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PubMed2005

Essential role for TRPM6 in epithelial magnesium transport and body magnesium homeostasis.

Magnesium is an important cofactor for many biological processes such as protein synthesis, nucleic acid stability and neuromuscular excitability. The extracellular magnesium concentration is regulated tightly by the extent of intestinal absorption and renal excretion. Despite their critical role in magnesium handling, the molecular mechanisms mediating transepithelial transport are still not understood completely. Recently, genetic studies in patients with primary hypomagnesaemia and secondary hypocalcaemia (HSH), a combined defect of intestinal magnesium absorption and renal magnesium conservation, have identified "transient receptor potential (melastatin) 6" (TRPM6) as the first component involved directly in epithelial magnesium reabsorption. TRPM7, the closest homologue of TRPM6, has a central role in Mg(2+) uptake in vertebrate cells since TRPM7-deficient cells become Mg(2+) deficient and are not viable. TRPM7 has been characterized functionally as a constitutively active ion channel permeable for a variety of cations including calcium and magnesium and regulated by intracellular concentrations of magnesium and/or magnesium-nucleotide complexes. Both proteins share the unique feature of cation channels fused to serine/threonine kinase domains. This review summarizes recent data that has emerged from molecular genetic, biochemical and electrophysiological studies on these fascinating two new proteins and their involvement in epithelial magnesium transport.

Homeostasis↗
PubMed1987

Cerebrospinal fluid levels of magnesium in patients with preeclampsia after treatment with intravenous magnesium sulfate: a preliminary report.

The purpose of this study is twofold: (1) to correlate magnesium levels of serum with those of cerebrospinal fluid in patients with preeclampsia receiving intravenous magnesium sulfate, and (2) to determine whether the magnesium ion crosses the blood-brain barrier in significant amounts after intravenous magnesium sulfate therapy. Of the 21 patients in whom spinal anesthesia was used for delivery, ten patients with preeclampsia with therapeutic serum magnesium levels made up the study group and 11 term nontreated normotensive gravid women served as controls. At the time of spinal anesthesia, a 1 ml aliquot of cerebrospinal fluid was obtained from each patient. The mean cerebrospinal fluid magnesium level for the control group was 2.56 +/- 0.19 mg/dl (range 2.2 to 2.8 mg/dl). For the preeclamptic group who received intravenous magnesium sulfate, the mean cerebrospinal fluid magnesium level was 3.04 +/- 0.12 mg/dl (range 2.9 to 3.2 mg/dl). Although only a small amount of magnesium crosses the blood-brain barrier after intravenous magnesium sulfate treatment, this increment is highly significant (p less than 0.001).

Adult↗
PubMed2002

Magnesium-DNA interactions and the possible relation of magnesium to carcinogenesis. Irradiation and free radicals.

Magnesium deficiency causes renal complications. The appearance of several diseases is related to its depletion in the human body. In radiotherapy, as well as in chemotherapy, especially in treatment of cancers with cis-platinum, hypomagnesaemia is observed. The site effects of chemotherapy that are due to hypomagnesaemia are decreased using Mg supplements. The role of magnesium in DNA stabilization is concentration dependent. At high concentrations there is an accumulation of Mg binding, which induces conformational changes leading to Z-DNA, while at low concentration there is deficiency and destabilization of DNA. The biological and clinical consequences of abnormal concentrations are DNA cleavage leading to diseases and cancer. Carcinogenesis and cell growth are also magnesium-ion concentration dependent. Several reports point out that the interaction of magnesium in the presence of other metal ions showed that there is synergism with Li and Mn, but there is magnesium antagonism in DNA binding with the essential metal ions in the order: Zn>Mg>Ca. In the case of toxic metals such as Cd, Ga and Ni there is also antagonism for DNA binding. It was found from radiolysis of deaerated aqueous solutions of the nucleoside 5'-guanosine monophosphate (5'-GMP) in the presence as well as in the absence of magnesium ions that, although the addition of hydroxyl radicals (*OH) has been increased by 2-fold, the opening of the imidazole ring of the guanine base was prevented. This effect was due to the binding of Mg2+ ions to N7 site of the molecule by stabilizing the five-member ring imitating cis-platinum. It was also observed using Fourier Transform Infrared spectroscopy, Raman spectroscopy and Fast Atom Bombardment mass spectrometry that *OH radicals subtract H atoms from the C1', C4' and C5' sites of the nucleotide. Irradiation of 5'-GMP in the presence of oxygen (2.5 x 10(-4) M) shows that magnesium is released from the complex. There is spectroscopic evidence that superoxide anions (O2-*) react with magnesium ions leading to magnesium release from the complex. From radiolysis data it was suggested that magnesium ions can act as radiosensitizers in the absence of oxygen, while in the presence of oxygen they act as protectors and stabilizers of DNA.

