Handbook of Metal-ligand

Interactions in Biological fluids

Bioinorganic Medicine

Volume I

edited by

Guy Berthon Centre N•tlonlll de I• Recherche Sclentifique (CNRSJ

lnstitut Nationlll del• S•ntl et de I• Recherche Medlc•le (INSERM)

Toulouse, France

Marcel Dekker. Inc. ·

New York • Basel• HonQ KonQ ·

INTE.RRELA TJONS BETWEEN MAGNESIUM AND CALCIUM

I. INTRODUcnON

by

MOdred S. Seell&

American College of Nutrition, 722, Robert E. Lee Drive Wilmington, NC 28412

U.S.A.

Calcium (Ca) and mapesium (M&) have reciprocal effects in a wide variety of functions. Their imbalance -whether caused by excess intalce of ooe with inadequate inwe of lhe other, or whether caused by nutrients or drup that enhance the absorption or cause loss of one over that of the other - can induce dysfunctions and patholoaic cbanaes. Jt ls possible to focus on interactions of Ca and M&. alone, oDly under controlled (usually in vitro) laboratory conditions in wbicb concentrations of each ls varied separately, a situation far from comparable to the wbole animal or clillic:al situation. These two cations affect eacb other not only directly, but throu&b their effects on the parathyroids and response to parathyroid hormone (PTII), on calcitonin (CT), aDd on vitamin D metabolism. In addition, tbe unount present of nutrients such as pbospbares, fiber and fa~, as well as other vitamins, affect the utilization, distribution, and chan&es caused by excess and/or deficiency of D and Me. At present, there is enthusiasm for iocreasin& D intake as prophylaxis qainst some chronic diseases. A recent epidemiolo&ic study of the dietary inW:es of an elderly population disclosed thai in those with bi&b Ca-int&ltes, their self-selected diets were also bi&h in M& and other important nutrients, and that therefore those postulatin& a protective role for Ca on the basis of epidemiolo&ic studies need to consider the multicolinearity in the Western diet (Holbrook and Barrett-Conoor, 1991).

Me is predominantly an intracdlular (ic) cation, in wbicb all but I~ of the body M& is fouod and as which it plays vital roles in III.U'DetOUS cellular processes: n"'bosomal, mitochondrial, enzymalk - in enero metabolism, protein synthesis, new tissue formation. potassium (K) transport, D utilization, membrane stability, muscle contractility, cardiovascular, renal, aDd bone pbysioloo aod struc:tura, aod nerve impulse transmission (Aibwa, 1911; Wacker, 1910). 1be less than I ~ of extracellular M& tbll is not bound participates principally in neuromuscular transmission (Chutkow, 1971; 1980). and inhibits Intravascular coa&ulatlon (Seeli&, 1980; 1990). Mobilization of bone Ca usually provides the Ca required for blood coaculation, transmission of ouve impulses, neuromuscular exc:itability, muscle contt'lctility, and enzyme activation, wbeo Ca needs exceed intake, or to compensate for lo.sses.

Jlle lOw lunll 01 Ule ranae 01 occlderual dietary supply ot ca (400 10 1300 ma/day) • inJdequate to meet the Deeds for normal bone formatioD of &iris and women wbo are subject to bone loss It the menopause (Avloli, 1988). Dietary surveys have Indicated that their Ca intake commonly falls below the rec:omended dietary allowance ( RDA) of 1200 m&lday (Nil. Res. Councii·RDA, 1989; U.S. Dept. H.E .W ., 19TI). Wbetha as muda as 1200 ma/day is needed to ensure lncreasilla bone mass In adolesum &irl& and youna womea is DOt certain, balf to two thirds bavift& bee.o adequate (Lich&on, 1989; ADderson and Metz, 1993). Brlnaina the intake up to J.5 &lday for postmenopausal women (Hotul ud Zinermann, 1989), in view of the low occidental Ma intake, causes ao imbalanced CalM& ratio (Seelia, 1990). Dietary surveys have indiated that the customary intake of Ma is often below 300 ma (Abdulla et al ., 1989; l..aksbmanan et al . , 1984; Moraan and Swnpley, 1988; Moraan et al. , 1985; Penninaton et al ., 1989; USDA, 1980), providina less than S malk&lday. This brin&s the dietary CalM& ratio to about 4/l. At a 2 I Ca/day intake, as bas been advised for preanant and lactllin& women (Du&&in et al. , 1974; Nordin, 1986), tbe ratio would be 6/1 or more. It is of interest that the extensive 1932 study of Ca. M& and phosphorus (P) aave 600 rna/day as tbe rec:ommended Mg intake with a CalMa ratio of 2/1 (Schmidt and Greenbera. 1935), a ratio that was lona considered suitable. Jt is provocative that as the dietary intake in urban Japan bas risen to approximately that in the occident witb a rise also in the CalMa ratio, cudiovascular disease bas become more prevalent (Kimura et al. , 1989).

