Biological Role of Magnesium(Biologicheskaia Rol’ Magniia)

A. Ia. Pleshchitser (Gor’kii)

HE BIOLOGICAL n#{248}ui of magnesium is of considerable importancein the processes of synthesis in the organic world. According to thework of Academician V. I. Vernadskii, chlorophyll contains up to 0.2per cent magnesium. Magnesium enters into the composition of pro-teins, of plasma, and of the basic colloids of the living body. Themagnesium in living matter constitutes n.10_2 of its weight. It isknown that chiorophylls a and b and bacteriochlorophylls containmagnesium coordinately linked with the nitrogen of pyrrole nuclei, inthe same way as iron in hemoglobin and cytochrome.

Magnesium is of great importance in the processes of photosyn-thesis by chlorophyll. According to Willstaetter and Stoll (1913), thepart that magnesium plays in the structure of chlorophyll and par-ticularly its complexes raises the question of its role in assimilationprocesses. In achlorophyllic plants magnesium also takes a promi-

From tT8pekM So.vremennoi Biologii (Advances in Contemporary Biology) XL, 1(4),52-67 (1955).

Translation of this paper has been furnished by the National Institutes of Health, PublicHealth Service, as a part of the Russian Scientific Translation Program.

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429

430 A. LA. PLESHCHITSER (6ORKll) Clinical chemistry

nent part in physiological synthesis (Kostychev, 1933). There is evi-dence of a catalytic action by magnesium in the processes of sugarformation from formaldehyde in plants (Schmalfuss, 1927).

Timiriazev regards magnesium salts as among those necessary forthe nourishment of plant roots.

It has been established that many enzymes participating in phos-phorylation require the presence of magnesium ions. The reactiontransferring the phosphoric acid is effected through coenzymes(magnesium and adenylic acid). Engel’gardt states that in the com-plete absence of magnesium every process of phosphorus transferand the activity of all phosphatases become impossible. In theseprocesses the role of coordinating central atom-linking enzyme andsubstrate is ascribed to magnesium. It brings the two elements in thereaction together, thus making possible the transfer of the phosphoricacid from one radical to the other. The same view is expressed byBraunshtein. According to Baldwin (1949), the presence of mag-nesium ions is necessary for all reactions in which diphosphothiaminetakes part; and, in fact, lack of magnesium in experimental animalsleads to symptoms of avitaminosis B1. Natural enolase enzyme is,apparently, a magnesium-protein. According to the lindings ofHaurowitz (1930), the myogenic fraction of muscle contains enolase.Each molecule of the enzyme contains one atom of magnesium. In thethiamine phosphate of yeast carboxylase the phosphoric groups areapparently linked with the protein component by magnesium ions.

The investigations of Lohmann and Meyerhof (1931) establishedthe specific role of magnesium in the coenzyme of lactic acid fermen-tation. According to Prescott and Dunn (1952) and other authors,magnesium is necessary for alcoholic fermentation, for the formationof citric acid in alcohol fermentation, for the activation of isocitricdehydrogenase. Magnesium is also essential in the processes of fer-mentation caused by molds. In the formation of itaconic acid(methylene succinic acid) and in fermentation, magnesium is neces-sary not only as a source of nourishment but also because it serves tostimulate the formation of itaconic acid and so promotes the acid re-sistance of the mold. Magnesium enters into the composition of nu-trient media for the production of penicillin, for inducing spore for-mation in molds, and for the production of fats from molds.

Vishniac (1950) noted that adenosine triphosphate or magnesiumare equally able to remove the inhibitory effect occurring during fer-mentation. This would suggest that in the course of the reaction the

Vol. 4 No. 6, 1958 BIOLOGICAL ROLE OF MAGNESIUM 431

magnesium becomes linked with the coordination centers of thehexokinase.

There is evidence that the suppression of the action of dihydro-streptomycin and terramycin on alkaline phosphatase that occurs invitro can be prevented by the addition of magnesium chloride(Ghatan and Krishna Murti, 1953).

According to Foster (1950), magnesium is present in mycelia inthe form of an inorganic or unstable organic compound.

Bresler and IRozentsveig (1951) came to the conclusion that theactive complex of chymotrypsin has the magnesium ion in the pros-thetic group. Sumner and Somers (1948) showed that intestinaldipeptidase is activated by magnesium ions. Smith and Lamry (1954)considered that the metal of the aminopeptidase-leucine reaction,magnesium, is linked probably only through the free amino group andthe nitrogen of the peptide linkage.

Smorodintsev showed that solutions of magnesium salts acceleratethe action of ptyalin, pancreatin, trypsin, erepsin, pancreatic lipase,and rennin. Magnesium salts hasten the processes of milk curdling.

According to Oppenheimer (1934), in the enzymatic processes con-cerned in the conversion of glucose in the muscles, magnesium is thereaction activator.

Snoke et al. (1953) reported that magnesium ions were necessaryfor the enzymatic synthesis of glutathione from y-glutamyl cysteineand that no other divalent ions could replace them. Gershenovich andKrichevskaia (1954) showed that the enzyme system responsible forthe catalytic synthesis of glutamine from glutaminic acid and am-monia is activated by cysteine and magnesium ions.

