SCD) of
adults, in which stress and Mg deficiency have been implicated as
factors (59,125-127).
MIGRAINE , COAGULATION
AND PROSTANOIDS
Among the conditioning factors considered in migraine is
stress, with its induced intravascular coagulability, associated
with hypomagnesemia, platelet hyperaggregability and decreased
cerebral blood flow (66,115,128-130). Weaver (115) has correlated
the high incidence of migraine in patients with eclampsia (131)
with the platelet hyperaggregation seen in both conditions (132).
Altura (128) hypothesizes that the Ca-blocking effect of Mg might
justify its trial in migraine, to prevent or ameliorate the
initiation of migraine attacks.
NOISE STRESS ,
HEARING LOSS AND ACCELERATED AGING
Among the stresses that increase vulnerability to cardiac
damage in rats is noise. It increased Mg loss from the heart, and
myocardial Ca and collagen deposition (133). Franz found impaired
hearing of surviving Mg deficient litter-mates, some of whom had
died of sound-induced seizures (134).
Noise stress damaged the inner ear; Mg deficiency intensified
ear damage; high Mg intake was protective (133,135-138). Ising
and Joachim et al have negatively correlated hearing loss with
perilymph and rbc Mg levels (133,138), and suggest that energy
requirements of the inner ear are compromised by Mg
deficiency-induced increased catecholamine secretion and
arteriolar constriction. Mg deficient rats exposed to noise over
a long period (i.e. 30 months), age rapidly (133). Cold stressed
rats, made Mg deficient enough to cause adverse reactions and
death of some in infancy, but to which adaptation took place in
survivors, experienced both reduced tolerance of cold stress (as
reflected by cardiac damage), and shortened life span (139).
OBESITY AND STRESS OF
STARVATION
Voluntary starvation to reduce obesity is not the severe
stress of famine, or of concentration camps - which has been
associated with myofibrillar disruption (140) and SCD (141).
During refeeding of surviving victims, strongly negative Mg
balances persisted for months on Mg intakes as high as 800 mg/day
(142). Even starvation to lose weight has caused arrhythmias and
sudden death, possibly associated with lipolysis of ample fat
stores, which as with catecholamine released during stress,
inactivates available Mg (supra vide). DeLeeuw et al (143),
commenting that sudden deaths of total starvation and some
low-calorie diets are probably cardiac, showed that total
starvation in an obese animal model caused severe myocardial Mg
depletion.
Shortand long-term fasting of normal volunteers has caused Mg
loss, but not necessarily hypomagnesemia (144,145). Balance
studies of grossly obese men who were fasted up to 3 months
showed urinary losses to be responsible for loss of 20% of the
body Mg, that resulted in development of carpal spasms requiring
MgSO4 infusions for relief (146). Although the Mg status was not
explored in the patient whose death after fasting had been
preceded by lactic acidosis (147), it is pertinent that high
lactate increases urinary Mg loss (148). A healthy young woman
developed refractory hypokalemia during starvation for obesity,
taking amino acid and protein supplements, despite high dose K
treatment (149). Her plasma Mg was normal at the time of death
from ventricular fibrillation after elongated QT interval and
persistent arrhythmias (seen with hypomagnesemia or hypocalcemia)
were treated with Ca infusion. Gross myofibrillar destruction was
found, like that described with experimental Mg deficiency (150)
and in starvation victims (140). Comparable myocardial lesions
were seen in a 38 year-old woman who died in ventricular
fibrillation after a liquid protein diet, supplemented with
multivitamins, Ca and K (151); i.v. Mg treatment of her
refractory ventricular tachycardia had not increased her serum Mg
above 1.6 mEq/L. Potentially life-threatening and fatal cardiac
arrhythmias have been reported in patients taking liquid protein
reducing diets (152-154). Most striking, in a study in which the
Mg levels were followed, was persistent magnesuria and normal
serum Mg levels despite low intake (153); three of the subjects
developed arrhythmia (154).