The early extensive Ma balance studies of normal youna adults have shown that at Ma intakes below 5 mg/ka/day, negative Ma and Ca balances are likely (Hathaway, 1962; Seelia. 1964). On Ma intake of less than 5 malka/day, Mg balances were either neaative or in bare equilibrium at Ca intakes of about 1 a/day. At 5-6 malka/day of Ma. Ca intakes below I a /day allowed for positive Ma balances that were reduced in decree at Ca intakes above I a/day (Seelia. 1964; 1971 (Fia. 1)). A more recent study with eiaht healthy younc women inaestina the RDA for Ma and Ca. supplemented with I .S & Cal day. r~ulted in increased fecal and urinary Mg of 140 mg/4 days and 30 mg/4 days, respectively (Spiller et at .• 1988). At Ma intakes of under 305 rna/day and Ca intakes of sliahtly over I a/day (CalMa ratio of almost 4/ 1), the Ma balances of healthy younc women remained stronaly

Mg INTAKE ~ 4 4·4 .9

mg/ kg / day 5·5 . 9 b·b .9 7·1 0 >10

Ca INTAKE < 10 10 <10 >10

"'9/ kg/ day ' 10 >10 <10 >1 >10

FECAL Mg 81 b9 bl bO 54 59 58 bO b2 bO 58 1>0 1'/. OF INTAKE>

URINE M<j 39 41 38 40 27 40 22 37 23 38 22 20 C;. OF INTAKE!

200

Fiaure I. Influence of calcium intake on mapesium balance iD normal adults. From Seeli& (1993).

dit11cult to interpret, since it may reflect either deposition in bone, or a.s soft tissue c:alcinosis (characteristic of Mg deficiency). A metabolic balance study of an elderly and two middle-aged men recovering from alcoholism, and an elderly woman with rheu~atoid arthritis with probable Me deficiency, all of whom were on high-Ca intake of 2 g/day . showed increased Mg and Ca retention after receiving Mg supplements of I g/day for three weeks (Briscoe and Ragan, 1966). Two metabolic balance studies of patients with osteopathies and/or hypercalciuria, whose Mg intalces were below 300 mg/day, showed that Ca supplementation intensified their negative Mg balances (Parlier et al . , 1963; Amiot et al ., 1968). Another patient with osteoporosis, whose daily Mg intake was higher (334 mg/day) and whose Mg balance was positive ( + 33 mg), responded to increased Ca intake (2 g/day) by reduction of Mg retention to bare equilibrium (Heaton et al . , 1964).

B. Laboratory animal data Since close to 99~ of the body's Ca is in the skeleton (Avioli, 1988), inadequacies of it< intake are reflected by growth failure, bone demineraliz.ation and bone loss. The manifestations of Mg deficiency, which differ by species, might be partially explained hy the different Ca/ Mg ratios of two species with disparate find ings. Rats fed Mg-deficient diets are usuall y kept on their customary high-C:1 diets to meet their growth requirements . Those not Mg deficient enough to die early in convulsions Qr of arrhythmia develop hypomagnesemia, and hypercalcemia and soft tissue calcinosis - with damage to arterie~ . heart and kidneys, not unlike that seen in children with hyperreactivity to vitamin D (see Chapter 5-A in Seelig, 1969). Ruminants consume forage that is not rich in Ca, and develop hypomagnesemia and hypocalcemia, which results in neuromuscular irritability (vide infra).

Ill. ABSORPTION AND EXCRETION OF MAGNESIUM AND CALCIUM

A. Intestinal absorption Interrelations have been demonstrated between Mg and Ca absorption (Aikawa, 1965). With low-Mg intalce, the proximal portion of the small intestine in rats exhibited increased Ca absorption - suggesting 1 conunon intestinal transport mechanism for Ca and Mg (Alcock and Macintyre, 1962), one that might be shared also by strontium (Hendrix et al ., 1963). When the intestinal Mg content was increased to above normal levels, Ca absorption was inhibited (Kessner and Epstein, 1966). Mg is actively transported in the intestine; in the terminal ileum, where Ca was secreted, Mg was absorbed by 1 vitamin-0 independent mechanism (Hardwick et al ., 1988; Karbach and Rummel, 1990). Most srudies of Mg absorption suggest that Mg is absorbed predominantly in the distal intestine. There is evidence, both in animals and humans, for a saturable component of Mg absorption in the small intestine and descending colon that is important at low dietary Mg intakes (Hardwick et al ., 1991). Increasing the Mg intake from suboptimal amounts bas improved Ca absorption (Larvor et al . , 1964; Clark, 1969). Zinc intake also influence$ the excretory pattern of Mg and Ca (Forbes, 1961). It bas been demonstrated iJI several specie$ that high intestiJial CJ content interferes with Mg absorption, causin& conditioned Mg deficiency. It bas recently been shown that the iJitestinal (brush border) saturable uptake of Ca is carrier­mediated, and that it is inhibited competitivdy by Mg and by strontium, a.s is the DOnsaturable electrostatic binding of Ca to the iJitestioal membrane (Schedl et al ., 1990). Increased inte$tinal absorption of Ca, which predisposes to hypercalcemia when associated with Mg deficiency, has long been known to lead to metastatic calcification (Hendrix et al . , 1963; Kessner and Epstein, 1966). A recently demonstrated inhibitory effect of Ca on taurine uptake by rabbit intestinal brush-border membrane vesicles (Miyamoto et al ., 1990) znight also be rdated to Mg deficiency, since it is postulated that taurine is a Mg-sparin& aubstance (Durlach and Durlacb, 1914).