Leibowitz and Schweitzer (1930-1931) investigated the effect ofmagnesium chloride on the respiratory function of cardiac musclesections from frog ventricle by the manometric method of Warburg,and found suppression of this function. The respiratory function offrog liver was not reduced.

The investigations of Koval’skii and his co-workers (Raetskaia,Redina, Tolcheeva, 1946-51) established that magnesium reduced thehydration function of the carboanihydrase of pregnant women, new-born and premature infants. Magnesium produced a notable increasein the oxygen-combining power of hemoglobin in pregnant women andnewborn infants. Magnesium had, however, the opposite effect onfetal hemoglobin (in the fetus of 25 weeks) and also on the hemo-

432 A. LA. PLESHCHITSER (GORKlI) Clinical Chemistry

globin of children born in a state of asphyxia; magnesium in asphyxialowered the oxygen-combining power of the hemoglobin.

The findings we have quoted show that magnesium, being one ofthe fundamental cations of the mineral complex in all plant and ani-mal tissues, fulfills a very special function in the organism.

Magnesium is regarded as extremely important in the processes ofphotosynthesis effected by chlorophyll, and in achlorophyllic plantsit plays an important role in the processes of physiological synthesisand assimilation.

It has been established that many enzymes concerned in phosphory-lation require the participation of magnesium ions.

In a number of biological reactions magnesium is the catalyzerand activator thereof.

There is evidence that a connection exists between the activities ofthe magnesium ions and the physiological state of the organism, as,for example, in the case of the oxygen-combining power of hemo-globin in pregnant women.

ANTAGONISM BETWEEN MAGNESIUM AND CALCIUM

Parallel with the study of the biological significance of magnesium,many investigations have dealt with its relationship with othercations entering into the composition of the tissues and fluids of plantand animal life. Special attention has been given to the relationshipof magnesium with calcium, which is regarded as antagonistic, therole of suppressing the vital activity of tissues being ascribed tomagnesium, and activity of the opposite character to calcium, that ofstimulating vital activity. The explanation of this is that for a verylong time in the physiology of plant and animal life the conception ofantagonism between various ions and of ionic equilibrium as factorstaking part in the regulation of metabolism in the organism has pre-vailed.

In the literature there are statements that the antagonism of mag-nesium to calcium is a general phenomenon applicable both to plantand animal life.

Hanstein (1910) showed that in magnesium salt solutions the rootsof Norwegian wheat became sick, whereas in calcium solutions, evenvery strong solutions, root development was normal. Osterhout(1909) found a clear antagonism between magnesium and sodiumsalts in their effects on the growth of spores of Botritis cinereaSchimmelpilz. The investigations of Gedroits and his co-workers

Vol. 4 No. 6, 1958 BIOLOGICAL ROLE OF MAGNESIUM 433

showed that the creation of an unfavorable calcium :magnesium ratioin the soil may destroy the crop completely.

Opinions vary as to where exactly the antagonistic action occurs.Hanstein, and likewise Kaho (1924), considers that the antagonisticaction occurs at the surface of the cell membranes of the growingcells. Lepeschkin (1924) suggests that the antagonism takes placewithin the cells.

A great many investigations have dealt with the antagonistic actionof calcium and magnesium in the animal organism. Loeb (1913), inhis experiments on the division of fertilized Arbacia eggs, obtainedthe best results in solutions of magnesium chloride and the worst insolutions of calcium chloride, a result which in the author’s opinionis explained by the differing power of these solutions to coagulatecolloids. The author explains both toxic and antagonistic activity ofthese ions by the valency of these cations.

This view of antagonistic activity between different cations hasmet with opposition from Matthews (1905), who considers that theaction of colloid tension and also the electrical charge of colloids andsalts play an important part in the processes of interaction betweencations and colloids.

In experiments on more highly organized members of the animalworld it has been shown that magnesium salts exercise an inhibitoryeffect on the vital activity of these organisms. In this connection wewould refer to Bethe’s experiments on medusas (1908) and those ofLillie (1907) on the larvae of Arenicola.

The investigations of Meltzer and Auer (1905) demonstrated anantagonistic action of calcium in magnesium narcosis in rabbits.These experiments have been repeated by other authors. Merkwalder(1917) considered that the antagonism of calcium to magnesium wasclearly seen only in relation to respiration, was absent in connectionwith the circulation, and was very slight in relation to peripheralmotor paralyses.

Vamawaki (1928) reached the conclusion that the stimulatingaction of calcium chloride in magnesium narcosis was due basicallyto stimulation of the corpus striatum, that calcium was not a directantagonist of magnesium and produced its effect by indirect means.Syollema, Seckles and Kaay (1932), in their experiments on calves,found that calcium possibly caused spasm of the coronary arteriesand that magnesium salts reduced these spasms. According to Stark-enstein (1914) calcium as an antagonist in magnesium narcosis could

434 A. LA. PLESHCHITSER (6ORKII) Clinical Chemistry

not be replaced by any other divalent cation. In a number of otherinvestigations this author found that calcium and magnesium ionsexerted a similar action; thus, for example, on isolated intestinemagnesium salts and calcium salts reduce tone and weaken peristalticmovements.

Mulli and Standenath (1932) considered that the antagonisticaction of calcium chloride in magnesium narcosis is based on the abili-ties of the two metals to form complex compounds which, as it were,neutralize one another.

