Effects of Mg²⁺ on vascular tone may contribute to its influence upon blood pressure. Empiric evidence for an effect of Mg²⁺ upon vascular tone is demonstrated by the observations that decreased extracellular Mg²⁺ or systemic Mg²⁺ depletion in animals produces vasospasm and reduces microvascular blood flow (Altura and Turlapaty, 1982; Altura et al., 1983; Altura et al., 1984). Humans given an acute MgSO₄ infusion exhibit increased renal blood flow, despite reduced blood pressure (Nadler et al., 1987).

Vascular smooth muscle constriction is stimulated when Ca²⁺ enters smooth muscle cytosol via L-type voltage-gated Ca²⁺ channels. Intracellular Ca²⁺ stimulates phospholipase C and production of diacylglycerol (DG) and inositol 1,4,5-trisphosphate (IP₃). IP₃ activates the IP₃ receptor, releasing Ca²⁺ from the sarcoplasmic reticulum. Cytosolic Ca²⁺ then binds to calmodulin, activating myosin light chain kinase (MLCK). Activated MLCK phosphorylates the myosin light chain, stimulating interaction of actin and myosin, and eliciting cell contraction (Webb, 2003).

Intracellular Mg²⁺ attenuates myocyte contraction via several mechanisms. Mg²⁺ diminishes cellular Ca²⁺ entry via L-type voltage gated Ca²⁺ channels (Zhang et al., 2007; Sharma et al., 2012). Intracellular Mg²⁺ inhibits Ca²⁺-stimulated Ca²⁺-release from the sarcoplasmic reticulum, at least in cardiac muscle (Dunnett and Nayler, 1978). The sarcoplasmic reticulum Ca²⁺-ATPase, which is required to return released Ca²⁺ to intracellular stores, requires Mg²⁺ for activity (Hasselbach et al., 1981). Consequently, low Mg²⁺ conditions prolong elevation of intracellular Ca²⁺ following release from intracellular stores (Gasallaherraiz et al., 1995). Thus, Mg²⁺ reduces smooth muscle contraction.

Prostacyclin release: Effects of systemic Mg²⁺ status upon vascular tone may be mediated, in part, by effects on prostacyclin release. Prostacyclin (PGI₂) is recognized to have important systemic vasodilatory effects (Zhao and Richardson, 1990). In the kidney, prostacyclin is critical for maintaining vasodilation and blood flow in the context of extrarenal vasoconstriction. Mice lacking prostacyclin synthase exhibit hypertension, thickening of the aortic medial and adventitial layers, and nephrosclerosis (Yokoyama et al., 2002). In humans, a repeat polymorphism in the promoter region of the prostacyclin synthase gene was found to reduce prostacyclin synthase transcription and to be associated with increased odds of hypertension (Iwai et al., 1999).

Mg²⁺ modulates vascular prostacyclin release. In cultured vascular endothelial cells or smooth muscle cells, increased extracellular Mg²⁺ stimulated prostacyclin secretion (Briel et al., 1987; Satake et al., 2004). In the rat deoxycorticosterone acetate (DOCA)-salt model of hypertension, a Mg²⁺-enriched diet significantly increased PGI₂ levels (Laurant et al., 1992). Infusion of MgSO₄ into humans enhanced urinary excretion of immunoreactive 6-ketoprostaglandin F1α (6-keto-PGF_1a), a stable break-down product of PGI₂, while reducing blood pressure (Nadler et al., 1987). The importance of prostaglandin synthesis in this blood pressure effect was demonstrated by the observation that cyclooxygenase inhibition prevented the decrease in blood pressure and increase in renal blood flow. Moreover, the Mg²⁺-stimulated increase in PGI₂ release was blocked by the calcium channel blocker, nifedipine, suggesting that the influence of Mg²⁺ on cyclooxygenase is dependent upon Ca²⁺ entry into cells.

Nitric oxide metabolism: Mg²⁺ also influences vascular tone through effects on nitric oxide (NO). Nitric oxide is an endogenous vasodilator produced in endothelial cells from L-arginine by endothelial NO synthase (eNOS) (Rees et al., 1989; Gamboa et al., 2007). In cultured endothelial cells, NO production was roughly 3-fold higher in cells grown in high (5 mM, or 12 mg/dL) than in control (1 mM, or 2.4 mg/dL) extracellular Mg²⁺ (Maier et al., 2004). This finding was attributed to an observed increase in eNOS protein abundance in cells grown in high Mg²⁺.

