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Comparative study of magnesium salts bioavailability in rats fed a magnesium-deficient diet

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Abstract

The purpose of this study was to compare efficiency of compensation of alimentary Mg deficiency after administration of 12 organic and 8 inorganic magnesium salts and to evaluate the ability of vitamin B6 to accelerate their effect. Two hundred eighty rats were placed on a Mg-deficient diet (Mg content (15 mg/kg) and demineralized water for 7 weeks. Twelve control rats were fed a basal diet (Mg content 500 mg/kg). Starting from day 49 of the Mg-deficient diet, the rats were given magnesium salts (50 mg magnesium and 5 mg pyridoxine per kg): Mg chloride, Mg sulphate, Mg oxide, Mg nitrate, Mg thiosulphate, Mg hydrophosphate, Mg carbonate, Mg trisilicate, Mg (L-, D- and DL-) aspartate, Mg (L- and DL-) pyroglutamate, Mg succinate, Mg gtycinate, Mg orotate, Mg taurate, Mg lactate or their combination with vitamin B6 (5 mg/kg b.w.). Erythrocyte and plasma Mg levels were measured by spectrophotometry following the colour reaction between Mg and titanium yellow. Mg L-aspartate compensated for magnesium deficit more effectively and faster than all other salts. Mg chloride showed the highest efficiency among inorganic magnesium salts. Both Mg chloride and Mg L-aspartate in combination with vitamin B6 caused statistically significant compensation of magnesium deficit.

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... Till now no characterization of MOD solubility and intestinal permeability has been performed in the literature for providing guidance on dosage form development based on its dose solubility ratio (D: S) so as to evaluate its bioavailability in terms of dose present in dosage form. Until now only two pharmacokinetics studies [16,17] had been performed in rats to evaluate the absorption of MOD but one study was conducted in the presence of absorption inhibitor (phytic acid) [16] while the other study was performed in the presence of absorption enhancer (pyridoxine hydrochloride) [17] in magnesium deficient conditions. Moreover, both of the studies were not based on single-dose administration of MOD. ...
... Till now no characterization of MOD solubility and intestinal permeability has been performed in the literature for providing guidance on dosage form development based on its dose solubility ratio (D: S) so as to evaluate its bioavailability in terms of dose present in dosage form. Until now only two pharmacokinetics studies [16,17] had been performed in rats to evaluate the absorption of MOD but one study was conducted in the presence of absorption inhibitor (phytic acid) [16] while the other study was performed in the presence of absorption enhancer (pyridoxine hydrochloride) [17] in magnesium deficient conditions. Moreover, both of the studies were not based on single-dose administration of MOD. ...
... Benefit of Mg repletion in patients suffering from cardiovascular diseases is evident [13], and some Mg-containing agents have been recommended for Mg repletion in patients with cardiovascular diseases: Magnosolv-Granulat (Mg carbonate and Mg oxide), magnerot (Mg orotate), Asparkam-L (K,Mg l-aspartate) and Panangin (K,Mg aspartate). However, the bioavailability of some of these compounds has been shown to be lower than that of Mg chloride and some organic Mg compounds, such as Mg l-aspartate, Mg oxybutirate and Mg N-acetyltaurate [14,15]. This fact suggests that the compounds could provide biological effects of different intensities. ...
... The more hydrated Mg sulphate molecule may chemically interact with paracellular components rather than with cellular components, which could presumably potentiate toxic manifestations while reducing the therapeutic effect [44]. The other studied compounds were organic and demonstrated a high rate of magnesium replenishment in our previous experiments [14,15]. ...
... The present study did not include a treatment group with Mg alone because Mg has to be administered as a salt with an anion such as MgCl 2 or MgSO 4 , and the anions affect the membrane permeation properties of Mg differently [56][57][58][59][60]. nNOS and iNOS are potent sources of NO generation [61], and as NMDA-induced expression of iNOS and eNOS was suppressed to a greater extent in the MgAT treatment group than TAU alone, we observed greater suppression of NO generation in the MgAT-treated group. ...
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Purpose Retinal nitrosative stress associated with altered expression of nitric oxide synthases (NOS) plays an important role in excitotoxic retinal ganglion cell loss in glaucoma. The present study evaluated the effects of magnesium acetyltaurate (MgAT) on changes induced by N-methyl-D-aspartate (NMDA) in the retinal expression of three NOS isoforms, retinal 3-nitrotyrosine (3-NT) levels, and the extent of retinal cell apoptosis in rats. Effects of MgAT with taurine (TAU) alone were compared to understand the benefits of a combined salt of Mg and TAU. Methods Excitotoxic retinal injury was induced with intravitreal injection of NMDA in Sprague-Dawley rats. All treatments were given as pre-, co-, and post-treatment with NMDA. Seven days post-injection, the retinas were processed for measurement of the expression of NOS isoforms using immunostaining and enzyme-linked immunosorbent assay (ELISA), retinal 3-NT content using ELISA, retinal histopathological changes using hematoxylin and eosin (H&E) staining, and retinal cell apoptosis using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. Results As observed on immunohistochemistry, the treatment with NMDA caused a 4.53-fold increase in retinal nNOS expression compared to the PBS-treated rats (p<0.001). Among the MgAT-treated groups, only the pretreatment group showed significantly lower nNOS expression than the NMDA-treated group with a 2.00-fold reduction (p<0.001). Among the TAU-treated groups, the pre- and cotreatment groups showed 1.84- and 1.71-fold reduction in nNOS expression compared to the NMDA-treated group (p<0.001), respectively, but remained higher compared to the PBS-treated group (p<0.01). Similarly, iNOS expression in the NMDA-treated group was significantly greater than that for the PBS-treated group (2.68-fold; p<0.001). All MgAT treatment groups showed significantly lower iNOS expression than the NMDA-treated groups (3.58-, 1.51-, and 1.65-folds, respectively). However, in the MgAT co- and post-treatment groups, iNOS expression was significantly greater than in the PBS-treated group (1.77- and 1.62-folds, respectively). Pretreatment with MgAT caused 1.77-fold lower iNOS expression compared to pretreatment with TAU (p<0.05). In contrast, eNOS expression was 1.63-fold higher in the PBS-treated group than in the NMDA-treated group (p<0.001). Among all treatment groups, only pretreatment with MgAT caused restoration of retinal eNOS expression with a 1.39-fold difference from the NMDA-treated group (p<0.05). eNOS expression in the MgAT pretreatment group was also 1.34-fold higher than in the TAU pretreatment group (p<0.05). The retinal NOS expression as measured with ELISA was in accordance with that estimated with immunohistochemistry. Accordingly, among the MgAT treatment groups, only the pretreated group showed 1.47-fold lower retinal 3-NT than the NMDA-treated group, and the difference was significant (p<0.001). The H&E-stained retinal sections in all treatment groups showed statistically significantly greater numbers of retinal cell nuclei than the NMDA-treated group in the inner retina. However, the ganglion cell layer thickness in the TAU pretreatment group remained 1.23-fold lower than that in the MgAT pretreatment group (p<0.05). In line with this observation, the number of apoptotic cells as observed after TUNEL staining was 1.69-fold higher after pretreatment with TAU compared to pretreatment with MgAT (p<0.01). Conclusions MgAT and TAU, particularly with pretreatment, reduce retinal cell apoptosis by reducing retinal nitrosative stress. Pretreatment with MgAT caused greater improvement in NMDA-induced changes in iNOS and eNOS expression and retinal 3-NT levels than pretreatment with TAU. The greater reduction in retinal nitrosative stress after pretreatment with MgAT was associated with lower retinal cell apoptosis and greater preservation of the ganglion cell layer thickness compared to pretreatment with TAU.