Our investigations (Pleshcbitser, 1942a) showed that preliminaryblockade of the reticuloendothelial system with collargol and splenec-tomy in rabbits produced a retarding effect on the antagonistic actionof calcium chloride in magnesium narcosis.

Antagonistic action of calcium and magnesium salts on muscletonus was observed by IRusetskii in patients with frank signs ofParkinsonism.

In a study of mineral exchange in the hard tissues of the teethKoval’skli observed antagonism between calcium on the one side andmagnesium, potassium, and sodium on the other; asymmetry of thisfunctional coefficient was also observed between the right and leftsides.

The various results quoted show that the nature of the antagonisticaction between calcium and magnesium has been interpreted differ-ently by different authors. Neither the physicochemical theory ofcalcium and magnesium antagonism nor, in fact, any other theoryhas been proved correct in application to living organisms. In connec-tion with the findings on calcium and magnesium antagonism givenabove the statements of TJkhtomskii (1930) are of interest. He con-sidered that the term “ionic antagonism,” which has played a posi-tive part in physical chemistry, becomes harmful when applied tobiological processes, in that people will begin to imagine that somesort of unconditional and absolute antagonism may exist betweenions, altogether apart from any actual conditions necessary for theirinteraction.

Even at the present time it is impossible to agree with this view ofUkhtomskli.

The suggestion is made that, under the natural conditions ofexistence of the plant or animal organism in a normal physiologicalstate, antagonistic action between calcium and magnesium ions ishardly possible. Basically, there is a labile ion equilibrium in the

Vol. 4 No. 6, 1958 BIOLOGICAL ROLE OF MAGNESIUM 435

living organism, which is a manifestation of the dynamic powers ofthe organism for adaptation to the conditions of the external medium.

MAGNESIUM METABOLISM IN THE ORGANISM

The metabolism of magnesium in the organism of man and animalshas long been the subject of investigation. In 1878 Bertram had al-ready obtained in experimental subjects given a diet containing 0.732Gm. magnesium an excretion of about 0.72 Gm. daily. According tothe work of Bertram and Renwall, magnesium equilibrium in theorganism of adult man is maintained by the daily administration of0.4-0.5 Gm. According to their findings 29-37 per cent of the mag-nesium is excreted in the urine and 61-71 per cent in the feces. Theamount excreted in the urine depends on the qualitative compositionof the food. Thus, according to Bumge, with a meat diet 0.17 Gm.magnesium is excreted in the urine, and on a vegetarian diet, 0.68Gm. Nagel (1909) showed that, quite independent of the compositionof the diet, a certain quantity of magnesium is eliminated from theorganism by the intestine. According to Tanhauser (1933), during aperiod of hunger, with excess elimination of calcium, there is reten-tion and accumulation of magnesium in the organism. Tigerstedt(1910) found that with a freely chosen diet the daily elimination ofmagnesium was 1.1 Gm. in women and 1.8 Gm. in men.

Academician A. V. Palladin gave the following details on mag-nesium metabolism. If in adults the diet contains more calcium thanmagnesium, then 0.05 to 0.23 Gm. magnesium and 0.12 to 0.47 Gm.calcium are excreted daily. If, however, the food contains moremagnesium than calcium, the daily excretion of magnesium is from0.08 to 0.15, Gm. and of calcium from 0.05 to 0.24 Gm. When solublesalts of magnesium are given with the food to adult animals, thequantity of calcium in the organism falls.

The entry of magnesium into the organism takes place, accordingto Abderhalden, from the bowel in an inorganic form or possiblypartly in the form of a complex salt. It has not, however, been deter-mined finally whether part of the magnesium is not also excretedthrough the bowel wall. Marek and Wallman (1934) suggested thatthe magnesium excreted by the bowel is partly in solution, this solublepart being met with as the phosphoric salt (MgH2PO4)2, and partly inthe form of unknown compounds. Wacker (1927) stated that in manabout 1.2 Gm. of phosphates is excreted in the urine daily, one-thirdof which is calcium phosphate and two-thirds magnesium phosphate.

436 A. LA. PLESHCHITSER (GORKIl) Clinical Chemistry

Starling (1931) noted that the contents in the urine of calcium andmagnesium are constant, although considerable less than the contentsof the alkaline metals. The amounts excreted in the urine do not indi-cate the amounts ingested in the food or absorbed from the bowel,since both bases can be re-excreted by the bowel and appear in thefeces as insoluble phosphates. According to Hirschf elder, magnesiumis excreted mainly by the renal tubules. In the presence of renal dis-turbance, there was a fall in the excretion of magnesium from theorganism.

In the light of what has been stated, the results obtained in ourclinic by S. A. Korchagina in a self-study on various diets are ofinterest. With a mixed diet (9 days’ observation) the amount ofmagnesium excreted exceeded its intake. With a milk diet (6 days)there was retention of magnesium in the organism. A vegetarian dietwas accompanied by magnesium excretion exceeding intake. With asugar diet (3 days), involving the taking of 100 Gm. sugar daily in1.5 liters distilled water, the average daily excretion of magnesiumwas 0.167 Gm. These concise results of Korchagina demonstrate quiteconvincingly the dependence of magnesium metabolism in the organ-ism on the amount ingested with the food and on the qualitative com-position of the diet.