Animals↗
PubMed2001

Acute cytoskeletal alterations and cell death induced by experimental brain injury are attenuated by magnesium treatment and exacerbated by magnesium deficiency.

Traumatic brain injury results in a profound decline in intracellular magnesium ion levels that may jeopardize critical cellular functions. We examined the consequences of preinjury magnesium deficiency and post-traumatic magnesium treatment on injury-induced cytoskeletal damage and cell death at 24 h after injury. Adult male rats were fed either a normal (n = 24) or magnesium-deficient diet (n = 16) for 2 wk prior to anesthesia and lateral fluid percussion brain injury (n = 31) or sham injury (n = 9). Normally fed animals were then randomized to receive magnesium chloride (125 micromol, i.v., n = 10) or vehicle solution (n = 11) at 10 min postinjury. Magnesium treatment reduced cortical cell loss (p < 0.05), cortical alterations in microtubule-associated protein-2 (MAP-2) (p < 0.05), and both cortical and hippocampal calpain-mediated spectrin breakdown (p < 0.05 for each region) when compared to vehicle treatment. Conversely, magnesium deficiency prior to brain injury led to a greater area of cortical cell loss (p < 0.05 compared to vehicle treatment). Moreover, brain injury to magnesium-deficient rats resulted in cytoskeletal alterations within the cortex and hippocampus that were not observed in vehicle- or magnesium-treated animals. These data suggest that cortical cell death and cytoskeletal disruptions in cortical and hippocampal neurons may be sensitive to magnesium status after experimental brain injury, and may be mediated in part through modulation of calpains.

Animals↗
PubMedDate not supplied

Bioavailability of magnesium diglycinate vs magnesium oxide in patients with ileal resection.

BACKGROUND: Patients who have undergone ileal resection are at risk for developing magnesium depletion/deficiency because of poor absorption and decreased intake as well as increased endogenous losses. Magnesium repletion is difficult to accomplish because of the cathartic action of most oral magnesium supplements at therapeutic doses. The results of in vitro and in situ studies show that magnesium diglycinate (chelate) represents a highly available form of magnesium that is absorbed in part as an intact dipeptide in the proximal small intestine. METHODS: We conducted a double-blind, randomized crossover trial with 12 patients who had ileal resections in order to compare the bioavailability of a 100-mg dose of 26Mg-labeled chelate with MgO in this patient population. RESULTS: For the patient group as a whole, 26Mg absorption was low but was not different for the two supplements (23.5% vs 22.8% for magnesium chelate and MgO, respectively). However, 26Mg absorption was substantially greater from the chelate (23.5% vs 11.8%; p < .05) in the four patients who showed the greatest impairment of magnesium absorption with MgO and was better tolerated by all patients. Peak isotope enrichment also occurred significantly earlier after 26Mg chelate than after 26MgO ingestion (mean difference 3.2 +/- 1.3 hours; p < .05), and the area under the enrichment vs time curve was greater after chelate ingestion (p < .05). CONCLUSIONS: Data from this study support the suggestion that some portion of magnesium diglycinate is absorbed intact, probably via a dipeptide transport pathway. Magnesium diglycinate may be a good alternative to commonly used magnesium supplements in patients with intestinal resection.

Administration, Oral↗
PubMed1988

Intracellular magnesium deficiency and effect of oral magnesium on blood pressure and red cell sodium transport in diuretic-treated hypertensive patients.

