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THE MAGNESIUM REPORT
Clinical, Research, and Laboratory News for Cardiologists
First Quarter 1999

Oral Magnesium and Hypertension: Research and Clinical Application

LAWRENCE M. RESNICK, MD



Knowledge of the association between magnesium and hypertension is almost a century old, beginning with the observations that parenteral magnesium sulfate reduced blood pressure (BP) in eclampsia and pre-eclampsia, and also in non-pregnant subjects with malignant hypertension. More recently, further observations support the BP-magnesium linkage:

Epidemiologically, multiple studies have identified an inverse relationship between dietary magnesium intake and BP. Pathophysiologically, cellular depletion of magnesium contributes to, and is a feature shared in common by subjects with hypertension, left ventricular hypertrophy (LVH), insulin resistance, obesity, and frank diabetes mellitus. This constellation of vascular and metabolic conditions is known variously as “syndrome X,” generalized cardiovascular-metabolic disease, or the plurimetabolic syndrome. Therapeutically, both animal studies and clinical trials have demonstrated that oral magnesium may exert a beneficial effect on hypertension.

Altogether, data now suggest that magnesium may be ready for “prime time” in hypertension management. The question-and-answer feature (below) describes in greater detail how oral magnesium may be used to treat appropriate patients with hypertension.

Epidemiologic studies

Ascherio and colleagues at Harvard examined the dietary habits of approximately 40000 nurses and 30000 male health professionals and found lower BPs in subjects consuming more magnesium (as fruits and vegetables). Similarly, of various dietary factors analyzed in the Honolulu Heart Study, magnesium was the strongest correlate of both systolic and diastolic BP among 615 men of Japanese ancestry living in Hawaii. Furthermore, in 14000 middle-aged adults followed for up to 7 years in the Atherosclerosis Risk in Communities (ARIC) Study, lower serum magnesium levels were associated with an increased risk of coronary heart disease and future hypertension and also quantitatively predicted the rate of atherosclerotic plaque accumulation in the carotid artery—the lower the magnesium level, the worse the outcome.

Magnesium-calcium link

Over 40 years ago, Altura and coworkers demonstrated that lower magnesium levels in vitro cause vasoconstriction, while increased magnesium dilates blood vessels and blocks the vasoconstrictor effects of substances such as epinephrine. In vivo, dietary magnesium deficiency itself may raise BP.

About 15 years ago, using nuclear magnetic spectroscopy, our group observed an intracellular magnesium deficit in human hypertension. Working with biophysicist Raj K. Gupta, we noted that BP among all subjects, whether hypertensive or not, is inversely related to basal fasting intracellular free magnesium levels—the lower the free magnesium level, the higher the BP. This demonstration parallels a Swiss report published the same year, showing the opposite relation for calcium—the higher the intracellular free calcium, the higher the BP. These clinical observations are relevant since in vitro studies have long observed opposite tissue effects of each mineral ion on the other—loading tissues with calcium depletes magnesium, and vice versa.

We subsequently showed this constellation of suppressed intracellular free magnesium and/or elevated intracellular free calcium levels not only in hypertension, but also in other conditions associated with it, such as arterial stiffness (decreased compliance), LVH, insulin resistance, hyperinsulinemia, and frank diabetes mellitus—all components of what has become known as the metabolic syndrome X. This led us to propose the “ionic hypothesis of cardiovascular and metabolic disease” in which each of the conditions mentioned above is linked by and represents different tissue-specific expressions of the same underlying cellular lesion, characterized at least in part by suppressed intracellular free magnesium and elevated cytosolic free calcium levels (Table 1).

