Persistent antihypertensive effect of oral nitrite supplied up to one year via the drinking water in spontaneously hypertensive rats.

The hypothesis was studied whether the chronic administration of nitrite lowers the blood pressure of spontaneously hypertensive rats (SHR) and prevents secondary hypertension-induced organ lesions. For this purpose totally 96 SHR received 50 to 75 mmol/l NaNO2 or equimolar amounts of NaHCO3 in their drinking water during 4, 8 or 12 months. At each point of time arterial blood pressure, determined with the tail cuff method, was significantly lower in the NaNO2-group in comparison to the controls indicating that no significant tolerance towards nitrite had developed. There was also a tendency towards reduced cardiac hypertrophy and renal atrophy in the NaNO2-group, however without reaching the level of significance. Drinking water containing 75 mmol NaNO2/l was not well tolerated by young rats in contrast to 50 mmol/l. Possible beneficial effects of high dietary nitrate/nitrite levels are discussed with respect to the low frequency of hypertension observed in vegetarians.

The role of magnesium in the generation and therapy of benign muscle cramps. Combined in-vivo/in-vitro studies on rat phrenic nerve-diaphragm preparations.

Rats received during 3 weeks a Mg-deficient or a Mg-rich diet; Mg-deficient animals revealed hypomagnesemia, cellular K-depletion and Ca-loading. Phrenic nerve-diaphragm preparations were studied; the physiological Tyrode solution contained low or high-Mg concentrations and 0 or 12 mmol lactate/L. Electric stimulation (indirect via the nerve or direct) produced tetanic contractions and increased force at increasing stimulation frequencies. Significantly lower frequencies were needed to elicit these effects when intra- and extracellular Mg levels were low, in comparison to plentiful Mg supply. Comparing unstimulated and stimulated diaphragmatic tissue electrolyte concentrations revealed tissue losses of Mg, K Ca from stimulated tissues which were less pronounced when Mg supply was optimal. These data support the empiric finding that relief from muscle cramps is promptly offered by Mg supplements.

Therapeutic availability of iron administered orally as the ferrous gluconate together with magnesium-L-aspartate hydrochloride.

Since in vitro experiments had excluded interactions between Fe-gluconate (Fe-gluc) and magnesium-L-aspartate hydrochloride (MAH) in aqueous solutions the present in vivo studies seemed to be justified. Animal studies: Rats were kept on magnesium-(Mg)- and iron-(Fe)- sufficient and deficient diets. The intragastral administration of Fe-gluc significantly increased plasma Fe after 3 h, either given alone, or in combination with MAH (inducing hypermagnesemia). Same results were obtained when fortified diets were offered to Fe/Mg-deficient animals. Human studies: The combination of Fe-gluc (2 x 50 mg Fe per day, per os) plus MAH (2 x 7.5 mmol Mg per day, p.o.) was well tolerated by healthy volunteers. Single dose experiments revealed that Fe-gluc alone and in combination with MAH increased plasma Fe levels during 3 h to the same extent. Two groups of pregnant women with moderately reduced hemoglobin levels either received Fe-gluc (out-patients) or its combination with MAH (at least temporarily hospitalised because of preterm labor). Treatments were well tolerated. Hemoglobin levels did not further decrease, as expected without Fe supplements, during the course of pregnancy, thus indicating the therapeutic availability of the electrolytes in both study groups. Progesterone-induced constipation is frequently observed during pregnancy; hence stool softening reported by 50% of the women receiving Fe-gluc plus MAH (versus 33% in the Fe-gluc group) can be regarded as desirable effect. It is concluded that MAH does not interfere with the enteral absorption of Fe-gluc when both electrolytes are orally administered together. Taking both electrolytes together instead of 2 to 3 h apart from each other, as actually recommended, means a less complicated dosage regimen and probably improves compliance.

Magnesium metabolism: basic aspects and implications of ciclosporine toxicity in rats.

