The cellular bioenergetic responses of isolated perfused working rat hearts to alterations in hemodynamic function caused by acute exposure to elevated levels of extracellular magnesium ions ([Mg2+]o) were examined using 31P nuclear magnetic resonance (31P NMR) spectroscopy. Results showed that in hearts working against 90 cm H2O afterload, an increase in [Mg2+]o from 1.2 to 4.8 mM reduced the heart rate by 35%, while coronary flow was increased by 38%. Unexpectedly, despite the pronounced bradycardia, the rate-pressure product was reduced only slightly (from 2.36 x 10(4) to 2.08 x 10(4) mm Hg/min) due to a significant increase (36%) in systolic pressure. In addition, cardiac output actually increased by 23%, owing to a > 100% increase in stroke volume, indicating that the performance of the heart was improved and suggesting that the efficiency of the heart was improved as well. In a separate series of experiments, 31P NMR measurements performed on hearts perfused in the Langendorff mode revealed that elevated levels of [Mg2+]o increase phosphocreatine (PCr) levels by 23% (from 9.2 to 11.3 mM), while Pi levels declined by a corresponding amount. Perfusion of hearts in the working mode with elevated [Mg2+]o was also observed to increase PCr levels from 6.3 to 9.0 mM, while ATP levels declined by 17%. Measurement of the chemical shift difference between Pi and PCr and that between the alpha and beta phosphate resonances of ATP were used to determine intracellular pH and the cytosolic levels of free Mg2+ ([Mg2+]i), respectively. These results showed that acute exposure of hearts, perfused in either the working or Langendorff mode, to increased levels of [Mg2+]o increased intracellular pH by 0.12-0.13 units, while free Mg2+ nearly doubled to a level of 1.1-1.2 mM. The latter observation may suggest that acute variations in the level of [Mg2+]o can influence a multitude of cellular processes requiring Mg2+ as an essential cofactor. Using the above data and assuming equilibrium of the creatine kinase reaction, the levels of ADP, cytosolic phosphorylation potential ([ATP]/[ADP][Pi]) and free energy change from ATP hydrolysis (-delta G/delta E) were also calculated. Results obtained illustrate that in the presence of elevated [Mg2+]o, ADP levels declined by 33-48%, the cytosolic phosphorylation potential increased from 41 to 112 mM-1 and -delta G/delta E increased from 56.7 to 59.3 kJ/mol. These changes are not completely accountable by the known bradycardia and vasodilatory effects of elevated [Mg2+]o and strongly argue for a direct action of [Mg2+]o on the myocyte as well.(ABSTRACT TRUNCATED AT 400 WORDS)

A novel ion selective electrode (ISE) for ionized magnesium (IMg2+) in whole blood (WB), plasma (PL), and serum (S) has been designed. We have undertaken a number of studies, experimental and clinical, to characterize and examine the linearity, precision, specificity, accuracy, and utility of this new ISE for IMg2+ in WB, S, and PL of normal human subjects, diseased subjects and animals. Using aqueous solutions, mean IMg2+ values are within 94.6-99.2% of their targets. The linearity of the ISE (0.1-3.0 mM) in aqueous solutions, and human PL and S ranges between 92.0 and 99.3%. The ISE is highly selective for IMg2+, yielding measurements in less than 2 min, and exhibiting no or negligible effects from pathophysiologic concentrations of Ca2+, Na+, K+, H+ or NH4+. Likewise such concentrations of heavy metals (e.g., Fe3+, Cu2+, Zn2+, Cd2+, Hg2+ and Pb2+) in aqueous solution and serum do not interfere with ISE measurements for IMg2+. Ligand binding studies in aqueous solution indicate that pathophysiologic concentrations of different anions (e.g., heparin, bicarbonate, phosphate, acetate, sulfate and lactate) bind to Mg2+ with varying intensities, effectively reducing its concentration in solutions. IMg2+ measurements on WB, PL, and S for a given person's samples are virtually identical. Typically, IMg2+ is 71% of total Mg (TMg) but varies from subject to subject. The IMg2+ is held within a narrow range (0.53-0.67 mM) in normal, healthy controls. Studies on diseased human subjects (i.e., cardiac cases, cardiopulmonary bypass, abnormal pregnancy, renal transplant recipients, diabetics, asthmatics, etc.) indicate that IMg2+ levels often exhibit significant alterations from normality, despite no change in TMg.(ABSTRACT TRUNCATED AT 250 WORDS)