B. Urinary excretion One of the earliest papers on the interrdations between Ca and Mg was the report that infusion of Mg salts increases urinary excretion of Ca (Mendel and Benedict, 1909). It was

dit11cult to interpret, since it may reflect either deposition in bone, or a.s soft tissue c:alcinosis (characteristic of Mg deficiency). A metabolic balance study of an elderly and two middle-aged men recovering from alcoholism, and an elderly woman with rheu~atoid arthritis with probable Me deficiency, all of whom were on high-Ca intake of 2 g/day . showed increased Mg and Ca retention after receiving Mg supplements of I g/day for three weeks (Briscoe and Ragan, 1966). Two metabolic balance studies of patients with osteopathies and/or hypercalciuria, whose Mg intalces were below 300 mg/day, showed that Ca supplementation intensified their negative Mg balances (Parlier et al . , 1963; Amiot et al ., 1968). Another patient with osteoporosis, whose daily Mg intake was higher (334 mg/day) and whose Mg balance was positive ( + 33 mg), responded to increased Ca intake (2 g/day) by reduction of Mg retention to bare equilibrium (Heaton et al . , 1964).

B. Laboratory animal data Since close to 99~ of the body's Ca is in the skeleton (Avioli, 1988), inadequacies of it< intake are reflected by growth failure, bone demineraliz.ation and bone loss. The manifestations of Mg deficiency, which differ by species, might be partially explained hy the different Ca/ Mg ratios of two species with disparate find ings. Rats fed Mg-deficient diets are usuall y kept on their customary high-C:1 diets to meet their growth requirements . Those not Mg deficient enough to die early in convulsions Qr of arrhythmia develop hypomagnesemia, and hypercalcemia and soft tissue calcinosis - with damage to arterie~ . heart and kidneys, not unlike that seen in children with hyperreactivity to vitamin D (see Chapter 5-A in Seelig, 1969). Ruminants consume forage that is not rich in Ca, and develop hypomagnesemia and hypocalcemia, which results in neuromuscular irritability (vide infra).

Ill. ABSORPTION AND EXCRETION OF MAGNESIUM AND CALCIUM

A. Intestinal absorption Interrelations have been demonstrated between Mg and Ca absorption (Aikawa, 1965). With low-Mg intalce, the proximal portion of the small intestine in rats exhibited increased Ca absorption - suggesting 1 conunon intestinal transport mechanism for Ca and Mg (Alcock and Macintyre, 1962), one that might be shared also by strontium (Hendrix et al ., 1963). When the intestinal Mg content was increased to above normal levels, Ca absorption was inhibited (Kessner and Epstein, 1966). Mg is actively transported in the intestine; in the terminal ileum, where Ca was secreted, Mg was absorbed by 1 vitamin-0 independent mechanism (Hardwick et al ., 1988; Karbach and Rummel, 1990). Most srudies of Mg absorption suggest that Mg is absorbed predominantly in the distal intestine. There is evidence, both in animals and humans, for a saturable component of Mg absorption in the small intestine and descending colon that is important at low dietary Mg intakes (Hardwick et al ., 1991). Increasing the Mg intake from suboptimal amounts bas improved Ca absorption (Larvor et al . , 1964; Clark, 1969). Zinc intake also influence$ the excretory pattern of Mg and Ca (Forbes, 1961). It bas been demonstrated iJI several specie$ that high intestiJial CJ content interferes with Mg absorption, causin& conditioned Mg deficiency. It bas recently been shown that the iJitestinal (brush border) saturable uptake of Ca is carrier­mediated, and that it is inhibited competitivdy by Mg and by strontium, a.s is the DOnsaturable electrostatic binding of Ca to the iJitestioal membrane (Schedl et al ., 1990). Increased inte$tinal absorption of Ca, which predisposes to hypercalcemia when associated with Mg deficiency, has long been known to lead to metastatic calcification (Hendrix et al . , 1963; Kessner and Epstein, 1966). A recently demonstrated inhibitory effect of Ca on taurine uptake by rabbit intestinal brush-border membrane vesicles (Miyamoto et al ., 1990) znight also be rdated to Mg deficiency, since it is postulated that taurine is a Mg-sparin& aubstance (Durlach and Durlacb, 1914).