In rapidly growing male Sprague-Dawley rats with an initial body weight of 100 +/- 10 g, we investigated how alimentary magnesium (Mg) supply, Mg metabolism and ciclosporine (Ci)-associated nephrotoxicity are interrelated. Food with 100 ppm Mg (1Mg) or 1,000 ppm Mg (stMg) or 10,000 ppm Mg (rMg), Ci 20 mg/kg body weight daily or olive oil were applied for 3 months (n = 10/group). Mg concentrations in various compartments were measured by atomic absorption spectrophotometry. Creatinine clearance (Jaffe), urinary N-acetyl-beta-D-glucosaminidase (NAG) activity (fluorometrically), urinary sodium excretion (flame photometry) and osmolality were measured. Histomorphological examination was done and renal renin expression was studied by monoclonal antibodies. Ci reduced the Mg concentration of the femur under 1Mg (72.6 +/- 9.7 vs. 112.6 +/- 14.3 mmol/kg dry substance, p < 0.05) and under stMg (150.6 +/- 16.6 vs. 194.1 +/- 10.2 mmol/kg dry substance, p < 0.05), thus indicating Ci-related Mg deficiency. This was due to a significant increase in Mg excretion in Ci treatment compared to dietary controls. Under rMg, there was no difference between Ci-treated and control animals. Ci treatment lowered creatinine clearance in 1Mg (1.42 +/- 0.05 vs. 3.02 +/- 0.58 ml/min) and in stMg (1.04 +/- 0.45 vs. 2.18 +/- 0.51 ml/min), NAG/creatinine and urinary sodium excretion were negatively affected by Ci under 1Mg and stMg. Histomorphology showed macrocalcifications due to Mg deficiency and Ci-specific findings, which were markedly enhanced in 1Mg and stMg. Animals with plentiful Mg supply had no functional alterations due to Ci and no or weakly expressed histomorphological lesions. Renin-positive stained cells were higher in Ci-treated animals. This seems to be functionally relevant under 1Mg and stMg, since it was associated with sodium retention and elevated relative heart weight, indicating hypertension. Alimentary or drug-induced Mg deficiency plays a relevant role in the pathophysiology of chronic Ci nephrotoxicity. Our data suggest that Mg supplementation is helpful to reduce Ci toxicity, even if there is 'normal' alimentary Mg intake.

Different effects of three high-dose oral calcium salts on acid-base metabolism, plasma electrolytes and urine parameters of rats.

The oral calcium (Ca) load test has been applied to estimate the enteral absorbability of Ca salts in humans; provided that the deep bone compartments are filled up, excess Ca should be excreted in the urine. Using this "overflow model" three Ca salts were tested in rats at increasing oral doses of 0 to 14 mmol/kg body weight: CaCO3 and two other compounds containing chloride at a Ca:Cl ratio of 1:2 (CaCl2) and 1:1 (Ca-aspartate-hydrochloride). The carbonate was poorly absorbed and hence did not significantly affect acid-base metabolism nor urine pH. Both chloride-containing salts increased Ca excretion to a significantly higher degree in a dose-dependent manner; in contrast to the organic compound, the CaCl2 induced metabolic acidosis at 14 mmol/kg body weight. At decreasing base excess and urinary pH, renal excretion of Ca and of magnesium (Mg) increased, indicating that acid-base alterations must be considered when evaluating the oral load test. All Ca salts induced moderate hypomagnesemia pointing to decreased enteral absorbability of food-borne Mg in rats. Studies on volunteers reported in the literature suggest, however, that this effect is not relevant for humans.

Potentiation of magnesium-deficiency-induced foetotoxicity by concomitant iron deficiency and its prevention by adequate supply via drinking water.

Magnesium (Mg) and iron (Fe) deficiency frequently develop during pregnancy. Therefore these factors were studied alone (Mg-L, resp. Fe-L) or in combination (Mg-L/Fe-L) on 16 female and 8 male adult fertile Sprague-Dawley rats. The animals were offered a basal diet containing 30 per cent and 17 per cent of the rat's requirement for magnesium and iron, respectively, starting 21 days before mating (2:1) until 49 days after mating. Offspring were also kept on this regimen during a 3-week lactation period and 7 days post weaning. Drinking water was either enriched with 101 ppm Fe2+ (ferrous gluconate): Mg-L, or 365 ppm magnesium (magnesium-L-aspartate hydrochloride trihydrate, MAH): Fe-L, or with any: Mg-L/Fe-L or with both electrolytes: Controls. Fertility remained unaffected under these conditions. Clinically, Fe-L induced iron deficiency and growth retardation of offspring. Pronounced reproductive toxicity was elicited by Mg-L and was even potentiated by Mg-L/Fe-L. In the parental generation, too, adverse effects of Mg-L were aggravated by Mg-L/Fe-L despite the fact that no iron accumulation occurred. Bioavailability of iron was not impaired by magnesium as MAH. With respect to human pregnancy magnesium supplementation has higher priority over iron supplements. To improve tolerance and compliance both minerals are suggested to be taken simultaneously.