While the problem of magnesium metabolism in the organism inhealth has been reasonably well clarified, the same cannot be said ofmagnesium exchange in individuals with pathological conditions. We(Pleshchitser, 1939a) have made some quantitative determinations innine patients. The results show that it is possible to balance the ex-cretion of magnesium with its intake. In patients with atrophiccirrhosis of the liver, ascites is accompanied by some retention ofmagnesium in the organism. In acute articular rheumatism mag-nesium retention was greater at the height of the allergic state (up to0.28 Gm. daily over five days’ observation) than in the stage of recov-ery (up to 0.14 Gm. daily over five days’ observation). It is obviousthat the investigation of magnesium exchange in pathological statesmight have a definite clinical importance.

When the magnesium intake with the food was insufficient, Kruse,Orent, and McCollum (1932) observed a characteristic symptomcomplex in rats, namely, dilatation of vessels, a state of excitement,cardiac arrhythmia, spastic and tonoclonic convulsive attacks. Theseauthors pointed out that magnesium tetany is not the same as hy-pocalcemic tetany; in the former, laryngospasm was not seen and

Vol. 4, No. 6. 1958 BIOLOGICAL ROLE OF MAGNESIUM 437

there was vasodilatation instead of vasomotor spasm. Brookfieldfound the following changes in the liver and kidneys of rats given adiet deficient in magnesium: the cytoplasm of many of the liver cellshad a wax-like porous structure; the kidneys showed profoundchanges in the glomeruli and tubules-not one tubule remained nor-mal. This author did not see the vasodilation described by Kruseet al. Brookfield regarded the renal changes as a result of changes inthe blood lipid content and not of changes in protein nitrogen, as wasthe view of Kruse and his colleagues.

Lowenhaupt, Schulman, and Greenberg (1950), in their experi-ments with magnesium-deficient diets in rats, observed widespreadinflammatory foci in the mesenchymal tissue and localized foci ofnecrosis in the perivascular spaces.

It has also been demonstrated that a marked dietary excess of mag-nesium may exert a harmful influence on the organism. Haag andPalmer (1928) found that a high magnesium content in the food sup-pressed the growth of animals. Rogozynsky and Glowazynsky (1934)quote the statement of Murinad that magnesium accentuates rachiticdisorders and may actually precipitate the disease. These workersmade a number of experiments on white rats to elucidate the role ofmagnesium in the pathogenesis of experimental rickets. They notedthat with a typically rachitic diet, poor in phosphorus and containingan excess of calcium, calcium was partially replaced by magnesium.Complete replacement of dietary calcium by magnesium did not in-crease the content of salts in bone, but the weight of the animal re-mained stationary.

Meyer zu Hoerste (1932) constantly observed rickets in rats rearedon a special diet containing 2.3 Gm. magnesium carbonate.

Petrov (1947) speaks of how certain authors are inclined to explainthe low incidence of cancer in certain countries, for example, Egyptand various provinces of Italy and France, by the high soil contentof magnesium in these countries and possibly also the high mag-nesium content of the diet of these peoples. He also points out thatserious objection is taken to these views by other authors.

The various investigations mentioned suffice to show that bothdeficiency and excess of magnesium in the diet are associated withchanges in the condition of the entire organism, characterized byshifts in mineral exchange, changes in the composition of the blood,destructive tissue changes, and disturbances in the nervous systemleading to death of the animals unless a normal relationship between

438 A. LA. PLESHCHITSER (GORKII) Clinical Chemstry

magnesium and calcium, as well as other cations in the organism, be

restored.

MAGNESIUM CONTENT IN THE BODIESOF MAN AND ANIMALS

A number of investigations have been made on the magnesium con-tent of tissues and body fluids. Vinogradov has shown that in someorgans of higher animals, e.g., muscle, brain, and liver, the mag-nesium content exceeds that of calcium. The magnesium content ofthe thyroid gland is low. In the blood of animals the calcium level isabove that of magnesium. Astanin gives the following Ca/Mg coeffi-cients for the various tissues: bone, 31.7; cartilage, 7.9-9.3; brain,0.19-0.93; muscle, 0.54-0.60; heart, 0.76-0.81; liver, 2.6-3.9; blood, 2.7-3.3.

Aloy defines the coefficient of magnesium to calcium in various tis-sues in the following percentages: brain, 374; muscle, 175; cardiacmuscle, 128; kidneys, 55 per cent. According to Tojonada, the mag-itesium/calcium coefficient for the white matter of the brain is par-ticularly high, being about 333 per cent, whereas that for the greymatter is only 36.6 per cent.

The magnesium contents determined for the various organs of manare shown in Table 1.

In some animals the magnesium contents of some organs are thesame as those for man, whereas the contents of other organs differ.It has been stated that in the dog the magnesium content in the lungsis 11.95 mg/100 Gm. and that of muscle 27.09 mg/100 Gm., whereasthe liver, spleen, and kidney contents are the same as in man.