... 49 Hence, addition of TAU to Mg further improves the efficacy of the compound compared to individually administered TAU. We did not include only Mg-treated group because Mg has to be administered as a salt with an anion such as MgCl 2 or MgSO 4 , and different anions differently affect the membrane permeation properties of Mg. [50][51][52][53][54] It is also important to note that pretreatment with both MgAT and TAU resulted in higher efficacy compared to coand posttreatment. Previous studies have also shown that MgSO 4 treatment during hypoxia-ischemia in fetal lambs or after hypoxia-ischemia in newborn piglets does not protect against brain damage. ...
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Purpose: Retinal ganglion cell apoptosis in glaucoma is associated with elevated levels of endothelin-1 (ET1), a potent vasoconstrictor. ET1-induced retinal ischemia leads to altered expression of nitric oxide synthase (NOS) isoforms leading to increased formation of nitric oxide (NO) and retinal nitrosative stress. Since magnesium (Mg) is known to improve endothelial functions and reduce oxidative stress and taurine (TAU) possesses potent antioxidant properties, we investigated the protective effects of magnesium acetyltaurate (MgAT) against ET1-induced nitrosative stress and retinal damage in rats. We also compared the effects of MgAT with that of TAU alone. Methods: Sprague Dawley rats were intravitreally injected with ET1. MgAT/TAU were administered as pre-, co- or post-treatment. Subsequently, expression of NOS isoforms was detected in retina by immunohistochemistry, retinal nitrotyrosine level was estimated using ELISA and retinal cell apoptosis was detected by TUNEL staining. Results: Intravitreal ET1 caused significant increase in the expression of nNOS and iNOS while eNOS expression was significantly reduced compared to vehicle treated group. Administration of both MgAT and TAU restored the altered levels of NOS isoforms expression, reduced retinal nitrosative stress and retinal cell apoptosis. The effect of MgAT, however, was greater than that of TAU alone. Conclusions: MgAT and TAU prevent ET1-induced retinal cell apoptosis by reducing retinal nitrosative stress in Sprague Dawley rats. Addition of TAU to Mg seems to enhance the efficacy of TAU compared to when given alone. Moreover, the pre-treatment with MgAT/TAU showed higher efficacy compared to co- or post-treatment.
... 20 However, magnesium bioavailability depends on the salts used with magnesium chloride the salt with highest bioavailability. 21 Phytate is typically present in urine at between 0.2 to 2 mM. 16 Magnesium is usually present at around 90 mg/l in adults but it is higher (120 to 150 mg/l) in children. ...
Article
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Thesis
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Magnesium deficiency can occur in several diseases. such as malabsorption syndromes, diabetes mellitus and renal disorders. It can be treated with oral magnesium compounds, of which several preparations are currently available: various complex salts, and the oxide or hydroxide of magnesium [1]. In the present study, two formulations of magnesium-L-asparate HCI (Magnesiocard® tablets and Magnesiocard® granules, Verla-Phann, FRG) were compared with magnesium-oxide (Magnetrans® forte capsules, Fresenius, FRG) with respect to bioavailability, tolerability, and stool frequency. The three magnesium preparations were each administered in an open manner to 3 groups of 8 healthy volunteers according to a parallel group design. The groups of 4 males and 4 females each were comparable with regard to age, height and body weight. After a control and a placebo period of one week, 60 mEq/d and 90 mEq/d magnesium were administered for 7 days each. No special diet was given. Cumulative urinary magnesium excretion was used to assess magnesium absorption [2. 3]. Plasma and urine concentrations of magnesium. potassium and calcium were measured by atome emission spectromtryusing a Spectraspan SR (ARL). Urine pH was assessed with indicator strips (Spezialindikator pH 4.0-7.0. Merck. Darmstadt ). Stool frequency was evaluated by the volunteers, recording the time and number of stools. Mouth to caecum transit time was estimated using salazosulfapyridine (SASP) as the test compound [4], measuring SP in saliva by a specific and selective HPLC method [5]. Means and SDs of the parameters were calculated and tested by analysis of variance (ANOVA, randomized factorial design) for differences. 95% confidence intervals were calculated for cumulative urinary magnesium excretion. For statistical analysis of stool frequency, the one criterion variance analysis of Kruskal and Wallis was applied [6]. During the higher magnesium dosage, stool frequency was increased 1.8-fold by magnesium-oxide, 3.2-fold by granules and 2.0-fold by tablets of magnesium-L-aspartate-HCI. The differences between the treatment groups did not reach statistical significance. Mean mouth-caecum transit time of about 4 h was not affected by magnesium treatment, suggesting that the magnesium preparations exerted their laxative effect mainly in the colon. Minor adverse effects were reported in each group, such as flatulence. diarrhoea, and gastric discomfort. There were complaints of an unpleasant taste of the granule formulation, which may influence patients compliance. Urine pH was decreased ( - 0.5) during magnesiumL-aspart ate-HCl and increased ( + 0.5) during magnesium-oxide (P < 0.01) administration, indicating a slight disturbance of the acid/base equilibrium. This aspect may be of clinical importance, particularly in elderly patients with multiple diseases. Calcium and potassium levels in plasma and urine were not altered by magnesium treatment. Plasma magnesium, remained unchanged too. The mean cumulative urinary magensium excretion was similar during the placebo and control periods, ranging from 77.5 to 93 .7 mEq/week. There was a significant increase during magnesium administra tion,more marked during the Mg-L-asparta te-HCl phase (P < 0.0001). The maximum value of 187.4 mEq/week was reached during treatment with magnesium-L-asparateHCI granules 90 mEq/d. The differences between the three treatment groups indicated better absorption of magnesium-L-asparate-HCI than of magnesium-oxide. One possible explanation might be the poor solubility of magnesium-oxide, which in water is 8.6 mg/di [7]. In conclusion, all three formulations of magnesium given in the trial were well tolerated, but they increased the number of stools. Magnesium-oxide showed significantly lower absorption than magnesium L-asparate-HCI. As there were complaints of an unpleasant taste of the resuspended granules, tablets of magnesium-L-aspartateHCI appear to be the first choice for magnesium substitution among the formulations investigated. References 1. Mudge GH, Weiner IM (1990) Agents affecting volume and composition of body fluids. In: Gilman AG, Ra ll TW, Nies AS, Taylor P (eds) The pharmacological basis of therapeutics 8th ed ., Pergamon, New York, pp 682-707 2. Drenick EJ , Hunt IF, Swcndscid ME ( 1969) Magnesium depletion during prolonged fasting of obese males. J Cl in Endocrinol Metab 29: 1341 - 1348 3. Lim P. Jacob E (1972) Magnesium status of alcoholic patients. Metabolism 2 1: 1045- 1051 4. Kennedy M, Chinwah P, Wade DN (1979) A pharmacological method of measuring mouth to caecum transit time in man. Br J Cl in Pharmacol 8: 372- 373 5. Owerbach J . Johnson NF, Bates TR, Pi eniaszek HJ , Jusko WJ ( 1987) High performance liquid chromatographic assay of sulfapyridinc and acetylsulfapyridine in biological fluids. J Pharm Sci 67:250-253 6. Kruskal WH. Wallis WA (I952) Use of ranks in one-criterion variance analysis. J Am Stat Assoc 47: 583-621 7. Weast RC (1975) Handbook of chemistry and physics, 55th ed. Cleveland. CRC Press, B-106