Altered NO release may contribute to effects of Mg²⁺ upon NO signaling. In mouse aorta and mesenteric vessels, endothelium-dependent, Mg²⁺-induced arterial relaxation is attenuated by blockade of eNOS activity with N (gamma)-nitro-L-arginine methyl ester (L-NAME) (Kudryavtseva et al., 2024). In canine coronary arteries, Mg²⁺-free conditions attenuated acetylcholine and ADP-stimulated, NO-dependent reduction in arterial tone (Pearson et al., 1998). The Ca²⁺ ionophore A23187, which induces endothelial NO release independently of receptor-mediated signaling mechanisms, reduced arterial tension in a Mg²⁺-independent fashion. Bradykinin-stimulated vascular relaxation, which occurs via endothelium-dependent, but NO-independent mechanisms, was unaffected (Pearson et al., 1998). These findings suggest that Mg²⁺ is required for stimulation of NO release but not for NO-stimulated relaxation. Evidence that Mg²⁺ influences NO signaling in humans comes from a study examining flow-mediated vasodilation of the brachial artery (FMD), a process that is at least partly NO mediated (Green et al., 2014). Oral Mg²⁺ supplementation in individuals with coronary artery disease significantly improved FMD and exercise tolerance (Shechter et al., 2000).

Mg²⁺ likely also promotes relaxation via additional, NO-independent pathways. Blockade of SK and IK Ca²⁺-activated K⁺ channels, which participate in endothelium-derived relaxation factor-stimulated arterial relaxation, blunted Mg²⁺-dependent arterial relaxation additively with eNOS inhibition (Kudryavtseva et al., 2024).

Together, these observations suggest that systemic Mg²⁺ status could influence blood pressure through multiple effects on vascular tone.

Mg²⁺ exerts an inhibitory effect on the sympathetic nervous system, whereas Mg²⁺ deficiency stimulates sympathetic tone.

Effects of Mg²⁺ upon the sympathetic nervous system are mediated, in part, through modulation of N-methyl-D-aspartate (NMDA) receptor activity. The NMDA receptor is a Ca²⁺-selective ion channel that opens in response to NMDA and L-Glutamate (L-Glu) (Dingledine et al., 1999; Kagiyama et al., 2001). NMDA receptor activity in the rostral ventrolateral medulla (RVLM) and hypothalamic paraventricular nucleus (PVN) increase sympathetic outflow and blood pressure (Dampney et al., 2003; Li and Pan, 2017). NMDA receptor activity is negatively regulated by Mg²⁺ (Dingledine et al., 1999). Thus, attenuation of NMDA receptor activity by Mg²⁺ may be expected to reduce blood pressure.

In support of this hypothesis, Kagiyama et al., studied the effect of Mg²⁺ in the RVLM upon blood pressure. Injection of magnesium sulfate (MgSO₄) into the RVLM exerted a dose-dependent attenuation of increased blood pressure occurring in response to NMDA injection (Kagiyama et al., 2001).

Mg²⁺ also negatively influences sympathetic tone through modulation of catecholamine release from peripheral nerve endings and by blocking N-type Ca²⁺ channels at nerve endings (Shimosawa et al., 2004). In neuronally differentiated PC12 cells, N-type Ca²⁺ channel activity was decreased by elevated extracellular Mg²⁺ and increased by reduced extracellular Mg²⁺. With cytosolic Ca²⁺ being a major stimulus for catecholamine release, low extracellular Mg²⁺ buffer enhanced norepinephrine release from the periarterial plexus of the mesenteric artery compared to control or high Mg²⁺ buffer. Urinary catecholamine excretion was found to be more than two-fold higher in Mg²⁺ deficient rats than control rats (Murasato et al., 1999). Mg²⁺ infusion also attenuated sympathetically mediated reflex tachycardia following hydralazine infusion (Shimosawa et al., 2004). In addition to reducing norepinephrine release from sympathetic neurons, Mg²⁺ also increased norepinephrine uptake in isolated adrenergic nerve granules, suggesting an influence upon norepinephrine reuptake in the synaptic cleft (von Euler and Lishajko, 1963; von Euler and Lishajko, 1973).