Gol’denberg et al. (1935) determined the magnesium content of thebrain of human embryos in the association area as 0.02 per cent offresh substance and 0.07-0.15 per cent dried brain substance. Accord-ing to Blum and Grabar (1930), the magnesium content of the grey

Table 1. MAGNESIUM CONTENT IN HUMAN ORGANS

OrganAmount

,ng/iOO Gin. OrganAmount

rngflOO Gin. Author

Liver 19 Muscle 17

Brain

Spleen

1818

KidneysHeart

1515 Haurowitz

Lungs 17 Prostate 14Skin 23-25 Doerifel

Vol. 4 No. 6 1958 BIOLOGICAL ROLE OF MAGNESIUM 439

matter is 10.4 mg/tOO Gm., and of the white matter only 1.7 mg/100Gm.

Krupakova (1938-1940) demonstrated changes in the electrolytic,including magnesium, composition of skeletal muscle in its variousfunctional states and in relation to the seasons of the year. On exer-cise of a muscle the magnesium content rose. The muscles of femalesnakes in winter differ from the muscles of females in summer in theirgreater content of magnesium, whereas the muscles of male hedge-hogs in summer contain more magnesium than those of males inwinter.

Lobachevskaia (1939) found more magnesium in the cardiac muscleof warm-blooded male animals than in the females, and the reverse incold-blooded animals.

Guzhovskaia (1939-1940) noted that sexual dimorphism in respectof magnesium content in the liver, bile, and blood serum is observedin all representatives of three classes of vertebrates, snakes, spar-rows, hedgehogs and foxes. It was impossible to trace any differencein content of metals between cold-blooded and warm-blooded animals.

Koval’skii (1941) observed that in man the maximum magnesiumcontent (serum or plasma) was somewhat higher in autumn than insummer. The most marked variation in serum magnesium was seenin autumn in frogs, rabbits, hedgehogs, and male snakes. This authorsuggested that the characteristic seasonal changes in content ofmetals are adaptational links of the organism with the surroundingmedium and that the seasonal changes in the content of magnesiumin the serum and erythrocytes in various types of animals follow cer-tain definite laws.

Koval’skii and Chulkova (1951) showed that the magnesium con-tent of erythrocytes was higher during the day hours in 51 per cent ofcases and lower in 39 per cent than in the night hours.

These investigations of Koval’skii and his co-workers show that inthe matter of the content of cations, and particularly of magnesium,in the blood serum and erythrocytes, it is more correct to think interms not of the average contents but of the diurnal and seasonalvariations which are dynamic characteristics of the species.

Florkin (1947), depicting the magnesium content of the blood ofvarious animals in the course of their evolutionary development,gives the following data: human blood plasma contains 2.4-1.5 mg/tOOGm.; the river crayfish, 6 mg/100 Gm.; the vine snail, 2 mg/100 Gm.;erlentates, 0.5 mg/100 Gm.; the plasma of water beetles, 43-54 mg/100

440 A. LA. PLESHCHITSER (GORKIl) Clinical Chemistry

Gm. A high blood content of magnesium is a particular feature ofinsects, differentiating them from the rest of the animals with theexception of marine invertebrates, the internal medium of which issimilar in composition to sea water.

Various findings on the magnesium content of human blood inmg/100 Gm. are shown in Table 2. Analogous findings are reported byKaplanskii and other writers.

Greenberg and his co-workers (1933) considered that the mag-nesium in the erythrocytes must play a specific role in the physiologyof erythrocytes, in which the magnesium is in the form of a salt andreplaces the alkaline earth cations. They also thought that the mag-nesium of the erythrocytes and the magnesium in the plasma werenot dependent on one another.

Investigations by Koval ‘skii and his colleagues (1948-1951) estab-lished that erythrocytes are permeable to cations. These authorsstated that the definite shifts they observed in the cationic composi-ion of the erythrocytes in asphyxia of the newborn, the daily changesin the cationic composition of the red cells of pregnant women, andalso the changes in the cation proportions in the erythrocytes occur-ring with great rapidity in the course of the respiratory cycle, shouldbe regarded as undoubted evidence of the permeability of the erythro-cytes to cations.

Fidler (1934) gave the ratio of the serum magnesium index to thered cell magnesium index as 0.49. This author noted that there wasno difference between the magnesium contents of arterial and venousblood in either healthy or sick subjects.

The findings of Koval’skii and Raetskaia (1951) were somewhatdifferent. They found that the magnesium content of venous blooderythrocytes was less by 19 per cent than the content of erythrocytesin arterial blood.

Lucchi (1934) presented evidence that the blood serum magnesiumincreased by 0.3 mg/100 Gm. during physiological sleep but that no

Table 2.

WhO1S blood Blood plasma Blood ssnnn Red osUs(Mg. per 100 Gm.)

Author,

3.5-5.42.78

2.033-6.02.18

5.5-7.83.36

1.6-3.61.8-2.3

2.35

Greenberg et aZ.

FidlerKramer and Teesdale

BotherJansen and Loew

Vol. 4, No. 6, 1958 BIOLOGICAL ROLE OF MAGNESIUM 441

increase occurred in hypnotic sleep. This was not supported by theinvestigations of other authors. Cloetta et at. (1934) examined theplasma of humans, dogs, and rabbits during sleep but failed to ob-serve any difference in the magnesium content from that of thewaking state.

