Additional antihypertensive effect of magnesium supplementation with an angiotensin II receptor blocker in hypomagnesemic rats

Article information

Korean J Intern Med. 2013;28(2):197-205
Publication date (electronic) : 2013 February 27
doi : https://doi.org/10.3904/kjim.2013.28.2.197
1Department of Internal Medicine, Inje University Haeundae Paik Hospital, Busan, Korea.
2Department of Internal Medicine, Inje University Busan Paik Hospital, Busan, Korea.
Correspondence to Yang Wook Kim, M.D. Department of Internal Medicine, Inje University Haeundae Paik Hospital, 875 Haeun-daero, Haeundae-gu, Busan 612-862, Korea. Tel: +82-51-797-0603, Fax: +82-51-797-3282, kyw8625@chol.com
Received 2012 February 13; Revised 2012 March 06; Accepted 2012 June 21.

Abstract

Background/Aims

Magnesium (Mg) is an essential element for vascular function and blood pressure regulation. Several studies have demonstrated that Mg concentration is inversely associated with blood pressure, and that Mg supplementation attenuates hypertension. The purpose of this study was to evaluate the effect of dietary Mg supplementation on the blood pressure effects of an angiotensin II receptor blocker (ARB) in hypomagnesemic rats.

Methods

Fifty male Sprague-Dawley rats were randomly divided into Mg-deficient (n = 30), normal diet plus Mg (n = 10), and control groups (n = 10). Mg-free, high-Mg, and normal-Mg diets were respectively fed to the rats. After 14 weeks, 10 of the 30 Mg-deficient rats were treated with Mg, 10 Mg-deficient rats received an ARB, and 10 Mg-deficient rats received an ARB plus Mg for 4 weeks.

Results

Systolic blood pressure was significantly higher in the Mg-deficient rats than in the control rats at week 14. Hypomagnesemic rats exhibited decreased systolic blood pressure after treatment with Mg, and systolic blood pressure showed a greater decrease after ARB treatment. Treatment with the ARB/Mg combination resulted in the greatest decrease in systolic blood pressure. Mg deficiency did not affect the serum angiotensin II level, but did increase the serum aldosterone concentration. Concomitant Mg/ARB supplementation significantly decreased the elevated serum aldosterone level in hypomagnesemic rats. Kidney tissues of the hypomagnesemic rats revealed mild to moderate inflammatory infiltrates. Mg and/or ARB treatment did not reverse the inflammatory reaction in the kidneys of hypomagnesemic rats.

Conclusions

Concurrent dietary Mg supplementation can enhance ARB-induced blood pressure reduction in rats with hypomagnesemic hypertension.

INTRODUCTION

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.

METHODS

Animals

Fifty male Sprague-Dawley rats (6 weeks old; average body weight, 180 g; Orient Bio, Seoul, Korea) were used in this study. The animals were housed in a climate-controlled vivarium with 12-hour light-dark cycle and were fed diet and water ad libitum. All animal experiments were conducted according to the guidelines formulated by the Inje University Animal Care and Use Committee (Busan, Korea).

Experimental procedures

The rats were randomly divided into control diet (#114551, Dyets Inc., Bethlehem, PA, USA) (n = 10), control diet with Mg treatment (n = 10), and Mg-free diet groups (n = 30). The Mg oxide composition of the control diet was 26.53 g/kg. After 14 weeks, the rats in the Mg-free diet group were randomly assigned to Mg treatment (n = 10), ARB treatment (n = 10), and Mg and ARB treatment subgroups (n = 10). For 4 weeks, the Mg treatment group received Mg (3,200 mg/kg/day) dissolved in food, the ARB treatment group was intraperitoneally administered losartan (30 mg/kg/day), and the Mg and ARB treatment group was given Mg (3,200 mg/kg/day) and losartan (30 mg/kg/day) as in the other two groups. After 4 weeks, blood pressure was determined by tail plethysmography (IITC Life Science, Woodland Hills, CA, USA). Conscious rats were placed in a restrainer on a warming pad and allowed to rest in a cage for 15 minutes before blood pressure measurement. Rat tails were placed inside a tail cuff, and the cuff was inflated and released several times to condition the animal to the procedure.