The effects of magnesium supplementation were tested in 20 patients with essential hypertension receiving long-term thiazide diuretic treatment (Th group) and 21 age-matched untreated patients (EHT group). Intra-erythrocyte cations, water content and the ouabain-sensitive sodium efflux rate constant were measured. The Th group received magnesium supplementations as MgO (600 mg Mg/day) for 4 weeks. In the Th group intra-erythrocyte magnesium and the sodium efflux rate constant were lower and red cell sodium was higher than in the EHT group. During magnesium supplementation, there were significant decreases (p less than 0.01) in intra-erythrocyte sodium content and mean blood pressure, and increases (p less than 0.005) in red cell magnesium content and the sodium efflux rate constant. These effects of magnesium were more evident in 9 patients who were unresponsive to diuretic therapy, a definite reduction in mean blood pressure, from 104.8 +/- 2.7 mmHg to 94.4 +/- 2.2 mmHg (p less than 0.001), being observed. In the remaining 11 patients, however, blood pressure remained unchanged. The sodium efflux rate constant was positively correlated with red cell magnesium content and negatively correlated with sodium content (r = 0.61, p less than 0.005 and r = -0.57, p less than 0.01, respectively). These results indicate that long-term diuretic treatment may give rise to intracellular magnesium deficiency and a suppression of cell membrane active sodium transport. The results also suggest that oral magnesium may decrease intracellular sodium, possibly through the activation of Na-K-ATPase, which in turn may contribute to the reduction in blood pressure. Therefore, magnesium supplementation may be a worthwhile additional therapy for diuretics.

Administration, Oral↗
PubMed1984

Relationship between magnesium intake and fecal magnesium excretion of ruminants.

Twenty-four wethers were fed fresh cut orchardgrass, fertilized so that the magnesium concentration in the forage varied, and six lactating dairy cows were fed a 60% concentrate diet supplemented so that the magnesium concentration in the diet varied. This was to evaluate relationships between intake of magnesium and fecal excretion of magnesium in ruminants. Linear and logarithmic equations were evaluated for sheep and dairy cows. Although there was little difference between equations in ability to predict apparent absorption of magnesium at normal intakes of magnesium, the logarithmic equation was more useful for predicting magnesium apparent absorption at extreme intakes of magnesium. Constants for logarithmic equations for sheep and cows were similar; therefore, the data were combined and a single equation was derived for both species on the same logarithmic scale. Apparent absorption of magnesium in ruminants may be a function of the amount of magnesium consumed per unit of digesta surface area exposed to the rumen wall.

Animal Feed↗
PubMed1985

Parenteral magnesium tolerance testing in the evaluation of magnesium deficiency.

Magnesium deficiency is a common clinical condition, frequently present even with normal serum magnesium (S-Mg) concentrations. We have studied retention of a low-dose (0.2 mEq/kg lean body weight), intravenously administered magnesium load in 6 hypomagnesemic patients and 18 normomagnesemic alcoholics as compared with 16 normal subjects. Both normomagnesemic and hypomagnesemic subjects retained significantly greater amounts of the administered magnesium than did the normal subjects. In patients who were restudied following parenteral magnesium repletion, retention of the magnesium load normalized. We conclude that increased retention of a magnesium load is a more sensitive index of magnesium deficiency than is the S-Mg concentration, and suggest that low-dose magnesium tolerance testing be used more frequently as a clinical tool in the evaluation of states of normomagnesemic magnesium deficiency.

Adult↗
PubMed2005

Therapy with both magnesium sulfate and nifedipine does not increase the risk of serious magnesium-related maternal side effects in women with preeclampsia.