B. Urinary excretion One of the earliest papers on the interrdations between Ca and Mg was the report that infusion of Mg salts increases urinary excretion of Ca (Mendel and Benedict, 1909). It was

276 Pan Two: Functional Rolts in Vivo

later shown tbat infusions of either a Ca or M& salt increases tbe urinary output of the other cation (Samiy et II., 1960}. Acute intravenous (iv) loadin& of do&s with Ca bas increased renal ucretion of M1 si1nificantly (Wallach aDd Caner, 1961; Cbartloo IDd Hoebtta. 1962). Contributory 10 tbe C.-induced increased Me excretioo mi&ht be tbe resuiWit increase in ultrafiltrable suum M&. caused by bindinc of Ca 10 plasma proteiD& (WaJiacb • al ., 1966). Patients whh bone-losin& diseases bave responded 10 iv Ca in.fusioo by increased urinary Me and falls in serum (Keclt et al., 1980). Mechanisms involved in iDtetactioDS iD renal excretion of Ca and M1 have been reviewed in deull (Massry aDd Coburn, 1913; Massry, 1981; Quamme, 1986). The reabsorption of M& occurs throu&bout the oepbtoa with most of filleted M& reabsorbed by tbe proximal rubule aDd the ascetldin& limb of the loop of Henle, which is also true for Ca. The tubular reabsorption of botb Ca aDd M& is so effective th11 0 .5-1.0" of tbe Ca filtered throu&b tbe &lomerulu.s (about I 1 &lday) and l -51. of the filtered M& (1 .8 &lday) is ucreted in the wine (Massry ID4 Coblllll, 1973). There is a awtimum rubular reabsorptive capacity for M& (TmM&), but oot for Ca (Massry and Coburn, 1973), which when lowered transiently or permanently, causes hypomapuemia (Parlin, 1980).

Supplemenwion of mar&inally M&-<leficient older woman with an amount of boron equivalent to that provided in 1 diet rich io fruits and ve&etables has been shown to dimioisb urinary loss of M& and Ca (Nielsen et al ., 1987).

Thebormones that affect bone metabolism: PTH, CT, and vitamin D meubolitu, and the effect of M& deficiency on their release and activity (Fateml ec al ., 1991) (cortsidered elswhere in this volume) affect rubular reabsorption and tbu.s their u.rinary excretion. New data have expanded our understandin& of mechanisms by wbicb renal bandlin& of Ca and M& a.re controlled. Jn water diuresed rau aiven I prosucyclioe (PGI)-inhibitor, the fractional excretion of botb Ca and Ma declined about balf (Roman et aJ., 1984). A Ca­ch&nnel bloc.ke.r prevented the renal blood flow reduction aDd Increased blood pressure produced by eodothelin (ET-J) in normotensive rats (Madeddu • aJ., 1990). Synthesis of PGJ, which counteractS the vasoconstrictor effects of norepinephrine In the kidney, Is increased by renal ischemia (Dunn, 1989). Differential renal excretion studies iD bypenensive patients disclosed that ischemic t.idneys reabsorb more Na and Ca than M&llld K (Parfitt and Lukin, 1968). Either Ca-cbannel blockade or PGI·lnhibitlon prevented M& infusion-induced decline in blood pressure and increased renal blood flow in oormal volunteers (Nadler et II., 1987).

IV. PLATELET· AND ENDOniEUAL-DERIVm FACTORS, CALCIUM AND MAGNESWM

Recent work on effects of platelet- and endothelial~ulved substances lodicates additional ways in which Ca and M& exen anu&onistic etl'ects. From platelets a.re dulved PCiiJ, with vasodUator and anti-platelet a&&re&lliD& properties, aDd thromboxane (TXB), with vasoconstrictor and platelet clumpina properties. lbe endothelium produces several substances, three of which are considered bue: tbe endothelial derived relaxin& factor (EORF), wbicb has been Identified as nitric oxide (NO), as well as PGl, and ET-1, th• is vasoconstrictive aod enhances platelet au.recation. Synthesis of and mediation by PGI is M& dependent (Nadler et al., 1987; Nicam et II., 1986). PGI mediates, It least iD p&n. the vasodllatory effects of infused Me (Woods, 1991). lD iu absc:DU, PG1·ioduced relaution iD isolated rat aonic strips is prevemed (AJrura et II ., 1980). PGl &Dd M& infusions elicit aimilar hemodynamic effects (Ber&DWI et aJ., 1981), aDd iD vitro exposure of (WDbilicaJ) vascular endothelial cells to vasodilllin& concenttllioDS of M& ltimWatea release of POl (WatsOn et al. , 1986; B.riel et al., 1917). The production of TXB bas beeD abowa to be increased by chronic M& deficiency in rau, as was PGJ, but to 1 lesser dqree (Ni&am • II., 1986; Soma et aJ., 1989); lhe 11et effect was interpreted to lodlcate tbo couoterac:Uoo by M& of facton that constrict the vasculature. Canloe coronary arteries exposed to twice oonnal Me levels did DOt alter NO-dependent relaxation, but direc:t.ly lobiblted spootaoeouJ release of NO, and was thus considered imporunt for exprusion of eodotheliaJ~ependeot relaxation induced by acetylcholine and thrombin (Ku and ADD, 1991). Dietary deficiency in normal humans caused marked iocre.a.~t in TXB. which w3< rf'rlnr-M llft"r M" ; .,~ .• :~-

(Nadler ec al . , 1989). Physical stress of marathoners cave rise 10 an Inverse relationship between serum M& and TXB. The TXB fellsli&htly early in the rau, but rose 9-fold by tbe end of tbe race, at which time serum M& levels bad fall eo (Franz ec al ., 198S).