Erythema formation in magnesium-deficient albino rats. A non-invasive model for the screening of anti-inflammatory agents and oral mineral supplements.

The enteral bioavailability of magnesium firmly bound to a fire-proof, inert SiO2-Al2O3 matrix (ground magnesia boats) was studied in magnesium-deficient albino Sprague-Dawley rats, with and without blocking gastric hydrochloric acid secretion with omeprazole. Magnesium was absorbed, although to a small degree, also at anacidity. Pronounced erythema, developing after only some days in hypomagnesemic hypercalcemic rats, are proposed as a non-invasive model for the screening of antiinflammatory substances. Using this model significant protective effects were proven for cromoglycate, polyenthylene glycol 400, and omeprazole; the latter, however, seems more likely to act via a magnesium-sparing mechanism.

Nephrocalcinosis without functional renal impairment in rats subjected to subacute moderate magnesium deficiency, and intervention studies on the mobilization of calcium deposits.

Female Sprague-Dawley rats (100-120 g) were kept for 12 d on diets containing 250, 1500, or 9000 ppm Mg. Then subgroups were loaded with water, frusemide or magnesium and urine was collected over 6 h. Moderately Mg-deficient diet (250 ppm) induced moderate hypomagnesaemia (62.3% of controls), but did not result in hypercalcaemia or the formation of typical erythema. Nevertheless, pronounced nephrocalcinosis developed, as shown by increased renal wet and dry weight and elevated tissue concentrations of Ca, P and Mg, the calculous deposits probably consisting to a large extent of Ca3 (PO4)2. Despite these alterations, renal function remained unimpaired in Mg-deficient rats, as shown by normal urinary creatinine excretion and the unaffected ability of the kidneys to concentrate urine. Loading with water, frusemide or Mg increased urinary excretion of calcium in all three diet groups to a similar extent; hence no significant proof can be given that calculous deposits are mobilized under these conditions. Since comparable conditions may also be present under clinical conditions in man, special care should be given to maintain optimal Mg balance.

[The clinical importance of magnesium. 2. The indications for supplementation and therapy]. / Die klinische Bedeutung von Magnesium. Teil 2: Indikationen zur Supplementation und Therapie.

Mg deficiency is characterized by diverse secondary electrolyte alterations. Extracellularly, hypocalcemia is a particular feature, which may be explained by increased resistance of bone towards parathormone. Intracellularly, decreased concentrations of Mg and K and increased amounts of Na and Ca are found in contractile organelles. At increased Mg levels, concentration of parathormone may decrease, leading to hypocalcemia. Calcium-antagonistic effects are observed in smooth muscle, the myocardium and the end-plate of skeletal muscles. Hence, Mg may be prescribed either to correct a deficit or to utilize its pharmacologic effects. Dosaging still needs to be optimized.

Magnesium in pregnant women and the newborn.

In this article the importance of Mg for pregnant women and fetal outcome is reviewed. The physiological changes of Mg-containing body fluids and of tissues are discussed. Mg supplementation during pregnancy seems to be necessary and the efficacy on maternal health and on the newborn are reported. Serum Mg levels decrease during pregnancy and there is a 25% increase of renal Mg excretion. Mg supplementation has a positive effect, with reduced incidence of hospital admission and preterm labour, while the gestational age of the fetus is longer. Convulsions may occur in newborns with hypomagnesaemia. Hypermagnesaemia of the newborn following MgSO4 infusions to toxaemic mothers has been reported.

Prevention of stress-induced damage in experimental animals and livestock by monomagnesium-L-aspartate hydrochloride.