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The present study was undertaken to investigate the effect of dietary magnesium (Mg) deficiency on vitamin B2 (riboflavin) and B6 (pyridoxine) status in rats. We fed Wistar rats an Mg-deficient diet (56 mg magnesium per kg food) for 70 days. On days 21, 35 and 70 we measured Mg and manganese (Mn) in plasma and whole blood, alkaline phosphatase in plasma, erythrocyte glutathione reductase activity coefficient (AC-EGR) for riboflavin status, and erythrocyte aspartase transaminase activity coefficient (AC-EAST) for vitamin B6 status. Intake of the Mg-deficient diet significantly decreased plasma and whole blood levels of Mg and plasma alkaline phosphatase activity on all sampling days. The Mg deficit had no effect on plasma concentrations of Mn, but significantly increased whole blood levels of this element on days 35 and 70. The Mg-deficient diet had no effect on AC-EGR, and thus appeared not to affect riboflavin status. However, AC-EAST was significantly increased on day 70, implying that the animals were at risk for vitamin B6 deficiency. Mg deficiency impairs vitamin B6 status by depleting intracellular Mg and thus inhibits the activity of alkaline phosphatase, a metalloenzyme required for the uptake of pyridoxal phosphate by tissues. Although part of the intraerythrocyte loss of Mg is countervailed by Mn, which can act as a substitute activator of alkaline phosphatase, the degree of compensation is insufficient to fully offset the decrease in activity caused by Mg depletion.
Article
The number of individuals with diabetes is now steadily increasing worldwide. 1 Research over 50 years has demonstrated that abnormal magnesium homeostasis exists in both type 1 and type 2 diabetes. In the 1980s and 1990s, the association between hyperglycemia and magnesium metabolism and the mechanisms of impairment of insulin sensitivity and secretion in magnesium deficiency were vigorously investigated. Later in the 1990s, epidemiological studies including large numbers of subjects established the close association of low dietary magnesium intake with development of type 2 diabetes. It is now of great interest to determine whether research on magnesium can provide new means of preventing diabetes. In this chapter, we review historical to contemporary findings concerning magnesium and diabetes in an attempt to obtain new insights in this field.
Article
The lore of magnesium in medicine, starting as far back as the 17th century up to the first quarter of the 20th century, covers a large span of the chemical and pharmacological fields of knowledge.
Article
Magnesium (Mg) is the fourth most abundant cation in the body. An average adult contains approximately 25g (2000 mEq) of Mg.1,2 Of the body's Mg, the vast majory of this ion is in the intracellular compartment (99%), and the remaining 1% is in the extracellular fluid.3 The principal site of intracellular Mg is bone (60%-65%) where two distinct pools, cortical and trabecular, have been described. It is thought that Mg forms a surface constituent of the hydroxyapatite mineral component. Initially, much of this magnesium is readily exchangeable with serum and therefore represents a moderately accessible magnesium store, which can be drawn on in times of defi ciency. Approximately 25% to 30% is localized within the skeletal muscle, and about 10% to 15% in other non-muscle soft tissues.4,5
Article
Epidemiological data suggest that plentiful magnesium (Mg) supply decreases the risk of cardiovascular and other stress-related diseases. Magnesium-L-aspartate hydrochloride (MAH) contains equimolar amounts of Mg and chloride and hence does not affect the equilibrium of non-metabolizable acids and bases. MAH is safe, main pharmacological actions are mediated via Mg-ions and their Ca2+-antagonistic activity. MAH does not bind gastric hydrochloric acid and does not interfere with the enteral absorption of iron, potassium and calcium under physiological conditions, nor with the cytostatic activity of cisplatin and cyclosporine. "Low utilizers" of oral supplements need higher than standard doses (15 mmol) of MAH, individual doses must be increased up to 30-40 mmol. MAH has been proven to attenuate stress reactions in experimental animals, livestock and in humans. Beneficial effects are proven under numerous clinical conditions, eg., in obstetrics and gynaecology, in pediatry, cardiology, internal medicine and traumatology. Oral therapy can be optimized by observing plasma/serum and urine Mg levels.
Article
Background The aim of this study was to determine the maternal serum concentrations of eNOS, ADMA, and homocysteine in preeclamptic pregnancies. Material/Methods The study was carried out on 62 patients with pregnancy complicated by early onset and 53 patients with late onset preeclampsia. The control group consisted of 65 healthy normotensive pregnant patients. The serum eNOS, ADMA and homocysteine concentrations were determined using ELISA assays. Results Our study revealed elevated levels of homocysteine and ADMA in the serum of women with preeclampsia. The highest levels were observed in patients with early onset preeclampsia, but the differences between both groups of preeclamptic patients with early and late onset of preeclampsia were not statistically significant. Both groups of preeclamptic women had slightly lower levels of maternal serum endothelial nitric oxide synthase than in normotensive pregnant women, but these differences were not statistically significant. Conclusions The higher levels of homocysteine and ADMA observed in patients with early onset preeclampsia may suggest that higher levels of maternal serum homocysteine and ADMA correlate with the severity, and may determine the earlier clinical onset of the disease. The elevated levels of ADMA and the unchanged levels of eNOS in preeclamptic pregnancies suggest that NO deficiency in this pregnancy disorder results not from a reduced level or activity of eNOS, but from elevated levels of ADMA, an endogenous eNOS inhibitor. The lowering of increased levels of homocysteine and ADMA may be helpful in therapy of vascular disturbances occurring in preeclampsia.