Hypertension Table 1

Rationale for using oral magnesium

Based on the above epidemiologic, dietary, experimental, and clinical research, it seems reasonable to consider the use of oral magnesium supplementation by either dietary or pill supplementation as a therapeutic option in subjects with these common cardiovascular and metabolic conditions. This is especially relevant since currently, both men and women consume considerably less than the recommended dietary allowance (RDA) of magnesium (Table 2). Indeed, over the course of this century the per capita dietary intake of magnesium in the United States has decreased by 50%.

hypertension Table 2

The cumulative experience from published clinical trials of magnesium supplementation in hypertension has been encouraging. Kawano and colleagues recently studied the effects of 8 weeks of magnesium oxide, 400 mg twice daily (20 mmol or 480 mg of elemental magnesium), on office, home, and ambulatory BP in 34 male and 26 female Japanese subjects with essential hypertension, ages 33-74. Both diastolic and systolic BPs fell significantly during supplementation; those having the highest baseline BPs experienced the greatest magnesium-induced fall in pressure (Figure). Similarly, Itoh and colleagues found that oral magnesium supplementation for 4 weeks (548 mg/d as magnesium hydroxide to male subjects and 411 mg/d to female subjects) not only increased serum levels of magnesium, but lowered BP and improved total cholesterol and high to low density lipoprotein (HDL:LDL) ratios in otherwise healthy volunteers.

hypertension Figure

Supporting these reports are various others suggesting the utility of magnesium supplementation in hypertension. Witteman and colleagues evaluated the antihypertensive effect of oral magnesium supplementation (22 mmol/d as magnesium aspartate) in 91 middle-aged and elderly women with mild to moderate hypertension in a 6-month, double-blind, placebo-controlled trial. Magnesium lowered systolic and diastolic BP by an average of 2.7/3.4 mm Hg. When combining potassium supplementation and salt restriction to magnesium supplementation, these workers found a greater fall in BP (7.6/3.3 mm Hg). Brazilian researchers reported that a 6-week course of magnesium oxide reduced BP in 15 hypertensive subjects by 5.9 mm Hg.

In other studies, oral magnesium supplementation has also further lowered BP in the following subjects already receiving antihypertensive drugs: a) hypertensive adults on beta-blocker therapy given magnesium aspartate for up to 12 weeks; and b) subjects taking diuretics, in whom magnesium lowered pressure and increased tissue magnesium and potassium levels, and/or Na+, K+ or ATPase activity.

Although these reports are suggestive, other clinical trials have demonstrated no BP effects of magnesium supplementation. As emphasized in a recent editorial, these controversies may not be resolved no matter how many progressively larger or more expensive clinical trials are performed, as long as hypertensive subjects are considered as a homogeneous group, which they are not, either pathophysiologically in general, or with respect to their magnesium metabolism in particular.

Proper patient selection

Specifically, as early as 1983 we observed that despite a uniform intracellular magnesium deficit, hypertensive subjects exhibit a range of extracellular magnesium values, within the normal range, that seem to be closely related to the activity of pressor hormone systems such as the renin-angiotensin system. Subjects with normal to high plasma renin activity (PRA) exhibit lower serum magnesium values that predict a hypotensive response to magnesium supplementation. Other hypertensive subjects who have low PRA and/or salt sensitivity may exhibit no response or even a mild pressor response to magnesium. Interestingly, such patients may respond better to calcium supplements. Grouping all subjects together according to only blood pressure levels as if they were the same obscures the dramatic magnesium responses in those with high PRA; the net result for the entire group might appear modest or nil.

Hence, progress in this area will require a priori identification of subgroups of patients on the basis of PRA, dietary salt sensitivity, reproducible and sensitive measures of extracellular magnesium, or other criteria useful in identifying subjects for whom oral magnesium supplementation will be particularly effective.

For now, all subjects should at least increase their magnesium intake to achieve current RDA standards. Similar to current recommendations for dietary salt restriction in hypertension, magnesium supplementation beyond these levels should only be used on a trial basis for 1 to 6 months and continued only if a clear-cut response is observed.

Suggested reading

Itoh K, Kawasaki 1, Nakamura M. The effects of high oral magnesium supplementation on blood pressure, serum lipids and related variables in apparently healthy Japanese subjects. Br J Nutr. 1997;78:737-750.