GASTROINTESTINAL STRESS REACTIONS;
HISTAMINE RELEASE
Classen's studies of the alarm reaction are pertinent to
gastrointestinal (GI) reactions to stress (155). Peptic ulcers in
rats are characteristic of the early stress reaction, which
sensitizes the mucosa to irritants and other stimuli, especially
in Mg deficiency (156-157). Their incidence and extent were
decreased by Mg administration. The effect of Mg deficiency on
intestinal motility (157) may help to explain the stomach aches
and acute abdominal pain in nervous children with marginal Mg
deficiency and the beneficial effects of Mg supplementation in
these patients (157,158).
How Mg inhibits stress-induction of peptic ulcers is
uncertain. Several biochemical changes (decrease of ATP, ADP, and
extent of phosphorylation reactions, and increase of cAMP, AMP)
preceded the macroscopic appearance of stress ulcers in normal
stressed rats (159). The Mg status was not explored, but it is
noteworthy that ATP synthesis is Mg-dependent, as is
phosphorylation (160), while cAMP levels are low in Mg deficiency
(161). In view of the classic use of histamine to test for
gastric acid secretion, and the usefulness of histamine
receptor-antagonists in management of peptic ulcer disease, it
seems plausible that Mg deficiency intensifies stress ulcers
through its stimulation of histamine secretion. Mg deficiency in
rats increases degranulation of mast cells with histamine release
(162-164).
Bronchial asthma (165,166), which is very stressful when
seriously impeding respiration, has long been associated with
hypomagnesemia. Itevokes adrenergic and corticosteroid secretion,
which lower tissue Mg levels (supra vide) and it is characterized
by histamine release, which has been correlated with
hypomagnesemia (supra vide). It is noteworthy that the toxicity
of theophylline- a phosphodiesterase inhibitor that lowers
myocardial Mg levels, is intensified by beta-adrenergic agonists
and CS (167), and resembles the effects of experimental Mg
depletion: early tremor, later convulsions, and tachycardia,
arrhythmia, myocardial necrosis and death (168-170). The
favorable effect of Mg in counteracting toxic theophylline
reactions has been attributed to the Ca-blocking effect of Mg
(168,169), and to the membrane-stabilizing effect of Mg (169). In
addition to counteracting adverse effects of standard drug
therapy of asthma, Mg solutions (i.v. or aerosol) have been
reported effective, at intervals from 1934 to 1973 (165,171-173),
and more frequently in the past ten years (168,169,174-190).
Since the early anecdotal reports, there have been case reports
on the ameliorative and even life-saving effect of Mg in
intractable asthma (179,182-184,186-188) and favorable double
blind studies (174,180). The usefulness of Mg in bronchial
asthma, however, has been disputed (191-193). When effective for
bronchodilatation and to reduce bronchial reactivity to
administered histamine (justifying its adjunctive use with
standard drug therapy), doses of Mg sufficient to achieve
pharmacologic serum Mg levels were usually used
(176-183,185-188,194-196). The need for higher than physiologic
levels of Mg to counteract bronchial spasms induced in vitro had
been shown by Classen et al (197) for serotonin, acetyl choline
or histamine, and by Spivey et al (198) and Lindeman et al (199)
for bethanechol, electrical stimulation or histamine. Pertinent
to Mg and stress interrelationships in this disease, is the
increased stress hormone secretion effected by low Mg/Ca ratios
(supra vide). Mathew and Altura (200) have suggested that Mg
should have value as an adjunct in treating asthma because it
modulates smooth muscle contraction through its Ca-blockage or
competition. In their recent review, Landon and Young (201) point
out that the increased dietary Ca/Mg ratio of recent years, and
loss of Mg caused by diuretics and other drugs, may be a factor
in bronchial asthma, in view of Ca-binding to sites that increase
acetyl choline release which initiates smooth (bronchial) muscle
contraction.