Article
Atherosclerotic vascular disease not only remains the leading cause of death in the Western countries, but it has become the most common cause of morbidity and mortality in the low- and middle-income countries as well. Therefore, better understanding of the pathogenesis of atherosclerotic disease and its prevention are of fundamental importance. It is well known that it affects sequentially the aorta followed by coronary, carotid, peripheral, and intracerebral arteries, with some individual variability. The mechanisms of progression are similar in each of the beds, with increasing lipid accumulation in the arterial wall along with macrophages and T-cell infiltration, paucity of smooth-muscle cell proliferation and collagen deposition, and endothelial-cell dysfunction and hypercoagulability playing an important role at the time of acute manifestations of the disease. Fundamental to this inflammatory process is the presence of classic risk factors, regardless of the involved territory. Therefore, the concept of palliative treatment must be reserved for only those who have progressed beyond preventive measures. Mt Sinai J Med 79:641-653, 2012. © 2012 Mount Sinai School of Medicine.
Article
Magnesium is an ubiquitous element and its formulation determines its efficacy and administration. It is used for gastrointestinal and obstetric disease and recently cardiovascular and neurological indications have also been explored. The role of serum/dietary magnesium intake on cardiovascular disease, carotid intima-media thickness (CIMT), hypertension (HTN) and cholesterol synthesis has been investigated. Despite differences in patient populations, some observational and interventional studies have suggested that low serum/dietary magnesium is associated with higher CIMT and more cardiovascular risk factors. A few clinical and basic science interventional studies have also shown the benefits of magnesium administration in cardiovascular disease prevention and as a neuroprotective agent. Low magnesium levels have been implicated in inflammation and endothelial dysfunction. Hypomagnesemia results in increased C-reactive protein and cytokine exaggeration, increased nuclear factor kappa B and platelet dysfunction, which can lead to thrombosis. Magnesium appears to play a vital function in cardiovascular stability and health, but an optimal dose and formulation has not been defined. Potentially promising avenues include the combination of magnesium with a statin to reduce cholesterol, C-reactive protein and CIMT, and its early use to reduce stroke morbidity and mortality. Understanding the role of magnesium in inflammation and mineralization and how it has the potential for playing a role in modulating cardiovascular and neurological disease can be a new frontier in medicine.
Article
Hypomagnesemia is an important but underdiagnosed electrolyte abnormality in critically ill patients. There are many studies to find the prevalence of hypomagnesemia and its effects on mortality and morbidity in these patients. Most of these studies have been carried out in intensive care units caring for patients with medical and surgical conditions and postoperative patients or those in respiratory intensive care unit, or critically ill cancer patients. This study was carried out on patients admitted to the medical acute care unit in a major tertiary care hospital. To study serum magnesium levels in critically ill patients and to correlate serum magnesium levels with patient outcome considering the following parameters: length of stay in MICU, need for ventilatory support, duration of ventilatory support, APACHE score and mortality. To identify the primary medical conditions associated with abnormalities of serum magnesium. To identify the factors predisposing or contributing to hypomagnesemia in critically ill patients admitted in a medical intensive care unit. To detect other electrolyte abnormalities associated with hypomagnesemia, if any. On admission to MICU 52% patients had hypomagnesemia, 7% patients had hypermagnesemia and 41% patients had normomagnesemia. The patients with hypomagnesemia had higher mortality rate (57.7% vs 31.7%), more frequent need for ventilatory support (73% vs 53%), longer duration of mechanical ventilation (4.27 vs 2.15 days), more frequently had sepsis (38% vs 19%), hypocalcemia (69% vs 50%) and hypoalbuminemia (80.76% vs 70.8%). Patients with diabetes mellitus had hypomagnesemia more frequently (27% vs 14%). The duration of stay in the MICU or APACHE score on admission did not vary in patients with low or normal magnesium. There was a high prevalence of hypomagnesemia in the critically ill patients. Hypomagnesemia was associated with a higher mortality rate in critically ill patients. The need for ventilatory support was significantly higher in hypomagnesemic patients. Hypomagnesemic patients required ventilator support for longer duration. Hypomagnesemia was commonly associated with sepsis and diabetes mellitus. The duration of MICU stay and APACHE score on admission did not vary in patients with low magnesium and normal magnesium. Hypomagnesemia is more commonly seen in patients with hypocalcemia and hypoalbuminemia.
Article
Microvascular disease is a major feature of type1 diabetes and results from long-standing structural and functional changes especially in the skin microvasculature. Magnesium (Mg) deficiency has recently been proposed as a novel factor implicated in the pathogenesis of diabetes complications such as vascular disturbance, but its mechanism of action is not completely elucidated. The present study was designed to determine whether chronic magnesium sulfate administration could control streptozocin-induced diabetes and improve endothelium-dependent and endothelium-independent dilatation, and identify its probable mechanism in the skin microvasculature of diabetic rats. Fifty male Wistar rats (220 ± 10 g) were divided into two diabetic and one control groups. One subgroup of diabetic received magnesium sulfate (10 g/l) in their drinking water, while two other groups had only tap water. Laser Doppler flow meter with iontophoresis was used to measure the relative changes in skin blood flow. We used acetylcholine (Ach), sodium nitroprusside (SNP), and N w-nitro-l-arginine (LNNA; NO synthase inhibitor) with magnesium sulfate (0.1 M) in control and experimental animal by microsyringe pump microinjection. SNP- and Ach-induced cutaneous perfusion increased significantly by Mg treatment in the diabetic groups, and local microinjection of magnesium sulfate (0.1 M) increased cutaneous blood flow in all groups (p < 0.01). However, the administration of LNNA prior to magnesium sulfate attenuated (p < 0.05) but not abolished the increase in cutaneous blood flow in diabetic and normal rats. From the results of this study, it may be concluded that Mg could improve skin microvasculature of diabetic rats with potentiation of nitric oxide pathway.
Article
Magnesium (Mg) ions directly influence vascular tone and responsiveness and are cofactors for acetylcholine-induced endothelium-dependent relaxation. Alterations in extracellular Mg are able to modify the formation and release of nitric oxide (NO), altering arterial smooth muscle tone. Previous in vivo studies in humans have shown that parenteral or oral Mg supplementation increase endothelial-dependent vasodilation. The aim of the present study was to evaluate the effects of Mg oral supplementation on endothelial function in elderly diabetic and hypertensive subjects. Sixty elderly (≥ 65 years) diabetic patients were recruited (mean age: 71.1 ± 6.1 years; M/F: 35/25). Endothelial function, evaluated by non-invasive flow-mediated dilatation of the brachial artery, as well as anthropometric and laboratory data, including ionized Mg (Mg-ion), were measured in all patients before and after one-month. Thirty patients underwent oral Mg supplementation with 4.5 g/day of Mg pidolate (368 mg/day of Mg ion), while the rest were used as a control group. The usual management of diabetes and hypertension was not changed during the month of study participation for all the patients. In the group of patients that underwent Mg supplementation, Mg-ion concentration significantly increased from 0.42 ± 0.05 mmol/L to 0.49 ± 0.06 mmol/L; p < 0.05. Mg intervention resulted in a significant improvement of the post-ischemic endothelial-dependent flow-mediated dilation (from 3.3 ± 3.6% to 8.4 ± 3.9%; p < 0.05). No significant differences were found, either in ion-Mg or endothelial function, in the control group. In conclusion, the present study suggests that oral Mg improves endothelial function in diabetic elderly subjects.