Effects of Mg²⁺ on the sympathetic nervous system have also been demonstrated in human subjects. James et al., studied the effect of MgSO₄ infusion upon simulation of catecholamine release and blood pressure in response to endotracheal intubation. In controls, intubation rapidly increased circulating epinephrine levels, norepinephrine levels, and systolic blood pressure. MgSO₄ infusion attenuated the increase in each of these (James et al., 1989).

Thus, Mg²⁺ modulates peripheral sympathetic nervous system activity, reducing blood pressure.

Systemic Mg²⁺ status could influence blood pressure indirectly, through effects on handling of K⁺ and Na⁺.

Bodily K⁺ balance influences blood pressure. Several meta-analyses of clinical trials find that K⁺ supplementation reduces blood pressure in hypertensive individuals (van Bommel and Cleophas, 2012; Poorolajal et al., 2017; Filippini et al., 2020). The influence of K⁺ upon blood pressure is likely mediated by multiple mechanisms, including effects upon vascular tone and upon extracellular fluid volume. In Dahl salt-sensitive rats, a high K⁺-diet promotes vascular relaxation (Raij et al., 1988). Fluid volume effects may occur secondary to enhanced tubular Na⁺ reabsorption in the context of systemic K⁺ depletion. In the kidney’s proximal convoluted tubule (PCT), a low K⁺ diet enhanced protein abundance of the Na⁺/H⁺ exchanger, type 3 (NHE3), promoting Na⁺/H⁺ exchange (Shirley et al., 1990; Soleimani et al., 1990; Elkjær et al., 2002). In the distal convoluted tubule (DCT), K⁺ deficiency stimulates phosphorylation-mediated activation of sodium-chloride cotransporter (NCC) through modulation of the WNK/SPAK/OSR1 (with no lysine/SPS1-related proline-alanine-rich kinase/oxidative stress-responsive kinase 1) signal transduction pathway (Terker et al., 2015).

Mg²⁺ depletion promotes K⁺ depletion. Because serum K⁺ represents only 2% of total body K⁺, even when plasma or serum K⁺ is not appreciably reduced, intracellular and total body K⁺ stores can be depleted (Patrick, 1977; Brown, 1984). In rats subjected to dietary Mg²⁺ restriction, intramuscular K⁺ declined (Macintyre and Davidsson, 1958; Manitius and Epstein, 1963; Whang and Welt, 1963; Ginn et al., 1967; Dørup and Clausen, 1993). This was associated with decreased whole body K⁺ following prolonged (60-day) dietary Mg²⁺ restriction (Whang and Welt, 1963). In human subjects given a low Mg²⁺ diet, urinary K⁺ excretion increased overall and total exchangeable K⁺ decreased (Shils, 1969). Intracellular Mg²⁺ depletion is thought to promote urinary K⁺ excretion through loss of voltage-dependent blockade of the outer medullary K⁺ channel (ROMK) in the kidney tubule, enhancing tubular K⁺ secretion (Huang and Kuo, 2007). Additionally, systemic Mg²⁺ depletion increases circulating aldosterone levels (discussed below), enhancing urinary K⁺ excretion in exchange for Na⁺ reabsorption.

Taken together, these findings suggest the hypothesis that Mg²⁺ depletion could contribute to urinary Na⁺ retention and increased blood pressure by stimulating NCC activity in the DCT. Surprisingly, rats given a low Mg²⁺ diet exhibit reduced NCC expression (Fanestil et al., 1999). Ferdaus et al. confirmed these findings in mice and found that dietary Mg²⁺ depletion reduced both total and phosphorylated NCC protein abundance in the kidney. NCC mRNA levels were unchanged, suggesting post-transcriptional effects on NCC expression. The hypothesis that dietary Mg²⁺ restriction may stimulate NCC degradation was supported by the observation that kidney-specific deletion of the ubiquitin ligase NEDD4-2 blocked downregulation of NCC by dietary Mg²⁺ restriction. Dietary Mg²⁺ depletion even blocked the ability of a K⁺-restricted diet to increase total and phosphorylated-NCC protein abundance, providing further evidence that the influence of Mg²⁺ depletion on blood pressure is not NCC-mediated.