ATHLETIC STRESS,
PERFORMANCE AND MAGNESIUM
Magnesium Deficiency and Supplementation in
Strenuously Exercised Animals
A series of studies by Keen and Lowney et al (202-206) with
rats, fed diets providing 50 and 100 ppm and half the adequate
intake of 400 ppm for 22 days, determined their endurance when
they were run on a treadmill to exhaustion. They showed that
decreased exercise capacity can be an early effect of Mg
deficiency. Analysis of plasma and muscle levels of Mg of rats
that had decreased endurance, sacrificed 2 days or immediately
after the stress test, showed slightly lower plasma Mg at both
times, and markedly lower muscle Mg immediately after exhaustion
(203). Mineral water containing 85 ppm Mg restored endurance
(202). Treadmill exercised, Mg deficient rats were shown by
Laires et al (207) to have reduced exercise capacity, increased
plasma lactate and FFA levels, and decreased plasma and rbc Mg
levels. In a test of endurance with the stress of fear (of
drowning), Hirneth and Classen (208) showed that Mg intake had to
be increased ten-fold (to 4000 ppm) in rats made to swim with a
weight attached to their tails, to significantly improve duration
of swimming before submersion.
Human Endurance Exercise, Magnesium, and
Metabolism
Refsum et al (210), in 1973, attributed transiently lowered
serum Mg and slightly increased rbc Mg, of cross-country skiing
racers, to shift of Mg from e.c. to i.c. fluid. Well trained
athletes were found by Casoni et al (210) to have significantly
increased mean rbc Mg and slightly decreased serum Mg after a
25-km marathon, compared to pre-race levels. Serum Mg decreased
and rbc Mg increased in 40 trained long-distance runners, 19 to
71 years of age, studied by Hoffmann and Boehmer (211) after each
of two 25 km marathon races. Lijnen et al (212) found lower rbc
and plasma Mg in teen-aged marathon runners just after the race
than before, that returned to pre-race values 12 hours later.
Urinary Mg decreased immediately after the race, and increased 12
hours later. Joborn et al found that long-term steady state
exercise had little effect on Mg levels, but there was a decrease
during the first hour of recovery (20).
High altitude intensive training resulted in negative Mg
balance, in Mader et al's study (213). Hypomagnesemia sufficient
to cause convulsions was seen in a man subjected to 4 hours
intense exertion under conditions of heat (Jooste et al [214]).
Non-supplemented marathoners lost muscle protein (Bertschat et al
[215]).
Important studies of long-term Mg loss by trained adults
undergoing sustained heavy exercise have been reported by
Stendig-Lindberg et al (216-219). Apparently healthy young
subjects who underwent a 7-month graded physical training program
before undertaking a 120-km march (of 22 hours duration) had Mg
intakes of 340 mg in food and 364 mg Mg in water (216). Despite
the higher than usual intake, the mean serum Mg pre-march (1.66
mEq/L) fell significantly 1 hour after the march ended to
(1.4mEq/L). After rising to almost pre-march levels at 24 hours,
it fell again, at 72 hours to 1.3 mEq/L; 89% had hypomagnesemia.
They exhibited elevated serum creatine kinase (CK) activity,
suggesting that the serum Mg rise at 24 hrs resulted from
exertional rhabdomoyolysis or loss of membrane integrity.
Significantly lowered serum Mg (1.51 mEq/L) persisted for 3
months (217). A study after a 70 km march extended the findings
to aspartate amino transferase (S-AST), alanine amino transferase
(S-ALT), creatine kinase activity (S-CK), and VO2 ml/min-1. kg-1
(VO2 max) (218). Maximal aerobic power, hemoglobin, hematocrit,
total protein and albumin were unchanged throughout. Immediately
after the march, serum Mg did not change, but S-AST, S-ALT, hours
after the march, serum Mg fell significantly; it remained low
after 18 days, with no intervening marches or dietary changes.
The means of S-ALT and S-CK rose & S-CK rose slightly. At
72significantly. For the first time there was a significant rise
of blood sugar, and of serum triglycerides, and a second rise of
total cholesterol. In a long-term follow-up of two additional
groups of young men subjected to the same training and 120 km
march as reported in 1985 (260), significant depression of serum
Mg persisted as long as 10-11 months after the march in the two
test groups; serum triglycerides showed a delayed rise (219).
Short-term Intensive Exercise and Magnesium
Plasma Mg was unchanged, but rbc Mg decreased significantly
during exercise on an ergometer in a study by Golf et al (10).