The vasoconstriction induced by ET-1 is Ca depeodeot, and can be blocked by Ca anuconists but DOt by nitrovasodila&ors or NO (Dinb-Xuan, 1989; IGowskl, 1991). ET-1 liberates le Cal+, and ltimulates Ca chanDeiS (Masaki et al. , 1990), effects an~~oniz.ed by C.-channel blockers (Lovenbera and Miller, 1990). As in vascular muscle, Ma + plays a role in ea2+ bomeowsls in endothelial cdls, probably via Na(+)-Ca2+ acblll&e: sudl M&( + )- reaulation panicipatea in upreuioo of eudotbelial~ependeat rclaution (Zbana It al ., 1990). Ca-cbannt1 bloctace also inbibits ET-1 contractioo of bronchial smooth IDUide in vitro (Lerman et al. , 1990). Since M& is a pbysiolo&ic Ca blocker (lseri a.od Freodl, 1984), the vse of M& in bronchial asthma m.i&bt be mediated, DOt Ollly throvah ils anti­bistarDine-release etrect (Huoaetford and Karson, 1960) which Is couotered by ucess Ca (Benelseo and Johansen, 1991), but throu&h its etrect on ET-1 (BNDDet et al., 191S; Mathew and AJtura, 1988; Rolla ec al. , 1988). More direct dm oo the influence of M& on the ET-1 effect bas beeD derived from studies of Ca-dlannel curnnts ill neurooes (Nishimura ec al., 1991). Hi&h-M& containincsolutioos depressed the ET-induced current.

V. II'ITERR.ELATIONS AMONG CATECHOLAMINES, MAGNESIUM AND CALCIUM

Studies with catecbolamlno-seaecin& Jflllules from adrenal medulla or nerve endin&s uposed 10 low· M&Ihiah-ca ratios or bi&)I·M&Ilow.Ca ratios have shown that low M& increases catecholamine release and that hi&b M& decreases it, whereas Ca bas reciprocal effects (Dou&la.s and Rubin, 1963; 1964; Boullin, 1967; Kirpekar and Misu, 1967; Euler and Llshajko, 1973; Baker and Rink, 1975). The effect of verapamil, a Ca-ch2nnel blocker, on catecbolamioe release has beal compared with lhat of M&. a physiolo&ic Ca-blocker~ Lowerin& Ma levels bas cavsed dose-dependent elevation of norepinephrine in cats. Reduction of M& caused increased vasocoDStriction of norepinephrine-contracted vein secmenu (Subo ec al., 1992), but 110rc:pipepbri~indu'ed (:Qfltractions were no1 affected in the mesenteric anery at low ec M& (0.1 mM vs normal, 1.2 mM); bi&b (1.6 and 2.0 mM) M& bad a modest inhibitory effect oa the contractile responses (Szabo ec al . , 1991). Cerebral arterial contractions of the at induced by norepinephrine in vitro were enhanced by low and Lnbiblted by hi&h M& concentrations, the etrect bein& attributed to both inhibition orCa influl and bindin& of acetylcholine 10 an endothelial receptor (Fara&o ec al ., 1991).

Evidence that Ma could counteract Ca·induced catecholamine release from arterial nerves led 10 the fint premise that low levels orCa In blood mi&ht lead to low arterial tone, which ill turn au&&ested tbat bi&)l Ca levels mi&ht Increase blood pressure (Burn and Gibbons, 1964). The earliest dinical use of iv MJ was to contrOl the hypertension of eclampsia (l..azard, 1925). AJthou&b thiazide diuretics lar&ely replaced M& for a time to mana&e prernancy-induced hypertension, retufll to Mr was ur&ed as lhe primary uutment, replacin& all other modalities, because in addition to lowerin& bi&h blood pressure of toumlc prernancy, it Increases uterine blood flow, depresses uwioe hyperactivity and is associMed with improved fetal ulva&e (Zuspan and Ward, 196S). It is noceworthy that the thiazide diuretics have 1oor been bowD to increase Ca retention (\.amber& and Kuhlback, 19S9; Duane and Bland, 1965), while iocrea.sio& Mr elcretion (Smith ec al. , 1962; Wader and Parisi, 1961; Uaslped Editorial, 197S; Dycber and Wester, 1984; Leary et al . , 1914). Contributory 10 lhe lldvene effects of M& Inadequacy In prqnancy is the effect of ~i&h CalM& ratio on lntravasc:ular coa,Wation- especially iD the placcnu, where endothelial dama&e paniclpa&es ill tbe pathoaeoesis of eclampsia, and iD which M& treatment increases PGiaynthesil by endothelial cells (WIISOD • al., 1986; Briel ec al. , 1987; SeeliJ, 1993).