Systemic K⁺ depletion may influence Na⁺ handling in other portions of the nephron, such as the thick ascending loop of Henle. The Na-K-Cl co-transporter (NKCC2) in the thick ascending limb (TAL) is also modulated by intracellular WNK/SPAK/OSR1 pathway (Moriguchi et al., 2005; Rinehart et al., 2005; Liu et al., 2011; Richardson et al., 2011; Park et al., 2013; Terker et al., 2018; Marcoux et al., 2019). Given the ability of systemic K⁺ status to influence the WNK/SPAK/OSR1 pathway, it seems likely that differences in Mg²⁺ homeostasis may influence this pathway via changes in systemic K⁺, but we are unaware of data directly exploring this hypothesis.

Mg²⁺ could also influence Na⁺ reabsorption in the TAL through modulation of the calcium-sensing receptor (CaSR). Activation of the CaSR on the basolateral surface of cortical TAL cells reduces apical K⁺ channel activity (Wang et al., 1996). Impaired cellular K⁺ efflux impairs Na⁺ and Cl⁻ reabsorption through NKCC2, producing a loop diuretic-like effect. Mg²⁺, like Ca²⁺, can activate the CaSR, which may explain the earlier observation that intravenous Mg²⁺ infusion can decrease TAL Na⁺ reabsorption (Ploth et al., 1976). Whether changes in plasma Mg²⁺ within the physiologic range modulate CaSR activity and TAL NaCl reabsorption remains unclear.

Systemic Mg²⁺ status may also influence Na⁺ and K⁺ handling via modulation of the renin-angiotensin-aldosterone system. In laboratory animals, dietary Mg²⁺ restriction appears to stimulate aldosterone levels. Sapna et al. found that in rats, 6 days on low Mg²⁺ chow resulted in serum aldosterone of 205.0 ± 66.2 pg/mL, which was not significantly higher than 138.1 ± 80.8 pg/mL seen on control chow (Sapna et al., 2006). However. Laurant et al. observed an increase in plasma aldosterone in rats given Mg²⁺-deficient diet for two and 21 weeks (Laurant et al., 1999). Stimulation of aldosterone levels by dietary Mg²⁺ restriction seems to occur independently of extracellular fluid volume status, as dietary Mg²⁺ depletion continued to stimulate increased serum aldosterone even in animals given a high Na⁺ diet (Solounias and Schwartz, 1975).

Acute intravenous Mg²⁺ administration also reduces aldosterone levels. A study examining six “healthy,” normotensive volunteers infused MgSO₄ at a rate of 0.6 mg/h (5 mEq/hr) and found that plasma aldosterone levels decreased to 4 ± 0.8 ng/dL (111 ± 22 pmol/L) compared with 6 ± 0.2 ng/dL (166 ± 5.5 pmol/L) in controls (p < 0.05) (Ichihara et al., 1993). This occurred despite an increase in plasma renin activity. Corica et al. infused 3 gm (24 mEq) of MgSO₄ into “healthy” volunteers and observed reduced serum aldosterone from 18.97 ± 11 ng/dL (526 ± 305 pmol/L) to 6.34 ± 5 ng/dL (176 ± 139 pmol/L) (Corica et al., 1996). This effect did not appear to be fluid volume mediated, as atrial natriuretic peptide levels did not change, and a control infusion with isotonic saline had no significant impact on aldosterone levels. Thus, Mg²⁺ sulfate infusion reduces aldosterone levels in humans, at least acutely.

