phosphocreatine and Magnesium-Deficiency

Physicians' use of micronutrients to improve symptoms or outcomes in chronic illness has until recently been guided by limited data on the actions of individual agents in vitro or in animal studies. However several recently published clinical trials have provided information about which groups of patients are likely to benefit from which combination of micronutrients. Patients with chronic cardiac failure (CCF), particularly elderly individuals, have several reasons to be deficient in micronutrients including reduced intake, impaired gastrointestinal absorption and increased losses on the background of increased utilisation due for example to increased oxidative stress. Studies of nutritional supplementation in CCF patients have usually concentrated on specific agents. However given that many micronutrients have synergistic influences upon metabolic processes this strategy might merely lead to a shifting of a limiting step. Rather, a strategy of increasing the availability of multiple agents at once might be more logical. The aim of this article is to briefly review the experimental rationale for each of the micronutrients of potential benefit in chronic heart failure and examine the current clinical trial evidence supporting their use.

Topics: Animals; Antioxidants; Ascorbic Acid; Calcium; Carnitine; Copper; Dietary Supplements; Heart Failure; Humans; Magnesium; Magnesium Deficiency; Micronutrients; Niacin; Oxidative Stress; Phosphocreatine; Ubiquinone; Vitamin B Complex; Vitamin B Deficiency; Vitamin E; Zinc

Magnesium (Mg) deficiency and oxidative stress are independently implicated in the etiopathogenesis of various cardiovascular disorders. This study was undertaken to examine the hypothesis that Mg deficiency augments the myocardial response to oxidative stress. Electrically stimulated rat papillary muscle was used for recording the contractile variation. Biochemical variables of energy metabolism (adenosine triphosphate (ATP) and creatine phosphate) and markers of tissue injury (lactate dehydrogenase (LDH) release and lipidperoxidation), which can affect myocardial contractility, were assayed in Langendorff-perfused rat hearts. Hydrogen peroxide (100 micromol/L) was used as the source of reactive oxygen species. The negative inotropic response to H2O2 was significantly higher in Mg deficiency (0.48 mmol Mg/L) than in Mg sufficiency (1.2 mmol Mg/L). Low Mg levels did not affect ATP levels or tissue lipid peroxidation. However, H2O2 induced a decrease in ATP; enhanced lipid peroxidation and the release of LDH were augmented by Mg deficiency. Increased lipid peroxidation associated with a decrease in available energy might be responsible for the augmentation of the negative inotropic response to H2O2 in Mg deficiency. The observations from this study validate the hypothesis that myocardial response to oxidative stress is augmented by Mg deficiency. This observation has significance in ischemia-reperfusion injury, where Mg deficiency can have an additive effect on the debilitating consequences.

Topics: Adenosine Triphosphate; Animals; Cardiotonic Agents; Cardiovascular Diseases; Female; Hydrogen Peroxide; In Vitro Techniques; L-Lactate Dehydrogenase; Magnesium Deficiency; Malondialdehyde; Myocardial Contraction; Myocardium; Papillary Muscles; Phosphocreatine; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

Mimicking in rats the reduced level of dietary magnesium (Mg) intake, seen in present-day Western World populations, short-term (4 weeks) restriction of Mg intake (30-35% normal) resulted in a 40% loss in brain intracellular free Mg2+ ions ([Mg2+]i) and significant rises in brain intracellular pH (pHi) and phosphocreatine ([PCr]) but no change in [ATP] or [Pi] as measured by 31P-NMR spectroscopy. Such Mg-deficient animals (serum Mg fell 65%), when given ED40 stroke doses of ethanol, demonstrated a 100% stroke mortality. These findings indicate that: 1) moderate, short-term Mg deficiency makes the brain vulnerable to hypoxic-lethal stroke insults induced by alcohol administration, and 2) brain [Mg2+]i appears to play an important role in finely regulating brain pHi and [PCr].