OBJECTIVE: Does the use of nifedipine and magnesium sulfate together increase serious magnesium-related effects? STUDY DESIGN: This was a retrospective chart review of women who were admitted to BC Women's Hospital and Health Centre (1997-2001) and were given intravenous magnesium sulfate for preeclampsia. Serious magnesium-related effects were compared among 162 cases who received magnesium sulfate and contemporaneous nifedipine and 215 control subjects who received magnesium sulfate and either another antihypertensive (n=32 women) or no antihypertensive (n=183 women) medication. Chi-squared test, Fisher's exact test, or the Student t test was used for data comparison between cases and each control group. A probability value of <.05 was considered statistically significant. RESULTS: The cases had more severe preeclampsia and a longer magnesium sulfate infusion. However, cases had no excess of neuromuscular weakness (53.1%) versus control subjects who received antihypertensive medication (53.1%; P=.99) or control subjects who received no antihypertensive medication (44.8%; P=.13) or other serious magnesium-related effects. Cases versus control subjects who received antihypertensive medication had less neuromuscular blockade (odds ratio, 0.04; 95% CI, 0.002-0.80). Cases versus control subjects who received no antihypertensive medication had less maternal hypotension (41.4% vs 53.0%; P=.04). CONCLUSION: The use of nifedipine and magnesium sulfate together does not increase the risk of serious magnesium-related effects.

Adult↗
PubMed1990

Magnesium metabolism in preterm infants: effects of calcium, magnesium, and phosphorus, and of postnatal and gestational age.

This study tests the hypothesis that increasing the calcium and phosphorus content of formulas for very low birth weight (VLBW) infants to the level required to decrease the incidence of rickets has a negative impact on magnesium balance. Using formulas variously supplemented with these minerals, we measured absorption and retention in two groups of preterm infants: (1) VLBW infants, less than 1500 gm and at less than 32 weeks of gestational age, with 3-day mineral balances begun at days 10, 20, 30, and 40; and (2) low birth weight infants appropriately grown and at 32 to 34 weeks of gestational age, with a single 3-day balance begun at day 10. Magnesium did not affect calcium balance in VLBW or low birth weight infants but promoted phosphorus retention in VLBW infants from day 20 onward. Absorption and retention of magnesium increased with postnatal age in VLBW infants, but this effect was obvious only when calcium or phosphorus intakes were low or when magnesium intake was high. Calcium and phosphorus supplementation further reduced magnesium absorption and retention in VLBW infants to the extent that they were in negative balance throughout the study; however, magnesium supplementation improved absorption and retention in VLBW infants. The low birth weight infants absorbed and retained more magnesium than VLBW infants at the same postnatal age whether or not magnesium was supplemented. We conclude that magnesium deficits occur at currently recommended intakes of 10 mg/kg/day for VLBW infants with calcium and phosphorus intakes that allow retentions equivalent to in utero accretions; however, with magnesium intakes approaching 20 mg/kg/day, appropriate retention can be achieved.

Absorption↗
PubMedDate not supplied

Bioavailability and pharmacokinetics of magnesium after administration of magnesium salts to humans.

Therapeutically, magnesium salts represent an important class of compounds and exhibit various pharmacologic actions. Examples of magnesium salts are ionic magnesium and magnesium citrate in nephrolithiasis, magnesium salicylate in rheumatoid arthritis, magnesium hydroxide as an antacid as well as a cathartic, and magnesium mandelate as urinary antiseptic. Various anions attached to the cation magnesium, such as oxide, chloride, gluconate, and lactate, affect the delivery of the amounts of elemental magnesium to the target site and thereby produce different pharmacodynamic effects. This review examines the bioavailability and pharmacokinetics of various magnesium salts and correlates pharmacodynamic action with the structure-activity relationship.

Biological Availability↗
PubMed1988

Evaluation of magnesium status in Crohn's disease as assessed by intracellular analysis and intravenous magnesium infusion.

The magnesium status was evaluated in 30 subjects with Crohn's disease and in 30 controls. Subjects with Crohn's disease had lower concentrations of magnesium in muscle biopsy specimens (p less than 0.001), mononuclear cells (p less than 0.05), and in urine collected during 24 h (p less than 0.001) as compared with controls. After intravenous infusion of 60 mmol magnesium and 80 mmol potassium to 17 subjects with Crohn's disease a significant increase in concentrations of magnesium in muscle specimens (p less than 0.05), mononuclear cells (p less than 0.01), and plasma (p less than 0.01) was noted. The retention of intravenously infused magnesium was significantly higher in subjects with Crohn's disease than in 11 healthy controls (p less than 0.001) and was inversely correlated with the content of magnesium in muscle specimens (r = -0.52; p less than 0.05). The implication of these findings is that analysis of magnesium in muscle specimens and estimation of magnesium retention during an intravenous magnesium infusion are useful to confirm a suspected magnesium deficiency.

