A Good Time to Reconsider the Associations of Calcium and Magnesium With Hypertension

The etiology of hypertension (HTN) is still unknown, and advocacy of its mechanism has been a hundredfold. A number of studies but not all studies have shown that minerals such as calcium (Ca), magnesium (Mg) and potassium (K) are associated with the development, maintenance and progression of HTN.^1–6

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Serum Ca concentrations are maintained within a narrow range of homeostasis through regulation by parathyroid hormone, calcitonin, and 1,25(OH)₂D₃. Although it is postulated that serum Ca concentrations reflect habitual Ca intake levels, the relationship between Ca intake and serum Ca concentration is unclear.

In 1984, McCarron et al showed that patients with HTN had a significantly lower intake of Ca than did normotensive subjects and that Ca intake was the most effective factor in predicting HTN using a multivariate analysis based on the National Health and Nutrition Examination Survey I conducted in the USA from 1971 to 1975, in which the relationship between blood pressure (BP) and nutritional intake was analyzed in a large study of 10,372 subjects.² Many other studies have found a negative correlation between Ca intake and BP levels after adjusting for confounding factors.^1,3,4 Not all studies have shown that oral Ca administration is effective for lowering BP in patients with essential HTN.^7–9 It is likely that Ca intake is associated with BP. However, the relationship between the Ca intake and BP level is complex.

In addition, the relationship between serum Ca concentration and BP has been investigated in many epidemiological studies.¹⁰ Some studies showed a negative or positive correlation, while other studies showed no relationship.¹⁰ Low Ca intake increases Na⁺-K⁺-ATPase inhibitors in vascular smooth muscle cell membranes, leading to an increase in intracellular Na, followed by an increase in intracellular Ca, resulting in vascular smooth muscle contraction, which causes HTN. The increase in intracellular Ca concentration is caused by a decrease in the function of the Na⁺-Ca²⁺ exchanger in the cell membrane and mitochondria or by a decrease in the activity of Ca²⁺-ATPase in the cell membrane and sarcoplasmic reticulum. In hypertensive patients with low Ca intake, the Ca channel in the membrane of vascular smooth muscle cells is disturbed and intracellular Ca increases.¹¹ In that case, oral Ca supplementation inhibits the factors that open Ca channels. The renin-angiotensin and Ca-regulating hormone systems that have been altered by salt intake are corrected by increased Ca intake, resulting in a decrease in intracellular and extracellular Ca, and the intracellular and extracellular Ca flow becomes normal, resulting in hypotension. It has also been reported that dietary Ca intake directly increases the circulating amounts of vasodilators (i.e., caltitonin-gene-related peptides).¹² In any case, there are various theories on the mechanism of Ca intake-induced hypotension, and none of them has yet been definitively proven. To date, although a negative correlation between Ca intake and BP has been observed in cross-sectional studies, the results of clinical trials using oral Ca loading are contradictory, and it is difficult to draw conclusions regarding its efficacy.^1–3,6

It is postulated that Mg as well as Ca contributes to BP regulation. Serum Mg concentrations are also maintained within a narrow range of homeostasis. However, the systemic Mg content in patients with essential HTN is lower than that in normotensive subjects, and decreases in serum Mg concentration, free Mg²⁺ concentration in erythrocytes, and BP are negatively correlated.¹³ Decreased Mg content in the body causes an increase in intracellular Na⁺ concentration due to decreased Na⁺-K⁺-ATPase activity, Ca²⁺ influx into cells, and Ca²⁺ release from Ca²⁺ storage sites, which in turn promotes vascular smooth muscle contraction and increases peripheral vascular resistance, resulting in increased BP.¹⁴ Therefore, it has been suggested that abnormal Mg metabolism is involved in the pathogenesis of essential HTN. Putative mechanisms of Ca- or Mg-related regulation of BP are shown in the Figure.

Figure.

Putative mechanisms of calcium- or magnesium-related regulation of blood pressure. PTH, parathyroid hormone.

In this issue of the Journal, Zhang et al¹⁵ report that the addition of serum Ca and Mg concentrations to a HTN prediction model more strongly predicted the risk of developing HTN in a Chinese population. After the inclusion of serum Ca and Mg concentrations, the C-indices were from 0.744 to 0.764 and from 0.768 to 0.791, respectively. It is thought that Ca and Mg concentrations, especially their ionized levels, play an important role in BP regulation. Measurements of ionized Ca and Mg concentrations would enable more specific conclusions concerning the roles of Ca and Mg in the development, maintenance and progression of HTN to be drawn.

Once again, this may be a good time to reconsider the associations of Ca (i.e., oral dose and serum concentration) and Mg (i.e., oral dose and serum concentration) with HTN.

References

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