Topics: Animals; Brain; Brain Injuries; Cerebrovascular Disorders; Diet; Ethanol; Hydrogen-Ion Concentration; Magnesium; Magnesium Deficiency; Magnetic Resonance Spectroscopy; Male; Phosphates; Phosphocreatine; Rats; Rats, Wistar

31P-NMR spectroscopic studies were performed in vivo on brains of rats fed 30-35% normal dietary Mg intake for 6 weeks. Within 2 weeks of the moderately restricted Mg diet serum Mg fell 50%, and brain intracellular free [Mg2+]i fell 15%; within 3 weeks of restricted diet, brain [Mg2+]i fell 40% and remained at this level for the additional 3 weeks. Intracellular pH (pH[i]) progressively rose in a reciprocal manner for 4 weeks. At no interval of time did brain phosphocreatine (PCr), [ATP], or inorganic phosphate change despite the fall in brain [Mg2+]i, brain pH(i) and serum Mg. The Mg-deficiency-induced cytosolic loss of protons (resulting in an alkaline cytosol) could be a compensatory mechanism to stabilize [PCr], [ATP] and [ADP] levels via creatine kinase, thus maintaining cytosolic phosphorylation potential. The rise in pH(i) associated with Mg-deficiency would also account for increased cerebral vascular muscle contractility under these conditions. Lastly, these studies indicate that brain [Mg2+]i may change without a concomitant change in cell [ATP], and that brain [Mg2+]i may be a useful marker for total body Mg2+ status.

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Brain; Hydrogen-Ion Concentration; Magnesium; Magnesium Deficiency; Magnetic Resonance Spectroscopy; Male; Muscle, Smooth, Vascular; Phosphocreatine; Rats; Rats, Wistar

This study examines the effects of Mg depletion on myocardial bioenergetic, carbohydrate, lipid and phospholipid metabolism. Rats were studied after long-term (12 week) selective dietary restriction of Mg (20% normal dietary intake). Myocardial biopsy samples were examined for glucose 6-phosphate and glycogen to evaluate carbohydrate pathways and for glycerol phosphate and mitochondrial fatty acid oxidation and phospholipid contents to evaluate lipid and phospholipid turnover. Dietary Mg deficiency resulted in falls in myocardial glycogen, glucose-6-phosphate, glycerol phosphate, as well as the contents of phosphatidylcholine (PC), phosphatidylethanolamine (PE), diphosphatidyl glycerol (DPG), phosphatidyl inositol (PI) and total phospholipid phosphorus. These observations demonstrate impaired phospholipid metabolism, probably at the biosynthetic level. The mitochondrial oxidation of long-chain fatty acids was also impaired after Mg depletion. Mg depletion (serum Mg fell 60%) also resulted in significant falls in myocardial [ATP], phosphocreatine (PCr), and Mg with a concomitant rise in myocardial Ca content. These observations are consistent with the tenet that prolonged low [Mg2+]zero can result in marked reduction in oxygen and substrate delivery to the cardiac myocytes, with concomitant changes in membrane phospholipids (potentially resulting in a pro-oxidant state) probably as a result of coronary vasoconstriction.

Topics: Adenosine Triphosphate; Animals; Calcium; Diet; Energy Metabolism; Fatty Acids; Magnesium; Magnesium Deficiency; Mitochondria, Heart; Myocardial Ischemia; Myocardium; Oxidation-Reduction; Oxygen Consumption; Phosphocreatine; Phospholipids; Rats; Rats, Sprague-Dawley

We describe a patient with the eosinophilia-myalgia syndrome (EMS) with persistent myalgias, cramping, and weakness that were not responsive to treatment. Despite a normal serum magnesium level, a loading study was performed, and the results suggested low tissue levels of magnesium. He was given parenteral magnesium and had dramatic improvement in symptoms as well as in muscle intracellular levels of this cation. After cessation of magnesium therapy the symptoms recurred, and magnesium repletion again led to an improvement in symptoms and ATP levels. Low tissue levels of magnesium, even in the setting of normal serum levels, may lead to the neuromuscular symptoms in EMS and related disorders.