Our investigations (Pleshchitser and Korchagina, 1935) showedthat among people in contact with MgO dust many of those examinedhad a high magnesium blood content; an increase was also observedby Veksler (1938) among workers in the magnesium factory.

Much information has accumulated in the literature on the bloodcontent of magnesium in various animals. From Abderhalden’s find-ings it is evident that among domestic animals the magnesium con-tent of the blood is approximately the same but that of the erythro-cytes is extremely variable.

Many investigations have dealt with the cerebrospinal fluid contentof magnesium, as will be seen from Table 3.

Stary et at. stated that in relation to calcium there was equilibriumbetween the cerebrospinal fluid and the blood serum, but in mag-nesium there was always a difference. Koval ‘skii established that inconvulsive conditions (eclampsia) in pregnant women there is a regu-lar change in the magnesium content of the blood and cerebrospinalfluid.

According to literature sources, the magnesium content of edem-atous fluid exceeds that of the blood serum. Transudates of variousorigins contain less magnesium (about 1.1 mg/100 Gm.) than theblood serum. Ascitic fluid in cases of atrophic hepatic cirrhosis wasfound by us to have a magnesium content varying between 0.017 and0.085 mg/100 Gm.

In the literature there are reports giving the magnesium content ofthe fluid in the chamber of the eye of the ox as about 0.96-1.05 mg/100Gm., and in that of the horse as 2.6 mg/tOO Gm.

Palladin states that of the total quantity of cations in milk those ofmagnesium amount to 5 per cent in women and 4 per cent in cows.

Table 3. CERaBRospniAI. Pi.um Oowrawr owMAGnswM

MagnuvnsCR!

(mg/100 Gin.)

Mg/Ca raUo

(ii 087(per cent)

Ratio of Mg in 087to Mg in blood seem

(per cent) Author,

2.11-3.37 Fridman and Petrova2.16.4.93 54.6-144 89-200 Stary et al.

3.24 Jansen and Loew

442 A. LA. PLESHCHITSER (6ORKIl) Clinical Chemistry

Lucchi quotes a communication by Cabito to the effect that the sexglands exercise some influence on the metabolism of magnesium, thatin the period of sexual maturity there is a sharp rise in the blood con-tent of magnesium at the time of the menstrual cycle. Wallas (1950)noted a higher magnesium content in skeletal muscle than in uterinemuscle. The administration of estrogenic hormones to castrated ratsled to a high Mg/Ca ratio in the blood.

According to Mendel (1935), magnesium metabolism is regulatedby the thymus.

It will have been seen from the various findings mentioned thatsome authors determined the Mg/Ca ratio in tissues, blood andcerebrospinal fluid, whereas others determined the Ca/Mg ration forthe same tissues and fluids. Koval’skii and Raetskaia determined theK/Mg ratio for red cells.

The foregoing investigations indicate that the magnesium level inthe tissues and blood of man and animals varies very little undernormal physiological conditions. The differences observed in thecontent of magnesium in various organs of different animals are ap-parently dependent on physiological state, dietary intake, and alsochanges in the external medium.

MAGNESIUM CONTENT OF HUMAN BLOOD IN VARIOUS ILLNESSES

Authors who have studied the blood content of magnesium in vari-ous pathological conditions in man emphasize the clinical importanceof such examinations. In Table 4 we give some data on the bloodcontent of magnesium in various human illnesses.

Becher (1932) observed a slight increase in blood magnesium incases of jaundice, but not constantly. In renal disease without signs

Table 4. BLOoD CONTENT OF MAGNESIUM DUIUNG HUMAN ILLNESSES

Content ofMg in blood Mg/Ca ratio

Disease (mg/100 Gin.) in blood Authors

Cardiopathy 2.5-4 1Hepatic disease 2.5-4 LucehiPulmonary tuberculosis 3.0-6 JPulmonary tuberculosis 1.4-4.4 verdinaPulmonary tuberculosis 1.4-4.2 0.15-0.55Syphilis 1.6-7.0 0.15-0.55Typhoid 2.02-5.65 0.15-0.65 PleshchitserOrganic disease of central nervous system 1.1.6.4 0.15-0.55

Vol. 4, No. 6. 1958 BIOLOGICAL ROLE OF MAGNESIUM 443

of insufficiency blood magnesium was not increased, and in cases withmoderate or advanced insufficiency was clearly increased. Becheremphasized that this point was of great importance, as in these latterpatients the magnesium increase could lead to a fall in the excita-bility of the nervous system. According to the work of Watchorn(1930) a 30 per cent increase in the magnesium of the blood serum isseen in nephritis and syphilitic iritis. As a result of his investiga-tions, Fidler came to the conclusion that the change frequently ob-served in the magnesium content of the blood in individuals sufferingfrom chronic cardiovascular or renal disease when insufficiency su-pervenes can serve as a pointer to decompensation in such patients.This author found the blood content of magnesium low in patientswith malignant tumors.

Puca (1934) observed an increase of magnesium in the CSF andblood in progressive paralysis, the ratio of blood magnesium to CSFmagnesium being 1.4 in this instance. There was less magnesium inblood taken from the paralyzed arm than in blood from the non-paralyzed arm. Hirschfelder found the blood magnesium increasedto 16.8 mg/tOO Gm. in cases of mercury nephritis and after bilateralnephrotomy.