Article
Phenotypic modulation of endothelium to a dysfunctional state contributes to the pathogenesis of atherosclerosis, partly through the activation of the transcription factor NFkB. Several data indicate that magnesium deficiency caused by prolonged insufficient intake and/or defects in its homeostasis may be a missing link between diverse cardiovascular risk factors and atherosclerosis. Here we report that endothelial cells cultured in low magnesium rapidly activate NFkB, an event which is prevented by exposure to the anti-oxidant trolox. It is well known that NFkB activation correlates with marked alterations of the cytokine network. In the present study, we show that exposure of endothelial cells to low magnesium increases the secretion of RANTES, interleukin 8 and platelet derived growth factor BB, all important players in atherogenesis. Moreover, we describe the increased secretion of matrix metalloprotease-2 and -9 and of their inhibitor TIMP-2. Interestingly, by zymography we show that metalloprotease activity predominated over the inhibitory effect of TIMP-2. These results indicate that low magnesium promotes endothelial dysfunction by inducing pro-inflammatory and pro-atherogenic events.
Article
To investigated the effect of Polygonum Bistorta L. n-butyl Alcohol (PBNA) extract on the NO content and NOS activity in ischemia/reperfusion (I/R) injury in the rat retina. The model of retinal I/R injury in SD rats was made by reperfusion for 1 h after occlusion of common carotid artery (CCA) for 1 h. The rats were randomly divided into four groups: control group, retinal I/R injury group, low-dosage PBNA treated group and high-dosage treated PBNA group. The control group was injected with 1 ml/kg NS through sublingual vein after CCA was dissociated. Other groups were treated with normal saline or PBNA before occlusion of CCA. After occlusion of CCA for 1 h following reperfusion for 1 h, blood was collected and serum was separated to determine the contents of NO, the activity of T-NOS, iNOS and eNOS. (1) The contents of NO in I/R group showed lower values than in control group (P<0.001) and low-dosage PBNA treated group (P<0.05). (2) The activities of T-NOS in both low-dosage PBNA group and high-dosage group increased, compared with I/R group (P<0.01). (3) The activity of serum iNOS in I/R group increased compared with control group (P<0.05) and low-dosage PBNA treated group evidently (P<0.05). (4) The activity of serum eNOS in I/R group decreased compared with control group (P<0.05), both low-dosage (P<0.05) and high-dosage PBNA (P<0.01) treated group markedly. The date suggest that PBNA have a therapeutic effect on retinal ischemia/reperfusion injury by increasing the activities of T-NOS and eNOS, decreasing the activity of iNOS, elevating the content of NO, enhancing the Anti-oxidation and expanding the blood vessel.
Article
We hypothesized that microparticles (MPs) released after ischemia are endogenous signals leading to postischemic vasculogenesis. MPs from mice ischemic hind-limb muscle were detected by electron microscopy 48 hours after unilateral femoral artery ligation as vesicles of 0.1- to 1-microm diameter. After isolation by sequential centrifugation, flow cytometry analyses showed that the annexin V(+) MP concentration was 3.5-fold higher in ischemic calves than control muscles (1392+/-406 versus 394+/-180 annexin V(+) MPs per 1 mg; P<0.001) and came mainly from endothelial cells (71% of MPs are CD(144+)). MPs isolated from ischemic muscles induced more potent in vitro bone marrow-mononuclear cell (BM-MNC) differentiation into cells with endothelial phenotype than those isolated from control muscles. MPs isolated from atherosclerotic plaques were ineffective, whereas those isolated from apoptotic or interleukin-1beta-activated endothelial cells also promoted BM-MNC differentiation. Interestingly, MPs from ischemic muscles produced more reactive oxygen species and expressed significantly higher levels of NADPH oxidase p47 (6-fold; P<0.05) and p67 subunits (16-fold; P<0.001) than controls, whereas gp91 subunit expression was unchanged. BM-MNC differentiation was reduced by 2-fold with MPs isolated from gp91-deficient animals compared with wild-type mice (P<0.05). MP effects on postischemic revascularization were then examined in an ischemic hind-limb model. MPs isolated from ischemic muscles were injected into ischemic legs in parallel with venous injection of BM-MNCs. MPs increased the proangiogenic effect of BM-MNC transplantation, and this effect was blunted by gp91 deficiency. In parallel, BM-MNC proangiogenic potential also was reduced in ABCA1 knockout mice with impaired vesiculation. MPs produced during tissue ischemia stimulate progenitor cell differentiation and subsequently promote postnatal neovascularization.
Article
In this review we consider the effects of endogenous and pharmacological levels of nitrite under conditions of hypoxia. In humans, the nitrite anion has long been considered as metastable intermediate in the oxidation of nitric oxide radicals to the stable metabolite nitrate. This oxidation cascade was thought to be irreversible under physiological conditions. However, a growing body of experimental observations attests that the presence of endogenous nitrite regulates a number of signaling events along the physiological and pathophysiological oxygen gradient. Hypoxic signaling events include vasodilation, modulation of mitochondrial respiration, and cytoprotection following ischemic insult. These phenomena are attributed to the reduction of nitrite anions to nitric oxide if local oxygen levels in tissues decrease. Recent research identified a growing list of enzymatic and nonenzymatic pathways for this endogenous reduction of nitrite. Additional direct signaling events not involving free nitric oxide are proposed. We here discuss the mechanisms and properties of these various pathways and the role played by the local concentration of free oxygen in the affected tissue.
Article
We studied the arrhythmogenic threshold of the myocardium after injection of CaCl2 to magnesium-deficient rats receiving Mg2+ L-aspartate, MgCl2, their combination with vitamin B6, and reference preparations Magne B6 and MgSO4 until complete compensation of magnesium level in the plasma and erythrocytes. Magnesium-deficient diet and deionized water were used for inducing alimentary Mg2+ deficiency and modeling pathological changes in rats. After reducing Mg2+ level to 0.7 mmol/liter in the plasma and to 1.5 mmol/liter in erythrocytes, Mg L-aspartate, MgCl2, their combination with vitamin B6, as well as Mg2+ deficiency led to a decrease in the dose of CaCl2 provoking heart rhythm disturbances in 50% animals and shortening of animal life span. Administration of the test magnesium salts increased the arrhythmogenic threshold; Mg2+ salts were comparable by their efficiency with Magne B6 and were far superior to MgSO4.
