Magnes Res 1992 Jun;5(2):147-53
Magnesium and blood pressure. II. Clinical studies.
J. Durlach1, V. Durlach2, Y.
Rayssiguier3, M. Bara4 and A.
Guiet-Bara4
1SDRM, Hôpital St. Vincent-de-Paul, Paris,
France; 2Clinique Médicale U52, Reims, France;
3Laboratoire des Maladies Métaboliques, INRA
Theix, France; 4Laboratoire de Biologie de la
Réproduction, Université P.M Curie, Paris,
France
Summary: Magnesium deficit may be
considered as a cardiovascular risk because of its
aetiopathogenic role in the genesis of atherogenous
dyslipidaemias and the so-called "idiopathic" mitral valve
prolapse. It does not, however, constitute a major
antihypertensive factor, though it may sometimes be an accessory
co-factor. Plasma magnesium is generally normal in untreated
hypertensive patients and normotension is the rule during
magnesium deficit. An inverse relationship between magnesium and
renin in the plasma of hypertensives has not been confirmed. In
practice, plasma magnesium seems to be related to the evolution
of the disease. An inverse correlation between blood pressure and
erythrocyte total and free magnesium levels has been observed in
diverse selected populations but no adjustment has been made in
these studies for important covariables. A weak positive
association between blood pressure and erythrocyte free magnesium
was lost in a multivariate regression analysis. As a rule there
is no difference between erythrocyte, leucocyte, and lymphocyte
magnesium in hypertensives and controls. More often no relation
between urinary magnesium and blood pressure is observed. Daily
urine magnesium may be increased with increased excretion of
urine adrenaline. Epidemiological data on dietary magnesium,
particularly in drinking water, should be carefully scrutinized:
these studies do not establish a major role for magnesium as an
antihypertensive factor but confirm the importance of magnesium
deficit as a nephrocardiovascular risk factor and sometimes gives
support for a role of magnesium as an antihypertensive cofactor.
The use of magnesium-depleting drugs in hypertensive patients may
induce magnesium depletion which must be palliated. In none of
the double blind placebo-controlled studies of magnesium therapy
in hypertensive patients was a significant fall in systolic or
diastolic blood pressure observed. Monotherapy with oral
magnesium cannot be considered as an efficient treatment of
hypertension or be used as a substitute for drugs of proven
efficacy. However, in some hypertensive patients with magnesium
deficit, its deleterious effects on the nephrocardiovascular
apparatus must be controlled. The well known pharmacological
hypotensive action of parenteral magnesium may be used in
hypertensive patients --in pre-eclampsia particularly--but the
pharmacological mechanisms are observed irrespective of magnesium
status. Such effects should not be used as a diagnostic tool in
the investigation of magnesium deficit.
Key words: Blood pressure,
diabetes mellitus, dyslipidaemias, magnesium, mitral valve
prolapse.
Introduction
Magnesium is an important factor in the physiology of the
cardiovascular apparatus and the pathogenesis of cardiovascular
disease. However several methodological errors are definitely
misleading.
Extrapolation from pharmacological effects to physiological
properties is obviously erroneous. Many papers consider that
proof of the importance of magnesium deficit in the pathogenesis
of cardiovascular diseases is provided by the effects of
parenteral magnesium or of high oral doses of magnesium (equal to
twice the RDA or more, ie 12 mg/kg/d), but such data are purely
pharmacological. The physiological properties of magnesium can
only be demonstrated by the occurrence of symptoms due to in
vivo magnesium deficiency, followed subsequently by its
specific control with supplementation through physiological oral
doses of magnesium (usually 5 mg/kg/d, always less than twice the
RDA, ie 12 mg/kg/d)1-3. The pathophysiological role of
magnesium deficit is shown by the parallel correction of the
related symptomatology.
Control of magnesium deficit depends on the nature of the
magnesium deficit1,2. The difference between magnesium
deficit, magnesium deficiency, and magnesium depletion should not
be overlooked. In magnesium deficit, it is very important to
distinguish between magnesium deficiency, where the
disorder corresponds to an insufficient magnesium intake which
merely requires simple oral physiological magnesium
supplementation, and magnesium depletion, where the
disorder is related to a dysregulation of the control mechanisms
of magnesium metabolism which requires appropriate
correction1,2.
The main expression of primary magnesium deficit is closely
linked with the consequences of long term chronic marginal
magnesium deficiency. Experimental and clinical forms of chronic
magnesium deficiency are now more and more easily identified and
differ from overt signs of acute deficiency1-3.
Coexistence of symptoms with markers of magnesium deficit,
even though correlated, should not be mistaken for causality.