Ion-sensitive microelectrodes (ISEs) have been used to measure intracellular [Mg2+] ([Mg2+]i) in cardiac muscle, although most measurements have tended to overestimate the value due to the poor selectivity of the Mg2+ ionophore in the sarcoplasm and to inaccurate collation of individual ISE measurements. This paper highlights the correct method for analysis of data from multiple ISE experiments. Since [Mg2+]i is constrained at a lower concentration than would be expected by passive distribution of the ion, some of the possible mechanisms underlying Mg2+ extrusion from ferret ventricular myocardium were investigated. During elevation of the extracellular [Mg], mean [Mg2+]i rose from 1.61 to 1.91 mM. The same intervention had no significant effect on membrane potential, intracellular [Na+] or pH measured with ISEs, and there was no change in resting [Ca2+], as assessed from fura-2 fluorescence. The data are not consistent with a simple mechanism for Na(+)-Mg2+ exchange as the primary mode of Mg2+ regulation in cardiac muscle or with an Mg2+ extrusion mechanism involving steady-state ion exchange.

Mg-selective microelectrodes allow continuous direct recording of intracellular free magnesium concentration ([Mg]i). Mg-selective microelectrodes utilizing the neutral carrier ETH 1117 have been used to determine [Mg]i in a wide variety of tissues. However, this type of electrode suffers from considerable interference from other cations (primarily potassium and sodium when used for intracellular studies). The recently developed Mg sensor ETH 5214 reveals a much improved selectivity and sensitivity as compared to ETH 1117. For intracellular measurements of [Mg]i the interference from Na+, K+, Ca2+ and pH can be neglected. Measurements of resting [Mg]i in ferret ventricular muscle and frog skeletal muscle gave values of 0.85 and 0.93 mM, respectively. These values indicate that [Mg]i is not in a thermodynamic equilibrium and Mg2+ ions have to be extruded continuously from the cytoplasm against their electrochemical gradient. In skeletal muscle, measurements of [Mg]i and [Na]i under experimental conditions, which included changes of the membrane potential and the transmembrane gradients for Mg2+ and Na+, provided evidence that an Na/Mg exchange mechanism participates in maintaining [Mg]i at low cytoplasmic levels.

The reference system, preanalytical variables, specimen requirements and methodology for determination of magnesium in serum by clinical laboratories are discussed. Most clinical laboratories determine the serum magnesium concentration by colorimetric methods. Four different chromophores (calmagite, methylthymol blue, formazan dye and magon) are commonly used for the determination of serum magnesium on automated instruments by clinical laboratories. The College of American Pathologists Proficiency Testing Survey shows that instruments using the chromophore magon have a larger coefficient of variation among laboratories than most instruments using a different chromophore.

Magnesium has a profound effect on neural excitability; the most characteristic signs and symptoms of Mg deficiency are produced by neural and neuromuscular hyperexcitability. These create a constellation of clinical findings termed tetany syndrome (TS). TS symptoms include muscle spasms, cramps and hyperarousal, hyperventilation and asthenia. Physical signs (Chvostek's, Trousseau's or von Bonsdorff's) and abnormalities of the electromyogram or electroencephalogram can usually be elicited. Signs and symptoms of TS are frequently encountered in clinical practice, especially among patients with functional or stress-related disorders. The role of Mg deficit in TS is suggested by relatively low levels of serum or erythrocyte Mg and by the clinical response to oral Mg salts, which has been demonstrated in controlled studies. Among the more serious neurologic sequelae of TS are migraine attacks, transient ischemic attacks, sensorineural hearing loss and convulsions. Mg deficiency may predispose to hyperventilation and may sensitize the cerebral vasculature to the effects of hypocarbia. Mg deficiency increases susceptibility to the physiologic damage produced by stress, and Mg administration has a protective effect; studies on noise stress and noise-induced hearing loss are taken as an example. In addition, the adrenergic effects of psychological stress induce a shift of Mg from the intracellular to the extracellular space, increasing urinary excretion and eventually depleting body stores. Drugs used in neurology and psychiatry may affect Mg levels in blood and may diminish signs of tetany, making assessment of Mg status more difficult. Pharmacologic use of Mg can decrease neurologic deficit in experimental head trauma, possibly by blockade of N-methyl-D-aspartate receptors. In conjunction with high doses of pyridoxine, Mg salts benefit 40% of patients with autism, possibly by an effect on dopamine metabolism.