Article
Inadequate magnesium intake and hypomagnesemia may contribute to chronic diseases, such as hypertension. The novel magnesium transporter TRPM7 is a critical regulator of magnesium homeostasis in vascular cells, but its role in pathophysiology is unclear. In a model of hypomagnesemia, we examined microvascular structure and function, TRPM7 expression, and vascular inflammatory status using inbred mice selected for normal-high intracellular magnesium levels or low intracellular magnesium levels (MgLs). Blood pressure was significantly increased in MgLs compared with normal-high intracellular magnesium levels. Pressurized myography of mesenteric resistance arteries showed that MgLs had significantly impaired endothelial function together with decreased plasma nitrate levels and endothelial NO synthase expression when compared with normal-high intracellular magnesium levels. Significant differences in vascular structure were also evident in both mesenteric arteries and aortas from MgLs. Aortas from MgLs had increased medial cross-sectional areas, whereas mesenteric arteries from MgLs had increased lumen diameters with increased medial cross-sectional areas, indicating outward hypertrophic remodeling. Expression of the magnesium transporter TRPM7 was significantly elevated in the vasculature of MgLs, whereas expression of a TRPM7 downstream target, the anti-inflammatory molecule annexin-1, was reduced. MgLs had increased expression of vascular cell adhesion molecule-1 and plasminogen activator inhibitor-1, indicating vascular inflammation. Taken together, these data demonstrate that the inherited magnesium status of MgLs and normal-high intracellular magnesium levels mice affects magnesium transporter expression, endothelial function, vascular structure, and inflammation. Our findings suggest a potential regulatory role for TRPM7 signaling in the maintenance of vascular integrity. Alterations in magnesium status and/or TRPM7 signaling may contribute to vascular injury in conditions associated with hypomagnesemia.
Article
1. Eighty-one hospital patients receiving digoxin were separated into groups with and without digoxin toxicity using clinical criteria. Serum digoxin, sodium, potassium, calcium, creatinine, magnesium and monocyte magnesium concentrations were compared. 2. Subjects with digoxin toxicity had impaired colour vision (P less than 0.0001, Farnsworth-Munsell 100 hue test) and increased digoxin levels (1.89 (1.56-2.21) vs 1.34 (1.20-1.47) nmol l-1, P less than 0.01) (mean (95% confidence limits], though there was considerable overlap between two groups. 3. Subjects with digoxin toxicity had lower levels of serum magnesium (0.80 (0.76-0.84) vs 0.88 (0.85-0.91) mmol l-1, P less than 0.01) and monocyte magnesium (6.40 (5.65-7.16) vs 8.76 (7.81-9.71) mg g-1 DNA, P less than 0.01), but there were no significant differences in other biochemical parameters. A greater proportion of toxic subjects were receiving concomitant diuretic therapy (20/21 vs 37/60, P less than 0.05). 4. Magnesium deficiency was the most frequently identified significant electrolyte disturbance in relation to digoxin toxicity. In the presence of magnesium deficiency digoxin toxicity developed at relatively low serum digoxin concentrations.
Article
Vitamin B-6 and magnesium appear to interact in vivo and it has been suggested that vitamin B-6 may enhance transport or accumulation of magnesium in cells. The purpose of this study was to evaluate the possibility of the formation of B-6 vitamer-Mg complexes in vitro using spectrophotometric analysis of ultraviolet or visible spectra or change in fluorescence intensity of B-6 vitamers. Pyridoxal phosphate but not pyridoxal appears to form a complex with Mg as evidenced by a change in the ultraviolet and visible spectra with an increase in absorption and spectral shift in the visible maxima from 389 to 388 nm and a decrease in the ultraviolet absorption maxima at 296 nm. Addition of Mg to pyridoxal phosphate but not the other B-6 vitamers enhanced the fluorescent intensity of pyridoxal phosphate at least threefold and evoked a spectral shift in both the fluorescence excitation and emission maximum. Electrochemical titration of pyridoxal phosphate in the presence of Mg affects the pKa- of the phenolic hydroxyl and the secondary phosphate ionization. These data collectively indicate that pyridoxal phosphate, but not pyridoxal, appears to form a coordinated complex with Mg and the coordination site is likely to be related to the primary phosphate and aldehyde moiety of pyridoxal phosphate.
Article
Seven patients (3 females, 4 males) developed symptomatic hypomagnesemia, hypocalcemia, and hypokalemia following gentamicin therapy. The excessive and inappropriate urinary excretion of magnesium and potassium in the presence of subnormal serum concentrations was noted. A significant correlation was found between the total cumulative dose of gentamicin and serum Mg concentration (r = 0.76, p less than 0.05), as well as between the renal wasting of Mg and the total cumulative dose of gentamicin administered (r = 0.89, p less than 0.01). The gentamicin-induced Mg depletion is a very rare but important complication which is most likely to occur when the drug is given to older patients in large doses over extended periods of time.
Article
This study compared magnesium oxide and magnesium citrate with respect to in vitro solubility and in vivo gastrointestinal absorbability. The solubility of 25 mmol magnesium citrate and magnesium oxide was examined in vitro in solutions containing varying amounts of hydrochloric acid (0-24.2 mEq) in 300 ml distilled water intended to mimic achlorhydric to peak acid secretory states. Magnesium oxide was virtually insoluble in water and only 43% soluble in simulated peak acid secretion (24.2 mEq hydrochloric acid/300 ml). Magnesium citrate had high solubility even in water (55%) and was substantially more soluble than magnesium oxide in all states of acid secretion. Reprecipitation of magnesium citrate and magnesium oxide did not occur when the filtrates from the solubility studies were titrated to pH 6 and 7 to stimulate pancreatic bicarbonate secretion. Approximately 65% of magnesium citrate was complexed as soluble magnesium citrate, whereas magnesium complexation was not present in the magnesium oxide system. Magnesium absorption from the two magnesium salts was measured in vivo in normal volunteers by assessing the rise in urinary magnesium following oral magnesium load. The increment in urinary magnesium following magnesium citrate load (25 mmol) was significantly higher than that obtained from magnesium oxide load (during 4 hours post-load, 0.22 vs 0.006 mg/mg creatinine, p less than 0.05; during second 2 hours post-load, 0.035 vs 0.008 mg/mg creatinine, p less than 0.05). Thus, magnesium citrate was more soluble and bioavailable than magnesium oxide.