Parallel control of both is necessary to prove this connection.
This shows the importance of the magnesium oral loading
test1,4,5. At a physiological dose level (5 mg/kg/d)
of a well absorbed salt for at least one month, oral magnesium is
totally devoid of the pharmacodynamic effects of parenteral
magnesium. Correction of biological and clinical symptoms after
one month of such treatment constitutes the best proof that these
were due to magnesium deficiency. Conversely, physiological doses
are ineffective in magnesium-repleted patients1,6-9.
The more precise diagnosis of magnesium depletion rests on the
identification of dysregulating factors concerned with magnesium
metabolism1,4,5. <./P>
Experimental studies on magnesium and blood pressure have
showed that in vivo chronic marginal magnesium
deficiency either did not affect blood pressure or initially
decreased and subsequently increased it3,10.
The aim of the present study was to establish the importance
of magnesium in hypertensive disease. We shall first discuss the
epidemiological and biological data; second, evaluate the role of
magnesium deficit in various cardiovascular risk factors:
dyslipidaemias, diabetes mellitus, and mitral valve prolapse; and
third, show the importance of magnesium supplementation as an
adjunct to the treatment of hypertensive patients.
Epidemiological data
Magnesium level in drinking water
Among the numerous variables involved in the inverse
correlation between cardiovascular morbidity and mortality and
the hardness of drinking water, magnesium appears
pre-eminent11. The critical quantitative intake of
water magnesium may palliate the absolute marginal magnesium
deficit commonly found in developed countries4 and its
multiple consequences, particularly on the nephrocardiovascular
apparatus. Even in the case of a balanced daily magnesium intake,
water magnesium may act qualitatively on the nephrocardiovascular
apparatus by palliating a magnesium deficit resulting from an
inadequate intake of this highly bioavailable source of
magnesium4,11-14. It can reduce the activation of the
neuroendocrine regulatory mechanisms of magnesium homeostasis
which also control the metabolism of Cl, Na, K, P and Ca and the
regulation of vasomotor tone1,11. Corrosivity is the
other major factor in the role of drinking water in
cardiovascular risk. The harmful effects of corrosive waters are
mainly due to two toxic metals, Pb and Cd, which have cumulative
toxicity on the nephrocardiovascular system particularly.
Magnesium appears to be a competitive inhibitor of these two
polluting metals at different sites, particularly during combined
intoxication1,11,15. It seems advisable to have at
least 30 mg/litre of magnesium in the drinking
water1,11.
Dietary magnesium
The data concerning the links between magnesium intake and
cardiovascular diseases are scanty and contradictory. Among other
multiple dietary factors, magnesium intake shows either an
inverse association or none at all with blood pressure(reviews
11,16-18). These studies do not establish a major role of
magnesium as an antihypertensive factor. People eat food, not
nutrients, and it may be difficult to demonstrate an independent
effect of a single nutrient in observational studies.
Epidemiological studies are necessarily interpreted in the light
of well established physiological principles. On the basis of our
present knowledge of the physiological relationship between
magnesium and blood pressure, magnesium does not appear to be a
major antihypertensive factor, but only a possible
antihypertensive cofactor in particular cases. Thus, by using the
interesting concept of multicollinearity, the same
epidemiological studies concerning magnesium and other nutrients
with better established links with blood pressure could be
differently interpreted11,16. In any case coexistence
does not mean causality and we shall see that controlled
magnesium supplementation studies are always ineffective.
Magnesium in urine
Various studies have examined the possible correlation between
urinary magnesium level and blood pressure. When renal function
is efficient, these levels should reflect the dietary intake of
magnesium; sometimes an inverse correlation between daily
magnesuria and blood pressure is observed19, but more
often no relation is found16.
A study of the relationship between daily magnesuria and
several hormones which regulate blood pressure in mild essential
hypertension has shown that daily urine magnesium significantly
increases but only in the group with comparatively increased
excretion of urine adrenaline20.
Serum or plasma magnesium
Plasma magnesium is generally normal in hypertensive
individuals and normotension is the rule during magnesium
deficit11,19. An inverse correlation between serum
magnesium and blood pressure is sometimes
observed16,21 but it is not the rule16,22
and it may depend on the concomitant use of magnesium-depleting
drugs1,22. An inverse relation between magnesium and
renin in plasma23 was not confirmed in other
studies19,24,25, in agreement with our recent
experimental data10. In fact serum magnesium seems
related to the evolution of the disease. A positive
correlation has been observed in moderate hypertension which
tended to disappear when hypertension became more
severe17,24. An early clinical study of patients who
had severe hypertension with end organ disease demonstrated high
serum magnesium concentrations16.