Monomagnesium-L-aspartate hydrochloride (Mg-Asp. HCl) is readily absorbed from the intestine of rats because this process is not saturable. Depending upon the dose administered, Mg-Asp. HCl exhibits Ca-antagonistic effects and inhibits the release of stress hormones. Higher concentrations of Mg salts, which do not contain chloride, e.g. MgO, tend to induce hypochloremic, metabolic alkalosis and changes of urinary pH, whereas MgCl2 produces hyperchloremic acidosis under these conditions. Evidence is given that oral supplementation with Mg-Asp. HCl has beneficial effects not only in experimental animals or livestock, but also in man, e.g. on exposure to muscular stress.

Systemic stress, magnesium status and cardiovascular damage.

Evidence is given that cardiovascular damage due to systemic stress is potentiated by a coexisting Mg deficit. Supplementation with Mg is not only a suitable measure to eliminate this risk factor, but can also increase resistance against stressors in experimental animals, livestock and probably in man, too. When Mg is supplied in larger amounts by the oral route, care must be paid to bioavailability and acid base status.

Experimental data on the problem of specific hepatosplenography with radiodense lipomicrons.

Investigations into specific hepatosplenography performed with the aid of radiodense lipomicrons of different size ranges and various surface layers are presented. It is concluded that certain synthetic neutral and/or negatively charged amphiphilic substances may enhance hepatic and splenic uptake of small lipomicrons. Kinetics concerning clearance of lipid globules from the blood and hepatic concentration as well as elimination rates are studied. Furthermore, circulatory reactions following the intravenous administration of lipid emulsions and interactions between lipid globules and plasma proteins or synthetic polymeric substances are discussed.

[Magnesium therapy in pregnancy. Pharmacologic and toxicologic aspects of magnesium supplementation and use in pre-eclampsia and threatened premature labor]. / Magnesium-Therapie in der Schwangerschaft. Pharmakologisch-toxikologische Aspekte zur Magnesium-Supplementation und zum Einsatz bei Präeklampsie und drohender Frühgeburt.

The efficacy of parenteral Mg therapy for pre-eclampsia and eclampsia is due to the Mg antagonism of Ca ions. Accordingly, the Mg additional treatment of medicamentous tocolysis reduces the risk of an over-increased cardial energy consumption; at the same time Mg has an effect which inhibits uterine contractions. The favourable effects on the nocturnal calf cramps are due to the compensation of a combined Mg and Ca deficiency and/or a membrane stabilisation caused by Mg. In animal experiments all reproduction processes were negatively influenced by Mg deficiency, whilst the rate of abortions in early and late pregnancy as well as premature births decreased in pregnant women after administration of Mg. The perinatal mortality is similarly favourably influenced. Since prophylactic oral Mg application is effective and safe, it can be recommended without reservations.

Magnesium and potassium deprivation and supplementation in animals and man: aspects in view of intestinal absorption.

States of K and Mg deficiency, deprivation or depletion, are difficult to detect by determining serum concentrations, since both cations are concentrated intracellularly. The intestinal absorption of K is rather quick and complete; the uptake of Mg probably comprises two mechanisms and proceeds continuously, although incomplete. The resulting different pharmakokinetic behavior must be kept in mind when K and Mg are supplemented by the oral route. Favorable effects of oral K and Mg supplementation are reviewed, and the fact is stressed that the body cannot retain K, unless the Mg status is adequate. Therefore, K should be supplemented together with Mg. Drugs like amiloride not only spare K, but at the same time prevent renal losses of other important electrolytes, especially of chloride and Mg.

Experimental studies on the intestinal uptake of organic and inorganic magnesium and potassium compounds given alone or simultaneously.

The peroral administration of magnesium and potassium compounds in effective doses (ED50) to rats yielded the following results: 1. Magnesium or potassium given as chlorides are significantly better absorbed than the corresponding aspartates. 2. In the presence of aspartate in higher concentrations the absorption of both magnesium and potassium is inhibited to a certain degree. 3. Increasing amounts of chloride cannot abolish the inhibitory effect of aspartate on potassium absorption, in contrast magnesium, which, in the presence of aspartate is better taken up when chloride is provided. 4. High concentrations of magnesium may perhaps impede the uptake of potassium to a small degree but not vice versa. 5. Magnesium losses from the body--induced by treatment with 9-alpha-fluorocortisol-acetate--can be effectively substituted by peroral administration of chloride-containing magnesium compounds over a reasonable time. The simultaneously occurring loss of potassium cannot be corrected correspondingly by potassium supplements.