Adolescent↗
PubMed1991

Magnesium supplement in pregnancy-induced hypertension: effects on maternal and neonatal magnesium and calcium homeostasis.

The objective of this study was to evaluate the effect of low dose magnesium supplement upon maternal and fetal serum levels of mineral status in pregnancies complicated with hypertension (PIH). Twenty-five patients with PIH agreed to participate and were randomly allocated, in a double-blind manner, either to intravenous magnesium for 2 days followed by oral magnesium (n = 12) until delivery or placebo (n = 13). In women supplemented with magnesium the level of magnesium increased from 0.74 to 1.02 mmol/l during the first 24 h of inclusion and simultaneously we observed an increased urinary loss of magnesium. Serum level and the urinary excretion of magnesium returned to pretreatment level at delivery. Maternal magnesium supplement increased the concentrations of magnesium in umbilical cord and neonatal blood 1 day after delivery. Serum ionized calcium did not change during the study period despite a significant increased loss of calcium during the first 24 h of inclusion. Low dose maternal magnesium treatment did not cause neonatal hypocalcemia.

Calcium↗
PubMed1995

Effects of dietary vitamin D on magnesium absorption and bone mineral contents in pigs on normal magnesium intakes.

The effects of three dietary levels of vitamin D (500, 1500 and 3000 IU/kg diet) on magnesium metabolism and on some bone parameters related to bone mineralization were studied in vitamin D-repleted pigs fed normal magnesium intakes (0.2 per cent) for two months. Apparent absorption and retention was measured in 10-day balance studies (prior to slaughter) in three groups of four 10-week old pigs. Except for vitamin D, the pigs received the same diet which met the recommended dietary allowances for growing pigs. The highest vitamin D level used was only three times the recommended level in French pig husbandry. At slaughter, the fibula and two main metatarsals (right hind leg) were collected to determine bone breaking strength, apparent density and bone mineral (ash, calcium, magnesium) contents. Blood was collected to determine plasma concentrations of calcium, magnesium and vitamin D metabolites. Magnesium absorption increased linearly from 28-39 per cent intake with increasing dietary vitamin D. Urinary magnesium was not affected, thus magnesium retention also increased linearly as a function of vitamin D intake. Plasma calcium and magnesium were not altered by vitamin D. Plasma 25-hydroxycholecalciferol concentrations reflected vitamin D intakes, while plasma 1,25 dihydroxycholecalciferol was unchanged. Density, breaking strength and mineral contents of the bones were lower in the pigs fed 1500 or 3000 than in those fed 500 IU vitamin D/kg diet. This suggests that bone resorption was stimulated by the higher dietary vitamin D. Thus, vitamin D at physiological doses may enhance magnesium absorption in non previously vitamin D-depleted pigs fed diets with abundant magnesium. This nutritional situation may help explain the predominant bone-resorbing effect of vitamin D supplementation.

Absorption↗
PubMed1997

Magnesium status and risk of coronary artery disease in rural and urban populations with variable magnesium consumption.

This survey was conducted to determine the association between amount of magnesium intake and prevalence of coronary artery disease (CAD) and coronary risk factors in north India. There were 3575 subjects aged 25-64 years including 1769 rural (894 men, 875 women) and 1806 urban (904 men, 902 women) subjects. The survey methods were questionnaires for 7-day food intake record, physical examination and electrocardiography using World Health Organization criteria. The overall prevalence of CAD was three-fold greater in urban compared to rural subjects (9.0 vs 3.3 per cent, p < 0.001). The prevalence of CAD was significantly higher among subjects consuming lower dietary magnesium. Lower magnesium status was inversely associated with risk of CAD in both rural and urban subjects in both sexes. Among subjects with low magnesium status, there was a higher prevalence of hypertension, hypercholesterolemia and diabetes mellitus showing a significant increasing trend with decrease in magnesium status. Multivariate logistic regression analysis after pooling of data from rural and urban subjects and after adjustment of age showed that magnesium intake had an inverse association with prevalence of CAD. Serum magnesium (odds ratio: men 1.14, women 1.05), dietary magnesium (men 1.21, women 1.12), serum cholesterol (men 1.15, women 1.15), blood pressure (1.26 men, women 1.21), diabetes mellitus (men 1.20, women 1.18) in both sexes and smoking in men (1.05) were significant risk factors of CAD. Lower consumption of dietary magnesium and low serum Mg level in north India have a higher prevalence of CAD and of the coronary risk factors hypertension, hypercholesterolemia and diabetes mellitus. It is possible that increased intake of magnesium to about 500 mg/day may be of benefit in the prevention of CAD.