Boehmer (220), however found that an hour's strenuous exercise
sharply lowered serum Mg in a large group of well-trained
athletes, whose resting serum Mg values were normal. On the other
hand, increased plasma Mg, attributed to reduction of plasma
volume and influx of Mg to the vascular pool during short-term
intense exercise on a bicycle ergometer, was reported by Joborn
et al (19) and Ansquer (221), who commented that when there was a
fall in serum Mg, it was accompanied by increased rbc Mg, the
total blood Mg remaining constant, indicating an
intercompartmental shift. Treadmill running until exhaustion was
shown by Deuster et al (222) to transiently decrease plasma Mg
significantly, with over 85% of the loss caused by shift to rbc.
There was significantly increased urinary Mg on exercise, and of
post-exercise blood lactate and oxygen consumption during
recovery versus a control period. Exercise-induced
inter-compartmental Mg shifts in blood Mg returned to
pre-exercise values in 2 hours; urinary Mg loss on the exercise
day returned to baseline the next day. They suggested that the
exercise-induced loss of urinary Mg might depend on exercise
intensity and relative contribution of anaerobic metabolism to
total energy expended during exertion. Lukaski et al (223), who
treadmill-tested 44 healthy male university athletes and 20
untrained men, observed that athletes' average maximum oxygen
consumption was greater than in non-athletes, and was
significantly correlated with plasma Mg, suggesting that Mg may
enhance O2 delivery to working muscles in trained subjects. Conn
et al (224) found that VO2max was significantly higher in
pre-adolescent swimmers than in controls for both sexes, despite
comparable plasma, rbc and whole blood Mg. Laires et al (225)
assessed the effect of swimming for 30 minutes on plasma Mg and
lipids in 6 well-trained swimmers before, just after, 30 minutes
after, and 24 hours after exercise. Serum Mg decreased
significantly shortly after exercise, returning to base line the
next day; rbc Mg did not change. Plasma total cholesterol
decreased significantly 30 minutes after exercise, with a
significant positive correlation between plasma Mg and plasma
HDL-cholesterol that disappeared after exercise but reappeared 24
hours later.
Magnesium Supplementation and Dietary Magnesium Intakes
of Athletes
Mg Supplements and Athletic Performance. The effect
of K + Mg aspartate supplements on the capacity for intense
exercise (90 minutes) was reported in 1968 by Ahlborg et al (226)
in six young men, the day before, and daily on four days of
testing on a bicycle ergometer until complete exhaustion and/or
muscle pain required stopping. Those supplemented on day 3
exhibited 50% increased work capacity before muscle pain
developed, versus those given placebo. It was postulated that Mg
accelerated glycogen synthesis or spared glycogen in muscle,
thereby sparing energy. That premise was justified by the
demonstrated fall in muscle glycogen and increase in lactate
after 20 minutes of heavy exercise on a bicycle ergometer,
without supplementation, shown by Bergstrom et al in 1971
(227).
Endurance (power) athletes under constant strain, given Mg
supplements by Boehmer in 1979 (228) did not exhibit the
declining Mg levels seen in the power athletes not so
supplemented, and had better performance and endurance. In the
study of de Haan et al (229), K and Mg aspartate supplementation
did not improve muscle performance during short intensive
exercise, as Vieth et al (230) had shown it to do in endurance
athletes. In a double-blind study of marathon racers, whom
Terblanche et al (231) described as Mg-replete, 365 mg/d of Mg
had no effect on performance or recovery. In another double-blind
study, of Mg supplemented athletes, Wodick and Grunert-Fuchs
(232) used a running board and bicycle ergometry and found that
480 mg of Mg as the aspartate-HCl salt/day for 4 weeks
significantly improved physical capacity. Four weeks of
supplementation with Mg aspartate-HCl was found to increase rbc
Mg and decrease maximal ventilation by 11% as compared to a
pre-Mg test in 14 male rowers in maximal-tests on a rowing
ergometer (Golf et al [233]). Plasma and urinary lactate
increased from 1 mM/l to 15 mM/l, and blood oxygen content
decreased.
