Magnesium (Mg) is the second most abundant intracellular cation in the body. Studies have demonstrated that Mg deficiency enhances reactivity of arteries to vasoconstrictors, promotes vasoconstriction, and increases peripheral resistance, leading to increased blood pressure [1-3]. In contrast, Mg supplementation is associated with a significant decrease in blood pressure [4,5]. Mg deficiency is related to vascular structural and functional changes such as media thickening, increased media-to-lumen ratio, and increased contraction, which are characteristic in vitro and in vivo vascular changes [6,7]. Furthermore, Mg deficiency is associated with inflammation, oxidative stress, and endothelial dysfunction [8-10]. In experimental models of hypertension, the intracellular free Mg²⁺ concentration was negatively correlated with blood pressure, while the intracellular free Ca²⁺ concentration was positively correlated with blood pressure; and these concentrations were inversely associated [11,12]. These findings suggest that Mg may compete with calcium in blood pressure regulation.

Although many clinical and experimental studies support a critical role for Mg in the development of hypertension, the therapeutic value of Mg in the treatment of hypertension has not been established [13,14]. Dietary Mg supplementation during prehypertension and hypertension development in spontaneously hypertensive rats prevented a rise in blood pressure [15,16], suggesting a Mg-dependent physiological mechanism of blood pressure regulation [17]. Few studies have investigated the effects of Mg deficiency on the hormonal systems that control blood pressure. Angiotensin II decreases intracellular Mg in a dose-dependent manner, and this effect is inhibited by angiotensin II receptor blockers (ARBs) [18]. Mg deficiency may promote an angiotensin II-induced rise in blood pressure, aldosterone concentration, and vasoconstrictive prostaglandins [19].

The aim of this study was to evaluate the effect of dietary Mg supplementation on the blood pressure effects of an ARB in hypomagnesemic rats.

Mg is an essential cation with crucial roles in many physiological functions. Mg may be physiologically important in blood pressure regulation, and changes in Mg levels may contribute to the pathoetiology of hypertension [17]. Many experimental and clinical studies support a key role for Mg deficiency in the pathogenesis of hypertension. Reports have demonstrated an inverse correlation between body Mg levels and blood pressure, as well as a hypotensive effect of dietary Mg supplementation [21-24]. Nevertheless, the therapeutic and preventive value of Mg supplementation for managing hypertension remains controversial. Some studies have documented blood pressure-lowering effects of Mg in essential and experimental hypertension [25-27], but other studies have not confirmed these findings [13,14,28]. Mg supplementation failed to significantly reduce blood pressure in mild to moderate hypertensive patients in some short-term studies, whereas long-term Mg supplementation had some beneficial antihypertensive effects, particularly in patients who are Mg deficient [29,30]. In recent clinical studies, oral Mg supplementation improved vascular functions in elderly patients with diabetes and improved borderline hypertension [31-35]. In the present study, we examined whether Mg supplementation, started after the establishment of hypertension, could influence the lowering of blood pressure and the progression of hormonal and renal histological changes in hypomagnesemic rats.

Long-term Mg deficiency in experimental animals potentiates responses to vasoconstrictor agents, attenuates responses to vasodilator agents, increases vascular tone, and elevates blood pressure [36,37]. Some of these effects may be attributable to endothelial dysfunction, vascular structural changes, vascular inflammation, and oxidative stress [7,38,39]. Hypomagnesemia can lead to enhanced intracellular calcium levels and calcium overload in blood vessels [40]. Mg may influence the production of certain vasoactive agents such as endothelin-1 [41] and prostacyclin [42]. Plasma endothelin-1 levels are elevated in hypomagnesemic rats, and the levels are reduced in Mg-supplemented rats [43]. Increased extracellular Mg levels induce endothelial release of prostacyclin [44]. These findings suggest that a direct effect of Mg deficiency on vascular smooth muscle may be involved in the elevation of vascular tone [17] and that Mg supplementation may have the effect of lowering blood pressure.

The present results confirmed that Mg deficiency is related to hypertension and that Mg supplementation in hypomagnesemic rats can attenuate high blood pressure. Serum angiotensin II levels remained unchanged in Mg-deficient rats, and Mg supplementation did not alter angiotensin II levels in hypomagnesemic rats. However, serum aldosterone levels increased in Mg-deficient rats, and Mg and/or ARB treatment significantly ameliorated these increased serum aldosterone levels. In a previous study, angiotensin II increased the concentration of cytosolic free calcium and sodium with a concomitant decrease in cytosolic free Mg²⁺ concentration, and these effects were inhibited by an ARB [18]. Our data show that serum aldosterone increased without a changed in angiotensin II in hypomagnesemic rats. This dissociation suggests that Mg may have a direct effect on aldosterone synthesis, rather than an indirect effect via the renin angiotensin aldosterone system. Additionally, a report has shown that decreased muscle potassium and increased sodium lead to Mg deficiency, indicating the possibility of increased aldosterone secretion [45]. The precise mechanism by which Mg deficiency stimulates aldosterone production is not known. These findings suggest that Mg²⁺ fluxes are under the control of various hormones such as insulin, endothelin-1, norepinephrine, epinephrine, aldosterone, and vasopressin [18].

Although the mechanism by which Mg treatment modulates vascular tone and reactivity is unclear, Mg²⁺-associated changes in intracellular signaling pathways, altered cellular Mg²⁺/Ca²⁺ interactions in vascular smooth muscle cells, and improved endothelial function may be important factors [46,47]. Mg can displace and compete with calcium, modulate intracellular calcium mobilization, and regulate calcium efflux [48]. We did not find a correlation between blood pressure and calcium levels because we did not measure the intracellular concentrations of Mg and calcium. Additionally, the duration of dietary Mg supplementation might have been too short in the present. Furthermore, the serum Mg level decreased significantly after 14 weeks of the Mg-free diet, suggesting that Mg cell turnover is not an acute phenomenon.

Studies investigating the effects of dietary Mg on blood pressure have reported contradictory results. Our data showing that Mg supplementation attenuated hypertension are in agreement with those of some studies, but differ from other studies reporting no blood pressure lowering effects of Mg supplementation [13,14]. These contradictory results may be related to differences in experimental factors, including diet composition, feeding protocol, rat strain, or definitions of hypertension. A physiological mechanism underlying blood pressure control may be dependent on the Mg status during a particular developmental stage. If so, the stage must lie between 6 and 14 weeks, the time during which blood pressure increases steeply in spontaneously hypertensive rats [16]. Our results support these suggestions, as we demonstrated that Mg deficiency significantly induced the development of hypertension after 14 weeks.

In the present study, kidney tissues of the hypomagnesemic rats revealed mild to moderate inflammatory infiltration, and dietary Mg supplementation did not change these histological findings, which were distinguishable among the treatment groups. The renal tissue changes in the hypomagnesemic rats probably reflected early renal damage associated with the late phase of established hypertension.

In conclusion, dietary Mg supplementation attenuated blood pressure in rats with hypomagnesemic hypertension and enhanced the antihypertensive effect of an ARB. Mg supplementation may affect aldosterone synthesis independent of the renin angiotensin aldosterone system. Our data suggest that Mg supplementation may be helpful for managing hypertension concomitant with hypomagnesemia.

1. Magnesium (Mg) is inversely associated with blood pressure and Mg supplementation attenuates hypertension.

2. Dietary Mg supplementation can attenuate the blood pressure in hypomagnesemic hypertension and enhance the antihypertensive effect.

3. Mg supplementation may be helpful in managing hypertension concomitant with hypomagnesemia.