Intracellular magnesium: magnesium in erythrocytes and
leucocytes
An inverse correlation between erythrocyte magnesium levels,
and free magnesium in particular, and blood pressure has been
observed in diverse selected populations of hypertensive patients
but no adjustments were made for important
covariables16. A weak positive association
was found between free magnesium and mean blood pressure. This
relationship was lost in a multivariate regression
analysis25. As a rule there is no difference between
erythrocyte magnesium concentrations in hypertensive patients and
controls26. There have been similar observations
relating to leucocyte magnesium27,28.
To sum up, these epidemiological and biological magnesium data
do not yet allow final conclusions to be drawn, but they do not
seem to support the notion that there is an important link
between magnesium deficit and the hypertensive state.
Magnesium deficit and cardiovascular risk
Parallel control of both magnesium deficit and cardiovascular
risk is necessary to establish a causality link: some magnesium
supplementation trials have appreciated the role of magnesium
deficiency in dyslipidaemias, and of magnesium deficit in mitral
valve prolapse where depletion appears more frequent than
deficiency, showing its aetiopathogenic importance. However,
studies on the control of magnesium depletion in hyperglycaemias
are very scarce or lacking.
Magnesium deficiency and dyslipidaemias
Correlation studies have indicated a positive correlation
between serum magnesium and HDL cholesterol and a negative
correlation between serum magnesium and total
cholesterol29. Epidemiological studies point to the
fact that high dietary magnesium is correlated with high serum
HDL cholesterol and low serum total lipid
concentrations30. Thus several open studies were
carried out to study the effects of oral magnesium
supplementation of at least one month's duration in physiological
doses, in addition to the usual dietary measures31.
There were no positive effects of these interventions on blood
pressure7,32,33, and the effects on the lipid profile
were either positive or negative7.
The beneficial effects mainly concerned serum
triglycerides33, with no significant
effects33 or with significant effects33 on
the cholesterol fractions (observed after the longest
supplementation - 118 d). In a double blind placebo-controlled
study in a group of patients with ischaemic heart disease, oral
magnesium supplementation controlled the deleterious lipid
profile33a. Another double blind study included 2
months of placebo, 2 months of oral physiological magnesium
supplementation, and a final 2 months of placebo; triglyceride
concentration decreased during magnesium treatment by 30% and
increased by 18.1% after switching over to placebo34.
Activation of serum lipoprotein lipase activity may be involved
since this is also observed in parallel with a decrease in
triglyceride levels following the pharmacological intravenous
infusion of MgSO4.35 The observed
data36 suggest that the subjects tested (with
hyperlipoproteinaemia types IIa, IIb, or IV) presented magnesium
deficiency, since they were diagnosed through a positive oral
magnesium load test5. These common types of
dyslipidaemia may thus depend on magnesium deficiency.
Aetiopathogenic importance of magnesium deficit in idiopathic
mitral valve prolapse
The so-called idiopathic mitral valve prolapse (IMVP) is
merely one form or aspect of latent tetany due to magnesium
deficit (MDLT)1,17,37-40. The prevalence, latent
nature, and symptomatology of these two conditions appear to be
strictly similar. Routine examination reveals the auscultatory
and echocardiographic findings of IMPV combined with clinical and
electromyographic data compatible with latent tetany. Clinical
chemical evaluation must involve at least the examination of
plasma and erythrocyte magnesium, plasma calcium and 24 h urinary
calcium. These should be assessed during dynamic testing with an
oral magnesium load in physiological dosage, with, in addition,
the measurement of 24 h urinary magnesium. Other more
sophisticated tests may be necessary in certain special clinical
forms. Like MDLT, IMVP would appear to be usually a benign
condition (95% of cases) and even capable of recovery, though in
a minority of cases it may be a risk factor. It is thus essential
to identify adverse prognostic factors such as very marked
symptomatology and in particular ventricular arrhythmias, low
body weight, evidence of mitral regurgitation, hyperechogenic
mitral valves, especially in elderly men, prolongation of the QTc
interval, a high "excitability index", thrombogenic disorders,
particularly of platelet origin, immunological disorders,
constitutional factors such as the presence of HLA
Bw35 antigen, rarely a family history of sudden death,
and finally a magnesium depletion requiring difficult and
sometimes chronic treatment. The aetiology of magnesium deficit
covers mesological factors (e.g., inadequate magnesium
intake, in particular during weight-reducing diets, stress etc.)