Vl. MAGNESJ\JMJCALCIVM RATIOS IN COAGULATION

Many lteps in the c:oaaulation cascade, that are stimulated by Ca, are Inhibited by M& (Hunuman ec al . , 1960; Zahnert and Oloffs, 1960; Oreville and Ldlmann, 1944; Born and Cross, 1964; Hovir, 1964; Lorand and Konishi, 1964; Silver, 1965; Penrlis and Mirta~•

!able !

Calcium and MIJIIeslum Etrec:u oa Blood Coqulalioa

Fld.Or VD actlvatlon Fld.Or X activation Produombio -+ thrombin Prothrombio time Prothrombio consumption Fibrino&en -+ fibrio Platdet adhesiveness Serotonin rdease

(increases platelet clumpin&) Fibrinolysis Fibrinolysis Inhibition

Calcium

Depelldeot• Depelldeot•• Depeodeot•• Shortened locrased IDcrcased IDcrcased IDcrcased

7 7

• + lipoprotein tissue factor. •• + phospholipid Taken from Scdi& (1993).

7 7 lllhibited Leo&theoed Decreased Decreased Decreased Decreased

Increased Decreased

1969; Herrmann et al . , 1970; Annie et al. , 1970; Doni and Fantin, 1975) (Table I) Practical application of the anticoa&Uiant activity of M& is aunested by the early worl 5howin& that M& supplements prevented spontaneous myocardial infarction (MI) occurrin1 in rats, do&s and cocks on M&-deficiency ioducin&, nutritionally Imbalanced athero&eni· diets, that were rich in calcemic vitarni.D D (Sos, l96S; Ri&o, 1971). In a more specifi study, M& deficiency was found to c:oauibute to increased platdcc aure,ability dill increased myocardial wlnerability to ischemic injury in M&-deficient hamsters (Rishi et al . 1990). Additionally, M& bas prevented platelcc a&&re&ation on upuimeolally darnaae.. endothelium, an activity that bas been interpreted as applicable to prevention and treatmen of ischemic heart disease (IHD) (Kuraan et al ., 1980; Genz et al ., 1987).

Mechanisms by which I hi&h CalM& ratio Increases platdcc anreaation also entail PG and TXB. Dietary M& deficiency i.o oonDJl volunteers stimulated PGI and TXB synthesh and increased platdet aure&ation that was corrected by M& infusion (Nadler et al., 1989 1991). Diabetics, who have low ic M& levds, Uld DOrrnalsubjects OD a low eoouah M& die to cause bypomaanesemla had increased platelet reactivity that could be reduced eith.er b~ M& infusions or by oral M& supplement$~ iiJO ma/day (Nadler et al. , 1992).

VII. NEUROMUSCUL.AR RJNCTIONS AFFECI'lD BY MAGNESIUM ANI CALCIUM

A. Historical aspects The first published account of the efficacy of M& in manaaement of a variety of nervou! complaints, lncludin& lnlliety, depression, hypochondria, aoorula, headache, and cramps. amon& other disturbances, was in a seventeenth century booklet (Grew, 1697). n~ functional similarity of Ca and Ma in muscle contraCtion (to vitro Inhibition of rbythmk contraction of froa 's aastrocnemius muscle) was an early subject of systematic iovesti&atior (Loeb, 1900). Not only Ca and M&, but beryllium, barium, strontium, tiWl&anese, ~ cobalt suppressed spontaneous muscle contractions. Ca was soon thereafter shown, ill rabbits, to antaeonize inhibitory effects of M1 on irritability of contraCtile tissue and moto• nerve endines (Meltzer and Auer, 1908). These early investi&ators emphasized the musclt relaxin& effect of M1 in lower than toxic doses . Spontaneously occurrin& imbalances between Ca and M& intakes that caused neuromuscular disturbances were first reco&nized in cattle (Seekles et al ., 1930; Sjollema, 1932).

Only the aspect of the effect of M& that relates to Ca is cons•dered here (based pnnc1pally OD reviews by Cbutkow (1971; 1980). Althou&h hypocalcemia and hypoma&nesemia each causes clinically manifest neuromuscular irritability, nerve physiolo&Y studies show that the mechanisms are not the same. Ca is chiefly involved in nerve axon membrane potential and stability. The effects of Ca or M& depletion at this site are similar, but that of Ca far outwei&hs that of M&. The moiety of ec: M& that is not bound participates principally in aeuromuscular transmission at the myoneural junction where Ca and MJ are anta&onistic. M& Impedes the entry of Ca into the nerve terminal, thereby reducin& the release of acetylcholine. MJ deficiency has the opposite effect. Penetration of the nerve presynaptic membrane by Ca is low when the membrane potential (Em) is at restin& levels. Depolarization of the presynaptic membrane &reatly inc.reases Ca influx and release of acetylcholine. Ma bloclca&e of neuromuscular transmission has lon& been known to be counteracted by Ca (Bryant et al ., 1939). The effects of M& on impulse transmission from nerve to muscle clarified its pharmacolo&ic effects at the neuromuscular junction (En&baek, 1952; del Castillo and Engbaelc, 1954). At concentrations above physiolo&ic, but below those that prevent nerve conduction, Ma activates cholinesterase, which destroys the neurotransmitter, and reduces the release of acetylcholine, effects which are counteracted by Ca.