Despite these observations, oral supplementation studies in humans have largely failed to demonstrate reduction in circulating aldosterone. One study gave 365 mg (15 mmol) of Mg²⁺, as Mg²⁺ aspartate, to 17 subjects for 4 weeks (Cappuccio et al., 1985). Neither blood pressure nor aldosterone changed compared with participants receiving placebo. Participants had a mean baseline serum Mg²⁺ level of 2.16 mg/dL (0.89 mmol/L), as compared to a normal reference range for Mg²⁺ of 1.82–2.32 mg/dL (0.75–0.96 mmol/L) from the U.S. National Health and Nutrition Examination Survey I study (Lowenstein and Stanton, 1986). In another study of 15 untreated hypertensive individuals given 600 mg/day of Mg²⁺ in the form of Mg²⁺ oxide, blood pressure decreased, but no difference in aldosterone levels was observed (Sanjuliani et al., 1996). In a third study that provided 600 mg of Mg²⁺ daily as Mg²⁺ oxide to 17 subjects, Mg²⁺ decreased blood pressure but again failed to significantly reduce plasma aldosterone (Haga, 1992). In this study, baseline serum Mg²⁺ levels were 1.88–1.91 mg/dL (0.77–0.79 mmol/L). In these three studies, mean baseline aldosterone levels ranged from roughly 9–13 ng/dL (240–260 pmol/L). This is on the lower side of the reference range of 5–30 ng/dL (140–830 pmol/L) determined in healthy adults on an unrestricted Na⁺ diet (Al-Dujaili and Edwards, 1978). Thus, although Mg²⁺ supplementation did not reduce aldosterone levels, these findings may be influenced by the observation that study participants exhibited neither Mg²⁺-depletion nor elevated aldosterone (e.g., from extracellular fluid volume depletion) at baseline.

Few studies have examined the response of aldosterone to oral Mg²⁺ supplementation in humans in the context of an aldosterone secreting stimulus, such as extracellular fluid volume depletion or a dietary K⁺ challenge. An exception is a study that measured aldosterone changes in response to an hour of exercise in nine men (Golf et al., 1984). Exercise increased plasma aldosterone from 9.4 ± 5.0 ng/dL (260 ± 140 pmol/L) to 19.1 ± 13.7 ng/dL (530 ± 370 pmol/L), perhaps secondary to either extracellular fluid volume depletion or increased plasma K⁺. Two weeks of daily oral supplementation with 360 mg (15 mmol) Mg²⁺ as Mg²⁺ aspartate abrogated this increase in aldosterone, leading to aldosterone levels before and after exercise that were 13.7 ± 3.2 (380 ± 90 pmol/L) and 11.9 ± 7.9 ng/dL (330 ± 220 pmol/L), respectively. Whether oral Mg²⁺ supplementation influences aldosterone secretion in response to thiazide diuretics used for hypertension, which both deplete Mg²⁺ and stimulate aldosterone secretion through fluid volume contraction, seems likely, though unreported.

What are the mechanisms by which Mg²⁺ may modulate aldosterone secretion? This effect could be mediated by a direct influence upon aldosterone-secreting zona glomerulosa cells or via modulation of upstream components the renin-angiotensin-aldosterone system. A direct effect upon adrenal function is suggested by studies showing that Mg²⁺ exerted a voltage-dependent blockade of inwardly rectifying K⁺ and Ca²⁺ channels in adrenal glomerulosa cells (Vassilev et al., 1992; Lotshaw and Li, 1996). Activity of each of these channel types modulates aldosterone secretion. Furthermore, in cultured adrenal cells, higher extracellular Mg²⁺ reduced basal aldosterone secretion (Antonipillai et al., 1997). Extracellular Mg²⁺ also attenuates stimulation of aldosterone secretion by angiotensin II. In adrenal cells in culture, increased extracellular Mg²⁺ reduced angiotensin II-stimulated aldosterone release (Atarashi et al., 1989; Antonipillai et al., 1997). This effect was also observed in vivo, as rats given an infusion of angiotensin II in combination with Mg²⁺ sulfate exhibited diminished plasma aldosterone, as compared with rats given angiotensin II alone (Atarashi et al., 1990). Evidence for an influence of Mg²⁺ on angiotensin II-mediated aldosterone secretion in humans is provided by a study showing that 3 weeks on a very low (<1 mEq/day) Mg²⁺ diet augmented angiotensin II-stimulated aldosterone secretion (Rude et al., 1989). This increase in aldosterone secretion was partially rescued by acute intravenous Mg²⁺ repletion with Mg²⁺ sulfate. Together, these studies suggest that extracellular Mg²⁺ decreases sensitivity of adrenal glomerulosa cells to angiotensin II-stimulated aldosterone secretion.