together with constitutional factors(e.g., HLA
Bw35 antigen, behavioural type A, etc.). The latent or
symptomatic state depends on the efficiency of magnesium
homeostasis. Magnesium deficit may cause abnormalities in
collagen as well as in the myocardium capable of inducing mitral
dyskinesia. Magnesium therapy is an essential specific feature in
IMVP. A simple increase in magnesium intake is required in the
minority of cases due to deficiency, but in the majority of cases
due to depletion it must be combined with magnesium-sparing
diuretics, pharmacological doses (of between 0.75 and 1.0 g/d) of
pyridoxine hydrochloride, or physiological doses of vitamin D
(e.g., 5 micrograms of 25-OHD/d). Propanolol, verapamil
and phenytoin may sometimes prove useful partial "magnesium
analogues". In cases of mitral insufficiency and/or thickened
hyperechogenic valves, antibiotics must be prescribed in the
presence of any circumstances likely to result in bacteraemia.
Such treatment is capable of controlling symptoms and more rarely
echographic abnormalities, sometimes (one case out of five)
leading to complete recovery. Early treatment of MDLT should
prevent the development of mitral valve prolapse. Comparison of
the well known prevalence of IMVP (5% of the population) and our
magnesium concept of its aetiology (a complication of 1/4 or 1/3
cases of MDLT) implies the high prevalence of MDLT (15 to 20% of
the population). The prevalence of this condition is an
epidemiological feature still underestimated in many countries
and in particular in the USA. However, recent international
studies would appear to confirm that these magnesium data are
well founded1,17,37,38,41,42.
Magnesium depletion and diabetes mellitus
Magnesium deficit in the diabetic patient represents a typical
example of deficit where depletion is mainly involved. It cannot
be explained by an insufficient intake (ie, magnesium deficiency
controlled by simple magnesium supplementation) but derives from
complex dysregulation which differs according to the various
clinical forms of diabetes mellitus (for example a negative
correlation between glycosylated haemoglobin was found in some
studies but not in others 1,17,39). The relationship
between diabetic macro- and microangiopathy (retinopathy mainly)
and magnesium deficit will only be explained by further
understanding of the mechanisms involved in diabetic magnesium
depletion, a requirement for its control.
To sum up, magnesium appears to be an important inducing
factor of atherogenous dyslipidaemia and mitral valve prolapse,
two well defined cardiovascular risk factors, and may be linked
with cardiovascular complications of hyperglycaemia through
complex dysregulations.
Magnesium deficiency and hypertension
Several uncontrolled trials of long term magnesium
supplementation have been performed in mild to moderate
hypertension. For instance the study subjects were being treated
concurrently with antihypertensive drug therapy inducing
magnesium leakage1,7,16,18. The results were not
consistent. They appeared to be better when magnesium deficit was
observed and perhaps in particular selected
subgroups6-9,16-18,40,43,44. But in none of the double
blind placebo-controlled studies was a significant fall in
systolic or diastolic blood pressure
observed16,18,45,46. Monotherapy with oral magnesium
cannot be considered as an efficient treatment of hypertension or
be used as a substitute for a drug of proven
efficacy11,40,47. In some hypertensive patients,
however, magnesium deficit must be controlled because of its
numerous harmful effects on the nephrocardiovascular
apparatus7,9,10,11,67, and because it may sometimes
behave as a cofactor of constitutional or acquired hypertensive
factors11. This seems to be particularly the case for
stress-sensitive patients with labile hypertension because of the
close links between magnesium deficit and
stress1,8,10,11,30,48.
The vasodilator action of parenteral magnesium has been well
known for over a century49. The hypotensive action of
parenteral magnesium may be used in hypertensive patients,
particularly in pre-eclampsia but its pharmacological mechanisms
are observed irrespective of magnesium status. Therefore such
pharmacological effects should not be used as a diagnostic tool
in the investigation of magnesium deficit because its
pharmacological actions are observed irrespective of magnesium
status1,5,11,17,50,51.
Conclusion
Magnesium deficit may be considered as a cardiovascular risk
on account of its aetiopathogenic role in the genesis of
atherogenous dyslipidaemias and of "idiopathic" mitral valve
prolapse.
Magnesium supplementation does not constitute a major
antihypertensive treatment and cannot be used as a substitute for
drugs of proven efficacy. However, in some hypertensive patients
magnesium deficit must be controlled because of its numerous
harmful actions on the nervous system and on the
nephrocardiovascular apparatus, and because it is sometimes a
cofactor of constitutional or acquired aetiological factors for
hypertension.
The well known hypotensive action of parenteral magnesium may
be used in hypertensive patients, ie in pre-eclampsia, but its
pharmacological effects, which are observed irrespective of
magnesium status, should not be used as a diagnostic tool for
magnesium deficit.
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Perinatol. 4, 352-355.
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