Kawano Y, Matsuoka H, Takishita S, Omae T. Effects of magnesium supplementation in hypertensive patients:assessment by office, home, and ambulatory blood pressures. Hypertension. 1998;32:260-265.

Paolisso G, Barbagallo M. Hypertension, diabetes mellitus, and insulin resistance; the role of intracellular magnesium. Am J Hypertens. 1997;1O:346-355.

Resnick LM. Magnesium in the pathophysiology and treatment of hypertension and diabetes mellitus: where are we in 1997? [editorial]. Am J Hypertens. 1997;10:368-370.



Q & A: Prescribing Oral Magnesium

Q: When do you suspect a magnesium deficit?

DR. RESNICK:

A cellular magnesium deficit should be suspected—independently of age—in subjects with hypertension, coronary and peripheral atherosclerotic disease, various cardiac arrhythmias, obesity, and or type 2 diabetes mellitus.

Q: Do you recommend that patients take supplemental magnesium?

DR. RESNICK: For the appropriate patient, yes. The efficacy of supplementation depends on targeting individuals who will benefit most from magnesium supplementation, and providing an adequate, absorbable dose. Furthermore, magnesium supplementation may be easier than increasing dietary magnesium, which may involve lifestyle changes most patients find difficult.

Q: Which hypertensive patients will most likely benefit from magnesium supplementation?

DR. RESNICK: Magnesium supplementation is most effective for lowering blood pressure (BP) in subjects whose renin system is activated. These are the patients who respond best to beta blockers, converting enzyme inhibitors, or angiotensin-II blockers—drugs that block the secretion, activation, or action of the renin angiotensin system. Interestingly, these drugs may also increase serum magnesium levels.

Q: What are the objectives of treatment with oral magnesium?

DR. RESNICK: We include magnesium supplementation early, both in the nondrug stage of therapy for borderline or mild hypertension, and also together with drugs before increasing medication dosage or adding another drug to the regimen.

Q: Should magnesium be considered routinely for patients on long-term diuretic therapy?

DR. RESNICK: Absolutely. Patients taking diuretics, especially those that do not spare potassium and magnesium, are at significant risk for magnesium depletion, which may limit the efficacy of diuretic therapy. When magnesium supplementation is added to antihypertensive regimens containing diuretics, BP lowering may be enhanced, symptoms may improve, and patients may feel better.

Q: What are common dosing strategies?

DR. RESNICK: We suggest adding at least the minimum recommended dietary allowance for magnesium (approximately 200 to 400 mg/day elemental magnesium), independent of dietary intake. Most patients take magnesium tablets after meals. Diabetic patients, who are uniformly magnesium depleted, receive the highest tolerated dosage.

Q: Is it worrisome that the latest guidelines recommend raising dietary calcium and vitamin D without commensurately increasing magnesium intake?

DR. RESNICK: For general health, hypertension not withstanding, it’s important to increase dietary magnesium commensurately with any increases in calcium and vitamin D. For example, current data suggest that salt may influence blood pressure only in subjects with concomitantly lower calcium intakes, but not in those with adequate calcium intakes. Similarly, a balance between calcium and magnesium intake should be maintained. Increasing vitamin D beyond approximately 400 UI/d also may be counterproductive. Higher amounts, especially in combination with high calcium intakes, can contribute to extraskeletal accumulation of calcium in the cardiovascular system, urinary tract, and other soft tissue sites, with potentially harmful results.

Q: Why do some clinical trials of magnesium supplementation in hypertension show no benefit?

DR. RESNICK: Hypertension is a heterogenous phenomenon, not a uniform epidemiologically-defined condition. As such, it needs to be treated specifically and individually, based on the type of hypertension present. If all patients are lumped together without attention to factors underlying the hypertension, which may differ drastically from patient to patient, the benefit of any single therapy in some patients may be minimized or even obscured by the results in others in whom this therapy is less relevant.

The above article is from the "The Magnesium Report", First Quarter 1999. Blaine Pharmaceuticals is the manufacturer of Mag-Ox 400 and Uro-Mag magnesium supplements.

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