C. Therapeutic aspects Neuromuscular irritability, that can cause seizures and tetanic spasms, occurs with either bypomaJnesemia or hypocalcemia, and respoods to appropriate repletion. Since Ca­refractory hypocalcemia not infrequently results from M& deficiency, which causes refractoriness of tar&et or&ans to YTH or failure of PTH-release and decreases synthesis of the active metabolites of vitamin D (Fatemi et al., 1991), its appropriate treatment is M& rather than Ca.

The latent tetany syndrome, accompanied by a variety of "psychosomatic" complaints, that develops despite normal Ca levels, bas been clearly identified as a Mg-i!eficiency disorder {Durlach, 1960; 1988) (see Part Five, Chapter 1-8).

VIII. CARDIOVASCULAR flJNCTION

A. Historical aspects The efficacy of iv M& in arthytbmias cllused by lv Ca was firSt demonstrated in cows bein& treated for &rass tetany (Seekles et al ., 1930). The potential clinical haurd of iv Ca was first shown in 1928 by Lloyd, who injected himself with CaCI2: SOcc of a 1 ~ solution produced no adverse effects, but after only 4cc of a 10~ solution bad been &iven, cardiac arrest ensued, with recovery on cessation of the injection.

The similarity of the effects of bigh-i!ose iv Ca to the therapeutic effect of di&italis, but with more rapid onset of effects, led to its being considered additive in cardiotherapy; it increased blood pressure and slowed the heart rate, but could cause bradycardia, heart block and artbytbmias (Lieberman, 1930). Therapy with combined diaitalis and Ca was deemed safe in the 1930s (Berliner, 1936), but death of digitalized patients alveo iv Ca (Bowers and Mengle, 1936) led to reevaluat.ion of this therapeutic approach (Golden and Drams, 1938). Conversely, the earliest human use of M& was in the treatment of arrhythmias caused by digitalis toxicity (Zwillinaer, 1935). Use of iv Ca salts to measure circulation time was replaced by Mg salts because of the risk of Ca injection, which bad to be rapid for this test despite the aenerally accepted caution that Ca bad to be injected slowly to minimize its toxicity (Berliner, 1936). ln contrast, such use of iv M& in a lar&e series of patients was free of deleterious effects (Bernstein and Simklns, 1939).

Subsequent disagreeme.nt as to use of Mg for cardiac arrhythmias stemmed largely the ephemeral effect of the customary use of sin&le doses (Enselber& et al. , 1950), despite the evidence of its efficacy in anta&onizin& the increase by Ca of cardiac stimulus formation (Boyd and Scherf, 1943) without untoward effects. The inward sbif\ of Ca stimulated by catecbolamines is important in cardiac contractility, but can be excessive in patients with IHD, in which case the chronotropic responses to catecholamines (that concern rhythmicity)

. r

predominate, and there is increased risk of arrhythmia and myocardial cWna&e (Nayler, 1981). When there is M& inadequ~cy, even in normal subjects, die chronotropic effea of catecholamines may cause arrhythmia and even sudden cardiac death.

There were only occasional publitllions on use of M& iD dia.ical arrllythmias and IHD (Zimdhal, 1946; Sz:dcely, 1946; Sz:dcely and WyMe, 19SI; Malkid·Sbapiro et al ., 19S6; Malkiei-Shapiro, 19S8; Panons et al. , 1959), until iu importance was clarified in 1be 1970s, even without oven Me deficiency (lseri et al ., 1975; Specter et al ., 197S). Its use ill di&i~is toxicity and in thiazide-induced arrllythmias which relate to coacomitant Ca excess became more popular (Dyckner and Wester, 1979; 198-4; 1987; Leary et al., 1984; Reya and Leary, 198-4; Reyes, 1987). At the Fifth International Me Symposium, ill Japan, lbe imponance of M& in correct in& tbe electrolyte disturbances associated with arrhythmias was reviewed (lseri , 1989; Whane, 1989). That Me trewnent actually replenishes a deficiency was pointed out by Charbon (1989), who further commented that Me and Ca act as antaronists with rerard to cardiac arrhythmia. Direct evidence of tbe life-uvin& potential of post-infarct M& infusions bas been shown by controlled double-blind studies ill which tbere was substantial reduction of post-Ml arrhythmias and deaths (reviews: Rasmussen, 1988; 1989; Shechter, 1990; Teo et al ., 1991).