Magnesium influences mineral metabolism in hard and soft tissues indirectly through hormonal and other modulating factors, and by direct effects on the processes of bone formation and resorption and of crystallization (mineralization). Its causative and therapeutic relationships to calcium urolithiasis (CaUr) are controversial despite an association between low urinary Mg and CaUr. Recent studies have also found a tendency to low serum and/or lymphocyte Mg levels in CaUr. Despite earlier studies demonstrating an inhibitory effect of Mg supplementation on experimental CaUr in animals and in spontaneous CaUr in humans, at least two properly controlled clinical trials of Mg supplementation have failed to demonstrate a beneficial effect on CaUr frequency. With regard to the skeleton, experimental studies have shown that Mg depletion causes a decrease in both osteoblast and osteoclast activity with the development of a form of 'aplastic bone disease'. At the same time, bone salt crystallization is enhanced by Mg deficiency. Conversely, Mg excess impairs mineralization with the development of an osteomalacia-like picture, and may also stimulate bone resorption independently of parathyroid hormone. Whether or not Mg depletion may be a causal factor in human osteoporosis is also controversial, and there are conflicting reports as to the Mg content of osteoporotic bone. Small decreases in serum and/or erythrocyte Mg in osteoporotic patients have been reported, and one author has noted improved bone mineral density with a multinutrient supplement rich in Mg. The extant data are sparse and indicate a clear need for more rigorous study.

Numerous studies indicate that alcohol can cause neural and vascular damage in the brain. Additional studies indicate that magnesium ions (Mg2+) possess the ability to modify vascular tone. We utilized an image-splitting television microscope recording system in an intact rat brain model in order to determine whether local (topical) application or systemic (intravenous or intra-arterial) administrations of MgSO4 exert vasodilator effects on cerebral arterioles (66-124 microns o.d.) and venules (66-137 microns o.d.). In addition, we investigated whether infusion of low doses of MgSO4 could modify cerebral vascular spasms induced by ethanol and a calcium mimic, i.e., Ba2+. Topical applications of MgSO4 (i.e., 1-100 mumol) in male and female rats produced dose-dependent dilations of cerebral arterioles and venules; male animals were clearly more sensitive to Mg2+. Systemic infusion of low doses of MgSO4 (i.e., 1.0 and 4.0 mumol/min) into the femoral vein or a branch of the internal carotid artery failed, completely, to induce changes in arterial blood pressure or diameter of arterioles and venules. However, such nonvasodilator doses of MgSO4, infused via either route, inhibited contractile responses induced by 5% Ba2+ and 10% ethanol in arterioles and venules in a dose-dependent manner in both male and female rats. Cerebral microvessels of male animals were more sensitive to inhibitory actions of Mg2+ against Ba(2+)-induced microvascular constrictions than were microvessels of females. Administration of a variety of pharmacologic antagonists as well as a cyclo-oxygenase inhibitor failed to influence either the local vasodilator effects of Mg2+ or the inhibitory actions of Mg2+. Basal plasma levels of Mg were higher in female vs. male rats (1.98 +/- 0.06 vs. 1.77 +/- 0.028 mg/dl). Systemic administration of MgSO4 in cerebral nonvasodilator doses resulted in rapid elevation of plasma Mg levels in a dose-dependent manner (e.g., 0.3-4.3 mg/dl over control levels). Plasma Mg levels were more elevated in female than male animals. It is concluded that magnesium ions can act as local vasodilators, in physiologic doses, on brain microvessels and that these divalent cations possess antispasmodic activities, in nonvasodilator doses, on intact rat brain arterioles and venules. In addition, our findings suggest that Mg2+ might be useful in the treatment and prevention of alcohol-induced brain vascular damage.

The earliest description of clinical magnesium deficiency was reported in 1934. In 1954, Flink reported alcoholism as a cause of magnesium deficiency. This has been confirmed by low serum and tissue levels, balance studies, low exchangeable 28Mg and parenteral Mg retention tests. Alcohol causes urinary Mg wastage, but other mechanisms related to alcoholism contribute to the magnesium deficiency including malnutrition, gastrointestinal losses, phosphate deficiency, acidosis and/or alkalosis, vitamin D deficiency and free fatty acidemia associated with alcohol withdrawal. Mg replacement therapy is recommended to prevent some of the serious sequelae of magnesium deficiency.

Diagnostic categories that are useful for describing patients with acute or organ failure disease are generally less useful labels for primary care and preventive medicine patients whose conditions are better described by signs and symptoms. Symptoms may be clues to ill health but are not often criteria for a major diagnostic labeling. In my practice I have used a computer-based medical record system that permits portrayal and comparison of symptom data to correlate varying degrees of retention of an intramuscular magnesium-loading study (IMMLS) with symptom patterns in 172 patients. The group of patients who show a paradoxical excretion of more Mg than they were given in the IMMLS are a distinctive group with lower blood pressures and significantly fewer digestive and skin symptoms, fewer symptoms of inflammation but more emotional symptoms than those with normal Mg excretion. The group who retained > 49% of the load had higher blood pressures and significantly fewer symptoms of inflammation of the skin and of the reproductive tract.