Policard et at. (1932) studied the magnesium content of the severallayers of normal and atheromatous aortas by a histospectrographicmethod. They found that magnesium is little if at all changed in theatheromatous aorta.

Petrov has pointed out that the magnesium content of malignanttumors is low. There are, it is true, reports of increased magnesiumin tumors, but the majority of authors consider that the magnesiumcontent of malignant tumors is less than that of normal tissue. Inthe opinion of some authors magnesium has an inhibitory effect ontumor growth, whereas others believe that it has no particular effecton tumor growth, and a few have noted some stimulation of tumorgrowth under the influence of magnesium.

Zbarskii et at. state that the muscle content of magnesium is re-duced in avitaminosis E.

The results quoted indicate the considerable clinical significance ofblood magnesium examinations in pathological conditions.

NARCOTIC ACTION OF MAGNESIUM AND ITS SALTS

The narcotic effect of the parenteral administration of magnesiumsalts has been the subject of investigation over the past eighty-five

444 A. LA. PLESHCHITSER (GORKll) Clinical Chemistry

years. Some authors have reached the conclusion that magnesiumsalts, in addition to their peripheral action, possess also an action onthe central nervous system, whereas others concluded that they hadonly a curare-like action.

Meltzer and Auer injecting solutions of magnesium sulphate andchloride subcutaneously and directly into the medulla in rabbits al-ways obtained general narcosis. When they injected moderate dosesof the magnesium salts into the spinal cord of monkeys and man, theyfound suppression of sensory and motor functions. In the opinion ofthese authors, magnesium salts have, in addition to their peripheralaction, a central action, and this action is the important one in thenarcotic effect of these salts.

Markwalder supports the view that magnesium salts act on the cen-tral nervous system. Initially there is blocking of the motor nerveterminations, followed by loss of the higher reflexes, and then loss ofsensation and consciousness.

Kravkov (1933) considered that magnesium chloride exercised itsaction mainly on the central nervous system, producing prolongednarcosis; the action of the heart was little affected. Zakusov (1953),as a result of his experiments, stated that magnesium sulphate altersthe summation of impulses in the central nervous system so that re-flex action supervenes after the delivery to the animal of a greaternumber of stimuli. This author also believes that simultaneously withits action on the central nervous system the magnesium ions alsomake the transfer of impulses from the motor nerves to the skeletalmuscle difficult, or in other words, they have a curare-like action.

A number of authors consider that magnesium salts act only in acurare-like manner. In this respect reference is made to the investi-

gations of Jolyet and Cahours (1868), Bardier (1907), and others.Wild (1906, 1911, 1935) concluded from his investigations that

magnesium salts have only a curare-like action and that a generalanesthetizing action cannot be proved. They produce an analgesiceffect by paralyzing the peripheral endings of the sensory nerves.

Kroll (1932), as a result of his experiments on the injection of soapor acetone extracts of the brain substance of animals narcotized withmagnesium sulphate into other animals, came to the conclusion thatmagnesium sulphate exercises a paralyzing effect only on the periph-eral motor nerve terminations, while in the central nervous systemexcitation processes may continue. Skvortsov (1937) quotes thestatement of Vorontsova that the curare-like action of magnesium

Vol. 4, No. 6, 1958 BIOLOGICAL. ROLE OF MAGNESIUM 445

sulphate is somewhat more complicated than that of curare itself, inthat magnesium affects both the muscle and the nerve fibers in addi-tion to the motor nerve endings.

Meltzer and Auer, and also Starkenstein, explain the production ofmagnesium narcosis by the power of the magnesium ions to penetrateinto the nerve tissues and to displace the calcium ions.

Mansfield and Bosany (1913) considered that magnesium salts,being insoluble in lipids, cannot penetrate into the nerve cells andact only on the cell membrane of the nerve cells, producing a reversi-ble suppression of cell function.

Wiechmann (1920) stated that magnesium acts mainly and selec-tively on the synapse and the connection between nerve and muscle.In the central nervous system it acts on the connecting substancebetween the neurons. According to Vamawaki, the narcotic action ofmagnesium is the result of its action on the medulla, the base of thebrain, and on the cerebral hemispheres. Bethe found the excitabilityof the nervous system of the medusa, Rhisostoma, reduced when theMgC12 added to sea water was increased fourfold.

The investigations of Benda (1913) showed that the excitability ofmotor nerves and skeletal muscle was reduced in weak concentrationsof MgCl2; the work capacity was also reduced. In all instances therewere signs of fatigue from the effect of the MgC12.

The foregoing results indicate that the action of magnesium on thecentral nervous system has been understood by many investigators asa purely local type of action. This explains why some authors saw inthe action of magnesium only a curariform effect, whereas others sawonly the effect on the central nervous system.

In line with the teaching of Pavlov and of Vvedenskii, the narcoticand curariform actions of magnesium salts should be regarded asconstituting a single inhibitory process, since the fundamental prop-erties of the nerve cell belong equally to the cells of the central andthe cells of the peripheral nervous systems.

PHARMACOLOGICAL PROPERTIESAND THERAPEUTIC APPLICATIONOF MAGNESIUM

In addition to its narcotic and curare-like actions, the effects ofmagnesium on the heart, vessels, and other organs have been the sub-ject of investigations.