Article
Magnesium is an essential cofactor for the synthesis and salvage of purine and pyrimidine nucleotides. It plays important roles in the structure of nucleic acids and affects their interaction with proteins and other ligands. Magnesium is required for DNA replication, transcription into RNA and translation into protein. In spite of the diverse roles of magnesium in these fundamental processes, metabolic regulation by magnesium has not been observed. Its role in the regulation of cell growth, division and differentiation remains uncertain.
Article
The physiological role of D-amino acid oxidase was investigated by using mutant ddY/DAO- mice lacking the enzyme. Free D-amino acid concentrations in the mutant mice were significantly higher than those of control ddY/DAO+ mice in kidney, liver, lung, heart, brain, erythrocytes, serum and urine. The results suggest that the enzyme is involved in the catabolism of free D-amino acids in the body, and that free D-amino acids are also excreted into urine.
Article
Tissues from female Fisher rats fed varying levels of magnesium (100 ppm or 700 ppm) and pyridoxine hydrochloride (PN.HCl) (7, 35, or 1500 mg/kg diet for six weeks) were dry ashed and analyzed for magnesium using atomic absorption spectroscopy. In tissues from rats consuming magnesium diets, tissue magnesium levels increased as levels of dietary PN.HCl increased. Increases in plasma, liver, kidney, and brain magnesium levels were statistically significant (p less than 0.05). With the exception of liver, no statistically significant changes in tissue magnesium levels occurred with PN.HCl supplementation in rats fed diets with adequate magnesium. Dietary supplementation with PN.HCl produces alterations in tissue magnesium levels in the rat and these alterations are modulated by dietary magnesium and PN.HCl supplementation.
Article
The influence of different magnesium salts (i.e., MgCl2, MgSO4, Mg aspartate HCl and Mg acetate) on reactivity of rat mesenteric arterioles (10-25 micron I.D.) and venules (15-30 micron I.D.) to standard constrictor doses of epinephrine and BaCl2 was examined utilizing perivascular, i.a. and i.v. administration of each Mg salt. Perivascular application (0.1, 1.0 and 10 mumol) of the four Mg salts on the microvessels attenuated the vasoconstrictor actions of both epinephrine and BaCl2, dose-dependently. With respect to arterioles, the vasoconstriction induced by BaCl2 was inhibited more potently by each Mg salt than that induced by epinephrine; the reverse was observed with respect to the venules. MgCl2 displayed the most potent antagonism to the constriction induced by BaCl2 in arterioles as well as by epinephrine in venules. Infusion of each Mg salt in very low doses (e.g., 0.1 mumol/min i.a.) resulted in significant attenuation of the arteriolar constrictions induced by both stimulants. However, the difference in the degree of attenuation on i.a. infusion of each Mg salt was significantly less than that observed by perivascular pretreatment. Arteriolar constrictions induced by epinephrine and BaCl2 were also attenuated by systemic i.v. infusion of each Mg salt, except for MgSO4, when low doses (e.g., 0.1 and 1.0 mumol/min.) were given; surprisingly, high dose i.v. infusion (10 and 20 mumol/min) often potentiated arteriolar constrictions induced by both stimulants, but the magnitude of this potentiation depended on the Mg salt utilized.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
The effect of amphotericin B on magnesium metabolism was studied in 10 patients (aged 30 to 68 years) with systemic fungal infections. Renal magnesium wasting resulting in mild to moderate hypomagnesemia was demonstrated by the second week of therapy following relatively small cumulative dosages of amphotericin B (208 +/- 40 mg). The lowest serum levels and largest fractional excretions of magnesium were observed by the fourth week of therapy after cumulative dosages of 510 +/- 118 mg. A plateauing of the renal magnesium wasting is suggested, as there were no further increases or reductions in fractional magnesium excretion and serum magnesium level, respectively, despite continued amphotericin B administration. Reversibility of the magnesium wasting is indicated by data in three of the patients approximately one year following discontinuation of amphotericin B therapy, in whom the serum magnesium level and fractional magnesium excretion had returned to pretreatment baseline values. Although the available data do not allow precise localization of this defect, increased urinary excretion of magnesium despite its reduced filtered load suggests a tubular defect in magnesium reabsorption. Therefore, routine monitoring of the serum magnesium level during treatment with amphotericin B is recommended.
Article
Magnesium has been shown to produce various effects on vascular smooth muscle, in that its absence elicits an increase in muscle tone and increases sensitivity to a number of stimulatory agonists. In the present study, the influence of MgCl2 and MgSO4 was investigated in human placental chorionic muscle cells (from arteries and veins with or without endothelium), especially on the membrane potential, Um. Classically, Um was obtained from microelectrodes inserted into smooth muscle cells through the endothelium or directly. In arteries with endothelium, the smooth muscle cells were depolarized by MgSO4 (threshold: 6 mM) and MgCl2 (threshold: 8 mM). In endothelium-free arteries, the smooth muscle cells were also depolarized by MgSO4 (threshold: 8 mM) and MgCl2 (threshold: 6 mM). Identical results were obtained with veins, but thresholds were different. The different thresholds may indicate that MgCl2 influences the cell membrane potential directly, while MgSO4 interferes first with the endothelial cells, which may act as an intermediary between the Mg2+ ions and the membrane of the smooth muscle cells.
Article
The objective of this study was to determine whether nitric oxide (NO) could function as a negative feedback modulator of endothelial cell function by inhibiting NO synthase in vascular endothelial cells. The rationale for this approach was a previous study from this laboratory, which revealed that NO inhibits neuronal NO synthase from rat cerebellum. In the present study, NO and NO-donor agents noncompetitively inhibited NO synthase derived from bovine aortic endothelial cells. Oxyhemoglobin blocked the inhibitory action of NO and by itself increased NO synthase activity. This finding suggests that NO acts as a negative feedback modulator of NO synthase. In intact aortic endothelial cells grown on microcarrier beads and perfused in a bioassay cascade system, pretreatment of cells with NO-donor agents caused a marked inhibition of endothelial NO biosynthesis in response to bradykinin and increased fluid shear or flow. When isolated bovine pulmonary arterial rings precontracted by phenylephrine were used, pretreatment of arterial rings with NO-donor agents diminished endothelium-dependent arterial relaxation involving the L-arginine-NO pathway without altering endothelium-independent relaxation to NO itself. On the basis of these studies, NO is suggested to play an important negative feedback regulatory role on endothelial NO synthase and, therefore, vascular endothelial cell function.
Article
The bioavailability was studied of three magnesium preparations-Asmag, Slow-Mag and magnesium oxide (wafer)-administered to healthy volunteers for two weeks. The observed increase of magnesium level in the serum was not statistically significant.