Magnesium, the second most abundant intracellular cation, is essential for life. The consequences of deficiency are severest in the smallest and youngest members of each species and may include sudden unexpected death. Magnesium deficiency, usually diagnosed by hypomagnesemia, may be congenital, as in premature infants, infants of magnesium-deficient mothers and infants with intrauterine growth retardation. It may be acquired or caused by low magnesium intake, the use of magnesium-wasting drugs, illness provoking gastrointestinal or renal losses of the mineral, or high metabolic demands imposed by catch-up growth or postsurgical healing. Finally, the deficiency may be conditioned, caused by excessive dietary calcium, phosphorus or protein in relation to dietary magnesium, especially during a period of rapid growth or tissue repair. Magnesium therapy is safe when a low dosage is given with monitoring of plasma or serum magnesium levels, with occasional checking of calcium and potassium levels. A parenteral dose of 0.1 ml/kg/day of 50% magnesium sulfate USP (approx. 0.2 mmol/kg/day or 0.4 mEq/kg/day) may be given for 5 dose days. An oral dose of 1.0 ml of 10% magnesium chloride solution providing 0.5 mmol/kg/day magnesium or 1.0 ml/kg/day of 10% magnesium chloride USP (0.5 mmol/kg/day) or magnesium magonate (Magonate) 1.0 ml/kg/day (0.45 mmol/kg/day) may be given for extended periods; higher doses may be required for malabsorption syndromes. Hypermagnesemia, which usually results from magnesium overdosage or inadequate renal function, is a potential threat to neonates born to magnesium-treated eclamptic mothers. Most show marked improvement after 36 h of conservative management that includes calcium salts and intravenous infusions of glucose and saline, but obtunded neonates may require dialysis.

Magnesium is the fourth most abundant metal found in the body. It plays a crucial role in numerous biological processes. It is a natural calcium blocker. It can block or compete with Ca2+ at voltage-dependent, receptor- or leak-operated channels and result in translocation of intracellular Ca2+. Mg2+ inhibits Ca2+ release from the sarcoplasmic reticulum. Intracellular Mg2+ is thought to modulate smooth muscle contractions and the rate of relaxation. Mg2+ is a cofactor of numerous enzymes and is coupled with cellular use of phosphate as an activator and energy source. cAMP-dependent protein and adenylate cyclase are among many enzymes that require Mg2+ for their function. Mg2+ has been used successfully in treating asthma. There is experimental evidence that Mg2+ is required for various immune responses, and in rats, Mg2+ treatment has been shown to attenuate chemically induced pulmonary hypertension. It is not clear if Mg2+ deficiency plays a role in development of some of these diseases, but Mg2+ salts appear to have therapeutic value and certainly it has a role as an adjunct to traditional therapy in various lung diseases.

Hypomagnesemia is the commonest electrolyte abnormality in the ambulatory diabetic patient and is also a frequent finding in patients with diabetic ketoacidosis. Excessive urinary magnesium loss associated with glycosuria is probably the most important factor in the genesis of hypomagnesemia in the diabetic patient. The clinical consequences of magnesium deficiency include impairment of insulin secretion, insulin resistance and increased macrovascular risk. The role of magnesium deficiency in microvascular complications has yet to be clearly defined.

The availability of methods to assess intracellular magnesium has caused great interest in the biologic role of this ion. Measurement of total intracellular erythrocyte magnesium (RBC Mg) by atomic absorption spectroscopy in 94 prospectively studied patients (87 female, age 44 +/- 12 years) with symptomatic primary mitral valve prolapse diagnosed by strict echocardiographic and clinical criteria (Perloff) identified 35 patients with normal (2.12 +/- 0.16 mmol/l) and 59 with low (1.51 +/- 0.31 mmol/l) RBC Mg (mean +/- SD). The two groups did not differ in demographic or clinical characteristics, incidence of thick mitral leaflets, joint hypermobility (by Beighton-Horan score), chest pain, fatigability, palpitations, anxiety, depression, orthostatic hypotension, autonomic test results or plasma catecholamines. Muscle cramps and migraines were more frequent in Mg-deficient patients (but p < 0.05). We postulate that the lack of differences between the groups may be due to poor correlation of RBC Mg with Mg concentration of tissue pools.

Ionic biology involving Ca2+, Na+, K+ and Mg2+ across the cell membrane and in the development of the action potential is reviewed with reference to cardiac arrhythmia. K+ and Mg2+ deficiency which frequently occur together lead to abnormal ionic transfer of Na+, K+ and Ca2+ with development of automaticity, triggered impulses and reentrant tachycardia. Tachycardia occurring in acute myocardial ischemia, congestive heart failure, hypertensives on diuretics and digitalis toxicity is examined according to the concept of ionic imbalance. A protocol for prevention and treatment of cardiac tachyarrhythmia is proposed with this concept in mind.