Kravkov stated that magnesium salts have a vasodilator action

similar to that of sodium salts. Turbina (1927) concluded from her

446 A. LA. P1.ESHCHITSER (GOR’Kll) Clinical Chemistry

experiments that the effect of magnesium in relation to the nerveendings in the heart is central, not peripheral. Tsyganov (1929) ex-plained the fall in blood pressure seen on parenteral administration

of magnesium salts by their depressor action on the central nervoussystem, on the vasomotor centers, and by the indirect effect of thesesalts on the cardiac vessels.

Veksler (1938) observed collapse of cardiac action amounting tocardiac paralysis on the parenteral injection of large quantities ofmagnesium salts.

Our investigations (Pleshchitser, 1939b), conducted both on the iso-lated heart of the frog and rabbit and on these animals themselves

(electrocardiographic and blood pressure examinations), showed thatthere is possibly simultaneous action on the central nervous systemand on the autonomic apparatus of the heart.

Lang (1950) stated that the effect of the parenteral administrationof MgSO4 in hypertensive encephalopathy and also at times whenthere was no exacerbation was the result of the depressor action ofthis salt on the central nervous system. Tareev (1952) recommendedthe administration of MgSO4 in the treatment of paroxysmal tachy-cardia as a method of reducing the activity of the ectopic centers.

Cholinolytic activity has been ascribed to magnesium. Anichkovand Belen’kii (1953) suggested that the cholinolytic action of themagnesium ion is apparently connected with its effect on links in tis-sue metabolism more closely associated with the functions of effectororgans than the cholino-reactive systems. Zakusov (1953) stated thatmagnesium ions are antagonists of cholinergic substances with astimulating type of activity, such as acetylcholine and physostigmine.

Deriuzhinskii (1915) and Markwalder (1917) used magnesium sul-phate successfully in the treatment of early tetanus. Skvortsov (1937)recommended the use of magnesium chloride in the treatment of

tetanus.Kocher (1912), Arnd (1913), and D. Brovkin (1934-52) used

parenteral MgSO4 for the treatment of eclampsia in pregnant women.Tareev recommended parenteral (intravenous or intramuscular)MgSO4 in the treatment of the eclampsia of nephritis.

Tamarin (1927) used MgSO4 for the treatment of bronchial asthma.Lumiere (1934) prescribed intravenous MgSO4 for the treatment ofmigraine. Isar (1953) reported a satisfactory antiallergic effect fromMgSO4 in combination with rutin in serum sickness.

As an analgesic medium MgSO4 has been used for the production

Vol. 4, No. 6, 1958 BIOLOGICAL ROLE OF MAGNESIUM 447

of painless childbirth (Brovkin and others) and as an adjuvant to thepain-relieving and narcotic effects of morphine or pantopon (Savich,1933).

Parenteral magnesium salts have been used in the treatment ofSydenham’s chorea (Skvortsov) and of psychoses (Balaban, 1935).

Tareev states that parenteral MgSO4 is widely used in acutenephritis, because of its vasodilator, dehydrating, and diuretic actionand its controlling effect on nervous system activity.

Vishnevskii (1953) and Nogaller et at. (1955) reported the use of amagnesium-rich diet in chronic cholecystitis. Baltsvinik and lako-vieva (1954) used a similar diet in the treatment of ulcerative diseaseand hypertension.

This short summary of the disease conditions in which the paren-teral (intravenous or intramuscular) administration of magnesiumsalts is indicated brings out the great therapeutic importance of thesepreparations.

CONCLUSION

Fersman (1934) commented on the relatively unimportant role ofmagnesium in biochemical processes. The comparatively limited ra-dius of its ions, the stability and relative insolubility of its compoundsprevent its taking an active part in the reactions of living matter.On the other hand, we have the statement of Vernadskii that in theplankton film of the ocean, in the ordinary accumulations and moremassive growths, the amount of magnesium-containing chlorophyllmust reach the order of t0 per cent by weight, if not higher, so thata small quantity of magnesium, entering into the composition of thechlorophyll-complex of the plankton, ultimately regulates the mainpart of the oxygenating function of living matter, the creation of freeatmospheric oxygen. The material summarized by us likewise affordsevidence of the importance of the role of magnesium in biologicalprocesses.

All this, however, does not justify sharp differentiation between thebiological role of magnesium and its role in biochemical processes.In all probability these processes are conditional to each other, al-though they are not identical processes.

It is important to note the established and incontestable role ofmagnesium in many enzymatic processes in both the plant and animalkingdoms.

The antagonistic action between magnesium and calcium, resulting

448 A. LA. PLESHCHITSER (GOR’KIlJ Clinical Chemistry

from artificial changes in the ratios of these elements in soil, plants,and animals, can hardly occur under natural conditions, and, con-versely, it must be assumed that a labile equilibrium between theseelements is always maintained.

The depressing action of magnesium ions on the central nervoussystem acquires considerable biological significance, since this per-mits the assumption that these ions in the animal organism mayfacilitate inhibitory processes in the nerve cell and insure the normalcourse of catabolic and anabolic processes.

The narcotic and cholinolytic effects of magnesium constitute thebasis for the wide therapeutic use of magnesium salts in medicalpractice.

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