Article
The effects of MgCl2 and MgSO4 are different on the total transfer through the human amniotic membrane: MgCl2 at low concentration (1 mM) decreases the total conductance Gt and increases it at high concentration (4 mM) on the fetal side (FS) and on the maternal side (MS), while MgSO4 has no effect on the MS and increases Gt on the FS. Moreover, whatever the concentration, MgCl2 increases the flux ration F1/F2 while MgSO4 decreases it to reach a value near to 1. Gt is the sum of various components: three paracellular components (Gp) and nine cellular components (Gc constituted from channels, exchangers, antiporters and cotransporters). All components of Gt, on the two faces, are decreased by 1 mM MgCl2 and increased at 4 mM. MgCl2 also has an effect on all ionic exchangers across the membrane. In contrast, on the MS, MgSO4 (1 mM) decreases GpNa, increases GpK and the antiport Na/H component and has no effect on any of the other components, while at 4 mM, MgSO4 has no effect. On the FS, MgSO4 (1 mM) increases GpNa and GpK, but does not modify the other components. At 4 mM, the effect is the same, except for an increase of GpCl. These data show the importance of the anion-cation association in the ionic exchanges through a membrane: MgCl2 and MgSO4 have a different action--MgCl2 interacts with all the exchangers, while the effect of MgSO4 is limited to paracellular components without interaction with cellular components excepted the antiport Na/H.
Article
The aim of our study was to describe the possible pathophysiologic mechanisms of hypomagnesemia in alcoholic patients. A total of 127 chronic alcoholic patients admitted to our university hospital for causes related to alcohol abuse were studied. Hypomagnesemia was the most common electrolyte disturbance observed in 38 patients (29.9%). In 18 of them inappropriate magnesiuria was evident, possibly due to hypophosphatemia, to metabolic acidosis or to a direct magnesiuric effect of acute alcohol consumption. The causes of hypomagnesemia in the remaining 20 patients were alcohol withdrawal syndrome and diarrhea. Respiratory alkalosis was evident in 10 hypomagnesemic patients and could have played a role in the development of hypomagnesemia. A decreased magnesium intake could also have contributed to the hypomagnesemia, especially in malnourished alcoholic patients. Hypomagnesemic patients more frequently had other acid-base and electrolyte abnormalities, such as hypophosphatemia, hypokalemia, hypocalcemia, and respiratory alkalosis, as compared with the normomagnesemic patients. Moreover, in hypomagnesemic patients serum magnesium levels were correlated with the indices of potassium and phosphorus excretion, suggesting that serum magnesium levels play a central role in the homeostasis of the other electrolytes. In conclusion, hypomagnesemia is the most common electrolyte abnormality observed in alcoholic patients, as a result of various pathophysiologic mechanisms.
Article
Magnesium salts have been shown to depolarize the membrane of the smooth muscle cells of human placental arteries and veins with and without endothelial cells. In the present study, the influence of MgCl2 and MgSO4 was investigated on the membrane potential, Um, of the endothelial cells of the same vessels. Um was classically recorded with microelectrodes. The endothelial cell membrane of arteries was depolarized by MgCl2 (depolarization threshold, d th: 4 mM) and by MgSO4 (d th: 8 mM). A depolarization was also observed with the endothelial cell membrane of veins. The depolarization threshold with MgCl2 and 4MgSO4 was respectively 6 mM and 8 mM. The different thresholds indicate that the influence of MgCl2 on the endothelial cell membrane potential is higher and more direct than that of MgSO4, and confirm previous hypothesis on the effects of magnesium salts on the vascular smooth membrane cells.
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Using Western blot and fluorescent immunocytochemistry, NOS III (or ecNOS) and NOS II (or iNOS), but no NOS I (or ncNOS), were identified in preparations of human platelets. Reverse-transcription polymerase chain reactions (RT-PCR) demonstrated NOS III mRNA, but no NOS II mRNA (which is short-lived) and no NOS I mRNA in platelets. Immunofluorescent staining of human bone marrow smears showed the presence of NOS III, but not NOS I in megakaryocytes. A subpopulation of megakaryocytes also expressed NOS II. In preparations of human neutrophils, immunocytochemistry demonstrated NOS I in all cells, whereas no NOS III was detected. The few NOS II positive cells were characterized as contaminating eosinophils. Similarly, in RT-PCR, transcripts for NOS I and NOS II, but not for NOS III, were identified. Thus, the constitutive NOS isoform in megakaryocytes and platelets is NOS III, whereas neutrophils express NOS I. Some megakaryocytes and eosinophils also express NOS II.
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This paper reports an electrophysiological study on the antiarrhythmic and proarrhythmic actions of magnesium chloride and magnesium sulphate intravenous infusions. Magnesium kinetics in control dogs, following a pulse of magnesium chloride or magnesium sulphate, was not affected by the accompanying anion. The experiments were performed with mongrel dogs divided into three groups fed either a normal diet (group I), a low magnesium diet plus chlortalidone treatment and potassium supplementation (group IIA) or a low magnesium diet plus chlortalidone treatment and magnesium sulphate infusion (group II B). In group I, infusion of magnesium sulphate solution decreased plasma sodium, potassium and ventricular fibrillation threshold (VFT), prolonged the ventricular effective refractory period (VERP) and increased the urinary excretion of potassium. The infusion of magnesium chloride solution did not affect VFT, prolonged VERP, QTc, AH and PQ. In this group, sodium chloride or sulphate infusion did not affect the electrophysiological variables but sodium sulphate decreased plasma potassium levels. The group II A was characterized by the decreased levels of potassium and magnesium contents of plasma, lymphocytes and myocardium, decreased VERP and VFT and prolonged QTc. The intravenous infusion of magnesium sulphate solution depressed further VFT and plasma potassium and increased VERP. The acute infusion of potassium chloride solution increased plasma potassium and VFT. In group II B, plasma electrolyte levels and electrophysiological variables were not affected. We conclude that the clinically demonstrable, antiarrhythmic effect of magnesium infusion can be attributed to prolonged VERP. Magnesium sulphate infusion, however, produced potassium depletion and decreased VFT (a pro-arrhythmic effect). These adverse effects can be avoided infusing magnesium chloride solutions.
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A refined method of repeated blood sampling is described: the tongue of the anaesthetized rat is pulled forward with the fingers and the sublingual vein is punctured with a 23 gauge hypodermic needle. Based on the requirement of a pharmacokinetic study, 0.5 or 1 ml of blood was collected 7 times at 0, 0.5, 1, 2, 4, 8 and 24 h. The degree of suffering was judged by determining the body weight and food and water consumption. All animals showed an increase in body weight already after 24 h and, therefore, the method of collecting blood from the sublingual vein can be recommended for repeated blood sampling. The haematological evaluation of groups of animals with differing body weight showed that sample volumes of up to 15% of the total blood volume lead to haematocrit values of approximately 40%. A remarkable initial drop in white blood cell counts followed by a marked rise 2 h after first sampling to values partly above the pre-test could not be directly related to the extracted blood volume.