Adult↗
PubMed1997

Parenteral magnesium loading test in the assessment of magnesium status in healthy adult French subjects.

Parenteral magnesium loading test has been proposed as an adequate mean to evaluate magnesium status. However, applied tests vary among different laboratories and standardized procedure is not available. In the present study, we assessed magnesium status in 32 healthy adult French subjects by magnesium loading test using MgCl2 and determination of magnesium concentrations in plasma and erythrocytes. We observed a positive correlation between plasma and erythrocyte magnesium concentrations, but there was no correlation between magnesium retention and basal urinary excretion of magnesium, and plasma or erythrocyte magnesium concentrations.

Adult↗
PubMed1994

Nutritional magnesium supplementation does not change blood pressure nor serum or muscle potassium and magnesium in untreated hypertension. A double-blind crossover study.

The aim of this study was to evaluate if a nutritional dose of magnesium given orally changes the blood pressure in untreated hypertensive patients and if orally-given magnesium had any influence on serum and muscle magnesium and potassium. A randomized, double-blind crossover study design was followed with magnesium 15 mmol/day or placebo treatment for two months. Thirty-nine patients aged 20-59 years, were treated. Samples for magnesium and potassium in blood, muscle and urine were taken at entry time, after two months (crossover time) and after four months (end of study). Systolic and diastolic supine and standing blood pressures were measured at the same times. No significant change in blood pressure, serum or muscle concentrations of electrolytes were observed on magnesium treatment. Urine magnesium rose significantly on magnesium, and it decreased significantly on placebo. Therefore results suggest that 15 mmol magnesium/day, given to untreated mild-to-moderate hypertensives does not alter blood pressure nor the concentrations of magnesium and potassium in serum and muscle, in patients with normal magnesium turnover.

Administration, Oral↗
PubMed2002

Early administration of intravenous magnesium to high-risk patients with acute myocardial infarction in the Magnesium in Coronaries (MAGIC) Trial: a randomised controlled trial.

BACKGROUND: The benefits of supplemental administration of intravenous magnesium in patients with ST-elevation myocardial infarction (STEMI) are controversial. Despite promising results from work in animals and the ready availability of this simple, inexpensive treatment, conflicting results have been reported in clinical trials. Our aim was to compare short-term mortality in patients with STEMI who received either intravenous magnesium sulphate or placebo. METHODS: We did a randomised, double-blind trial in 6213 patients with acute STEMI who were assigned a 2 g intravenous bolus of magnesium sulphate administered over 15 min, followed by a 17 g infusion of magnesium sulphate over 24 h (n=3113), or matching placebo (n=3100). Our primary endpoint was 30-day all-cause mortality. At randomisation, patients were stratified by their eligibility for reperfusion therapy. The first stratum included patients who were aged 65 years or older and eligible for reperfusion therapy, and the second stratum included patients of any age who were not eligible for reperfusion therapy. Analysis was by intention-to-treat. FINDINGS: At 30 days, 475 (15.3%) patients in the magnesium group and 472 (15.2%) in the placebo group had died (odds ratio 1.0, 95% CI 0.9-1.2, p=0.96). No benefit or harm of magnesium was observed in eight prespecified subgroup analyses of patients and in 15 additional exploratory subgroup analyses. After adjustment for factors shown to effect mortality risk in a multivariate regression model, no benefit of magnesium was observed (1.0, 0.8-1.1, p=0.53). INTERPRETATION: Early administration of magnesium in high-risk patients with STEMI has no effect on 30-day mortality. In view of the totality of the available evidence, in current coronary care practice there is no indication for the routine administration of intravenous magnesium in patients with STEMI.

Aged↗