Studies examining the influence of Mg²⁺ on upstream components of the renin-angiotensin-aldosterone system are more mixed. In laboratory rats, 14 weeks on a Mg²⁺-deficient diet resulted in no difference in angiotensin II levels (Jin et al., 2013). However, another study examining rats on a Mg²⁺-deficient diet for 6 days found increased angiotensin II, as well as increased plasma renin activity (Sapna et al., 2006). A third study examining dietary Mg²⁺-restriction in rats found increased plasma renin activity at 2 weeks but not at 21 weeks (Laurant et al., 1999). In dogs given a low Mg²⁺ diet, plasma renin activity did not increase at any of several time-points through 90 days, although plasma aldosterone excretion did increase (Helber et al., 1972). In humans, serum Mg²⁺ was found to correlate directly with renin activity (Lind et al., 1989). In contrast, acute Mg²⁺ sulfate infusion increased plasma renin activity (Ichihara et al., 1993).

Taken together, these studies suggest that systemic Mg²⁺ depletion promotes aldosterone secretion without necessarily stimulating increased renin or angiotensin II levels. Whether this increase in aldosterone is reversible or leads to persistent aldosterone secretion (e.g., by promoting adrenal hyperplasia) remains unexplored. Although mechanisms discussed above suggest that systemic Mg²⁺ depletion should promote tubular reabsorption of Na⁺, modulation of extracellular fluid volume by Mg²⁺ has not been described. In a study examining the impact of dietary Mg²⁺ depletion upon blood pressure and fluid volume in mice, although a Mg²⁺-deficient diet increased blood pressure, it did not increase body fluid content, as measured using quantitative magnetic resonance (Pitzer Mutchler et al., 2023). However, Na⁺ overload promotes hypertension via mechanisms that may be Mg²⁺-sensitive, discussed below.

Na⁺ can increase blood pressure via at least two pro-inflammatory mechanisms (Kirabo, 2017). First, high Na⁺ diet increases oxidative stress in antigen-presenting cells (APCs). Peroxidation of arachidonic acid forms isolevuglandins (IsoLGs), γ ketoaldehydes capable of covalently modifying endogenous proteins. Modified proteins are presented at the APC surface, stimulating inflammation. Genetic prevention of IsoLG formation or pharmacologic scavenging of IsoLGs prevents salt-induced hypertension in mouse models (Kirabo et al., 2014; Barbaro et al., 2017). Second, high Na⁺ diet increases expression of NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3), a key component of the inflammasome, in the renal medulla and other tissues (Zhu et al., 2016). The NLRP3 inflammasome catalyzes the production and secretion of the proinflammatory cytokines, IL-1β and IL-18 (Elijovich et al., 2021). Genetic or pharmacologic impairment of the NLRP3 inflammasome prevented blood pressure increases in mouse models of hypertension (Wang et al., 2014; Pitzer et al., 2022).

A Mg²⁺-deficient diet activates these hypertension-promoting inflammatory processes. In laboratory animals, dietary Mg²⁺ deficiency stimulates leukocytosis and circulating inflammatory cytokine levels (Weglicki et al., 1992; Malpuech-Brugère et al., 2000; Van Orden et al., 2006). Oral Mg²⁺ supplementation in humans suppresses circulating C-reactive protein (Mazidi et al., 2018). In mice experiencing hypertension in response to dietary Mg²⁺ restriction, circulating IL-1β levels increase (Pitzer Mutchler et al., 2023). NLRP3 and IsoLG positivity in splenic and renal dendritic cells increase to levels comparable to a high Na⁺ diet. Whether hypertension induced by dietary Mg²⁺ depletion is dependent upon activation of the NLRP3 inflammasome or production of IsoLGs was not examined, but these findings are consistent with a contribution of Mg²⁺ depletion to hypertension-promoting inflammation. Interesting questions remain regarding the mechanisms by which dietary Mg²⁺ restriction induces inflammation and whether dietary Mg²⁺ supplementation protects against high salt diet-mediated inflammation and hypertension.