Topics: Adenosine Triphosphate; Adult; Eosinophilia-Myalgia Syndrome; Humans; Infusions, Parenteral; Magnesium; Magnesium Deficiency; Magnetic Resonance Spectroscopy; Male; Muscles; Osmolar Concentration; Phosphocreatine; Phosphorus

31P-NMR spectroscopic studies were performed in vivo on brains of rats administered cocaine. Cocaine.HCl (1-5 mg/kg) administered systemically to lightly anesthetized rats resulted in significant and progressive deficits in whole brain intracellular free Mg ([Mg2+]i). Intracellular pH (pHi) also fell in a progressive manner but only after a significant fall in brain [Mg2+]i was noted. Both [Mg2+]i and pHi returned to normal in most rats. Brains of rats that exhibited stroke-like events, however, demonstrated continued intracellular acidosis associated with progressive loss of phosphocreatine and elevation of Pi up until death. These observations are consistent with the tenet that injection of cocaine can result in severe cerebral vasospasm, ischemia and rupture of cerebral blood vessels as a consequence of depletion of brain [Mg2+]i.

Topics: Animals; Brain Chemistry; Brain Ischemia; Cerebrovascular Disorders; Cocaine; Hydrogen-Ion Concentration; Magnesium Deficiency; Magnetic Resonance Spectroscopy; Male; Phosphates; Phosphocreatine; Rats; Rats, Wistar

The effect of prolonged magnesium depletion on contractility, phosphorylating activity, and organic phosphates of spontaneously beating isolated rat atria was studied. Rats were fed a Mg-deficient diet for 8 weeks, during which serum Mg fell from 1.85 +/- 0.02 to 0.52 +/- 0.10 mg/dl. Atrial contractile activity was measured for 1 hr and at the end of this period tissue samples were taken for the determination of the phosphorylated intermediates. Mg depletion was associated with (a) reduced intracellular inorganic phosphorus and adenine nucleotides; (b) elevated creatine phosphate; (c) reduction in contractile force (CF) with no change in atrial beat rate (BR). There were no significant differences in the activities of creatine phosphokinase and adenylate kinase in control and Mg-depleted rat atrial homogenates determined in the presence of 5 mM MgCl2. Addition of various concentrations of MgCl2 to the medium resulted in an immediate reduction in both CF and BR of normal and Mg-depleted rat atria. Intraperitoneal administration of MgCl2 to Mg-depleted rats resulted in complete recovery of CF of isolated atria. This improvement in CF occurred without changes in the levels of inorganic phosphate and adenine nucleotides. The reduced intracellular level of high-energy phosphate or inorganic phosphate cannot therefore be responsible for the impaired contractility seen in Mg-depleted heart muscle. On the other hand, the fact that the creatine phosphate levels were higher in magnesium depletion suggests that myofibrillar utilization of creatine phosphate is more impaired than production, analogous to phenomena seen in postanoxic recovery.

Topics: Adenine Nucleotides; Adenylate Kinase; Animals; Creatine Kinase; Magnesium; Magnesium Deficiency; Male; Myocardial Contraction; Myocardium; Phosphates; Phosphocreatine; Rats; Rats, Inbred Strains

Muscle weakness and abnormal electrical activity of muscle cells have been described in magnesium-depleted patients and animals. The cellular mechanisms by which magnesium depletion causes the skeletal myopathy are not known. We review here the available clinical and experimental data on the effects of magnesium on: skeletal muscle cellular bioenergetics; excitation-contraction coupling, and biochemical and functional integrity of the cellular membrane. The data suggest that abnormalities in one or more of the above pathways may mediate the myopathy of magnesium depletion.

Topics: Adenosine Triphosphate; Animals; Cell Membrane; Electric Conductivity; Energy Metabolism; Humans; Magnesium Deficiency; Muscle Contraction; Muscles; Muscular Diseases; Phosphocreatine