The effect on blood coagulation and fibrinolytic factors of
supplementing male swimmers for a month with 480 mg of Mg/day or
with a placebo before a 1500 meter race was studied by Pohlmann
et al (234). Those receiving Mg had both increased serum and rbc
Mg levels, and showed anti-coagulating effects.
Dietary Mg Intake of Athletes
Surveys of dietary intakes of athletes have shown that as many
as half consumed diets delivering less than the 1980 RDA (235)
estimated for sedentary adults, which was lowered in the current
edition(110). Those undergoing active anabolism and/or subjected
to stress have substantially higher Mg needs. Studies of diets of
athletes have shown that such needs are commonly not met by their
diets (222,236-242). Supplementation of athletes to keep their Mg
status optimal, to ensure their best performance without
interfering muscle cramps and premature fatigue, and to prevent
muscle damage, has been recommended or implied by those reporting
improvement in the Mg-treated group in placebo-controlled studies
(supra vide). Since athletes undergo severe physical stress, as
well as the psychological drive to win, and most ingest
sub-optimal amounts of Mg, they are vulnerable to Mg deficiency.
Diets very rich in Mg, or prophylactic use of Mg supplements
should be advised to be sure of Mg intake of not less than 6 to
10 mg/kg/day, and possibly more (97,221,236-238,243-246).
Sudden death of pigs and cattle being transported under the
stressful conditions of crowding has been reduced in incidence by
Mg supplementation with Mg aspartate HCl or MgCl2 in sufficient
dosage to raise serum Mg (247). Calmer behavior of Mg treated
animals was observed in 49.5% of groups during fattening and in
37.6% during transport and in the slaughterhouse. (248,249). Up
to half of losses of young chickens (broilers) have been
attributed to a sudden death syndrome, possibly from stress. A
study of 5180 broilers whose high protein and carbohydrate diets
were supplemented with Mg aspartate HCl, for 40 days during their
fattening period, disclosed significant reduction of losses from
sudden death (250).
Stress-intensification of Mg inadequacy may well be to blame
for the SCD associated with stress, even in young healthy
athletes. This report has evaluated data implicating high Ca/Mg
ratios in increased adverse responses to stress. Stress hormone
intensification of Mg loss, and stimulation of their secretion by
high Ca/Mg constitute a self-reinforcing loop. High Ca/Mg ratios
lead to increased blood coagulation and vasotonus, which are also
influenced by prostaglandins and fibronectin, that are affected
by low Mg levels. It is provocative that pharmacologic doses of
Mg, are therapeutic in conditions that are intensified by loss of
Mg, and in which Mg inadequacy might well be a contributory
factor. High serum Mg levels, such as are required to control
eclampsia, have been shown to be effective adjunctive therapy in
bronchial asthma unresponsive to standard therapy; prompt high
dosage i.v.Mg has prevented or reduced the incidence of post-AMI
complications and significantly improved survival in double-blind
trials (251-256).
Worth consideration and trial is the possibility that higher
than usual Mg intake - whether from a Mg-rich diet or from
supplementing the usual diet with Mg salts, possibly with
anti-oxidant nutrients, might be protective against damage caused
by the usual vicissitudes of life and unusual stresses. Might
higher Mg (and vitamin E) intakes decrease the risk of
arrhythmias and SCD in humans? Large intervention studies, like
those undertaken to elucidate the effects of lowering saturated
fat intake on cardiovascular disease and cancer, are needed to
determine the extent to which adding Mg (and anti-oxidant
nutrients) to already recommended dietary changes, might further
improve health and increase stress-tolerance. Such studies are
particularly urgent in view of the recent National Institute of
Health recommendation (257) that the optimum Ca intake be further
increased to 1500 mg/day (to prevent osteoporosis), which
disregards the low American Mg intake, less than 300 mg/day. This
would bring the Ca/Mg ratio to 5/1 - which is above the 4/1 ratio
of Finland, the land with the highest ischemic heart disease
death rate for young to middle-aged men (258,259).
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(This article has been placed on this web site with the
permission of the Journal of the American College of Nutrition.
We thank Dr. Mildred S. Seelig for providing us the information
on a diskette.)
This page was first uploaded to The Magnesium Web Site on
October 18, 1995
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