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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:


ABSTRACT

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:


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


INTRODUCTION

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


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).


Interrelations among Catecholamines, Magnesium and Calcium

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]) .


CARDIOVASCULAR REACTIONS TO STRESS INTENSIFIED BY MAGNESIUM DEFICIT

Cardiovascular reactions to stress intensified by magnesium deficit

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

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).


TRANSPORTATION /SUDDEN DEATH

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).

CONCLUDING COMMENTS

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.)


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