IX. DISE~ES WITii INTESTINAL OR RENAL LOSS OF MAGNESIUM OR CALCMI

Clinical Intestinal malabsorption can interfere witb absorption of botb Me and Ca. Routine laboratory procedures usually detect hypocalcemia; more likely to be missed is bypomarnesemia, because M& levels are not usually provided unless specifically requested. Thus. malabsorptive disorders, whetber inflammatory or ulcerative bowel disease, malabsorption of fat (i.e. celiac disease, steatorrhea), or after intestinal resection or bypass, persistent diarrhea, and other forms may result in Me deficiency lhat is severe before it is detected and treattld (Hammarsten and Smitb, 1957; Balint and Hirscbowitz:, 1961; Goldman et al . , 1962; Heaton et al . , 1964; Gerlach et al . , 1970; Ladefo&ed et al. , 1980; NyhliD et al ., 1982; Hessov, 1983; Selby et al ., 1984; Galland, 1988; SjOereo. 1988). Hi&h intestinal fat content interferes with absorption, not only of Me, but of Ca and Zn (Hessov et al., 1983). The specific renetic malabsorption of M& invariably results in Mr deficiency, that is usually first identified by failure of hypocalcemia 10 respond to calcemic therapy (Paunier and Radde, 1965; Paunier et al. , 1968; Skyberr et al., 1968; Friedman et al . , 1967). Decreased Mg absorption has also been reponed in renal failure, wilh progressive decrease of Mg absorption as renal failure prorresses (Parlier et al., 1963; Mountokalakis et al ., 1980).

Renal M& wastaae causes hypoma&nesemia, aaaio usually witb secondary hypocalcemia; it can result from thenpeutic drup, disease (illcludin& alcobol abuse and diabetes mellitus) (Flink et al ., 1957; Kalbfleisch et al. , 1963; Mendelson et al ., 1969; Medalle et al ., 1976; Hui et al ., 1985; Rude and Ryun, 1986; Flint, 1986) from renal &enetic defects, includin& Bartter's syndrome (Free.man and Purson, 1966; Gitelman et al., 1966; Michelis et al., 1972; Runeber& et al., 1975; Rude et al. , 1983; Rude and Ryun. 1986; Dupond et al. , 1989).

When hypocalcemia is dia&nosed, and M& deficiency is DOt suspected, treatment witb Ca salts andlor with calcemic a&ents is the usual approach, but is ooe that intensifies die · underlyin& M& deficiency and th~ can result in wft tissue Ca deposition (Seeli&, 1971; 1980; 1981; 1986; 1990; 1993; and Pan Four, Olapter S·A). Neuromuscular hyperirritability and increased vascular tonicity are exampla of lbe overlap of manifeswions of Ca and M& deficiencies. The combination of bypomapesemia witb hypocalcemia has been reco&nized as contributory to humaa neonatal t.etany, spasms IIIII convulsions (Tsang and Steichen, 1975), as well as to comparable manifestations ill adults with M& deficiency from malabsorption or renal wastare. The symptoms respond beuer to Mr than to Ca treatment (Turner et al., 1977).

Disorders associated with hypercalcemia and bypercalciuria Include conditions that increase intestinal absorption of Ca, as can result from wcoidosis (Pale, 1979), vitamin D toxicity or hyperreactivity to vitamin D (Seeli&. 1969). lbe hypercalcemia of

hyperparathyroidism and neoplastic osteolytic processes is derived from mobiliz.atioa of C. from the bone. lD c.ontrut, bype:r~mpesemia Is an uncommon di.Dical problan; ~ DeUrOmuscular, respiratory, and c:anSiac depressant effects can be temporarily coatroUed b) Ca infusioo.s (Rude and Sinaer, 1981). It can result from bi&h M& iDlake, • cathartia or anucids, almost exclusively by tbOK witb rmal decompensation. Hypermape&elllia ba! beta 1eeo iD neonatal infants before ldequate renal function bas devdoped (i.e. thole bon to eclamptic IDOthers wbo bid received bypenoa&naemia-indutin& pareateral Ma treatmen• tD control their convulsloas and byperunsion (Lipsitz, 1971) or very immature Infants. especially those whose hypocalcemia wu treated by biab-®se iv M& (TIIDJ, 1972).

X. CONCUJDING COMMENI'S

Wbether deficiencies of Ca or M& are caused by relative excess intake of oae iD tbe face ol inadequate iatalte of the other, or wbetber caused by dru1s or autrients that enbaDce du absorption or cause loss of oae over that of the other, they can bave serious coaseqveDCes ·

functional and structural. Mj dietary intakes In the Occ:ident are marainal or low; with some exceptions, du

dietary intake of Ca is usually adequate. Occult M& deficiency, IDd eveo franl bypomaanesemia (that is undetected) is a more common problem tban is Ca defiCiency Hypennaanesemia is uncommon as compared with hypercalcerrua. The current emphasis or Ca supplementation to brinJ intakes to u hi&h as 2 &!day, which with the RDA for Mr bein& about 300 m&lday or less, constitutes a public health risk.

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