At the end of the experiment, the rats were anesthetized with sodium pentobarbital (50 mg/kg, intraperitoneal) and euthanized by exsanguination using cardiac puncture. The kidneys were removed and weighed. A piece of the kidney was separated and fixed in 10% formalin for histological examination, and another piece was processed as described below. The remaining tissue was cleaned with phosphate-buffered saline, snap-frozen in liquid nitrogen, and stored at -70℃ until processed.

Values of serum Mg (Integra 800, Roche, Indianapolis, IN, USA), potassium (ADVIA 2400, Roche), calcium (ADVIA 2400, Siemens, Mannheim, Germany), angiotensin II, and aldosterone (Phoenix Pharmaceuticals, Burlingame, CA, USA) were analyzed using the appropriate specific procedures.

Histology

For light microscopy studies, the formalin-fixed kidney tissues were stained with hematoxylin and eosin, and Masson's trichrome by standard methods. Interstitial inflammation, fibrosis, and tubular atrophy were graded by the renal pathology study group of the Korean Society of Pathologists according to the following grading system: negative (≤ 10%), mild (11% to 25%), moderate (26% to 50%), and severe (> 50%) [20].

Statistical analysis

Analysis of variance and a post hoc Tukey test (SPSS Inc., Chicago, IL, USA) were used for statistical evaluation of the data, which are presented as means ± SD. Values of p ≤ 0.05 indicated significance.

RESULTS

Blood pressure effects of Mg and/or ARB treatments in Mg-deficient rats

Systolic blood pressure was similar between the control group and the Mg-free diet group (Mg-deficient rats) during the first 5 to 10 weeks. At week 14, systolic blood pressure was significantly higher in the Mg-deficient rats than in the control rats (p = 0.034) (Fig. 1A). Systolic blood pressure decreased during treatment with Mg and/or ARB in the hypomagnesemic rats. Each Mg/ARB treatment resulted in a similar reduction in systolic blood pressure. The decrease in systolic blood pressure was significantly greater (p < 0.028) in the Mg/ARB treatment group (44.3% ± 6.9% decrease) than in the Mg-only (28.7% ± 5.6% decrease) or ARB-only (28.9% ± 4.8% decrease) treatment group (Fig. 1B and 1C). These findings suggest that long-term hypomagnesemia induces hypertension and that concurrent dietary Mg supplementation enhances ARB-induced blood pressure reduction in hypomagnesemic rats.

Figure 1

(A) Changes in systolic blood pressure during magnesium (Mg) deficiency, (B) Mg and/or angiotensin II receptor blocker (ARB) treatment, and (C) reduction of systolic blood pressure after Mg/ARB treatment. Values are presented as means ± SD. ap < 0.05 vs. normal diet group, bp < 0.05 vs. 14 weeks.

Effects of the Mg-free diet and Mg and/or ARB treatment on biochemical parameters

As shown in Table 1, serum calcium and potassium levels were similar among the study groups at weeks 14 and 18. Fig. 2 presents the serum levels of angiotensin II and aldosterone in the rats. The serum angiotensin II level did not differ among the groups during the study period. However, the serum aldosterone level was significantly higher in the hypomagnesemic rats compared with the rats in the other two diet groups. Treatment with Mg and/or ARB tended to decrease the serum angiotensin II level in hypomagnesemic rats, but the difference was not significant. In contrast, Mg and/or ARB treatment resulted in a significant decrease in the elevated serum aldosterone level in hypomagnesemic rats. These findings suggest direct effects of Mg deficiency on aldosterone production, independent of the renin-angiotensin system.

Table 1

Serum biochemical parameters in each diet group during induction of hypomagnesemia and treatment of hypomagnesemic rats

Figure 2

(A) Change in serum angiotensin II during magnesium (Mg) deficiency and (B) Mg and/or angiotensin II receptor blocker (ARB) treatment. (C) Change in aldosterone level during Mg deficiency and (D) Mg and/or ARB treatment. Values are presented as means ± SD. ap < 0.05 vs. other group, bp < 0.05 vs. 14 weeks.

Effects of the Mg-free diet and Mg and/or ARB treatment on renal pathology

The kidney tissues of the hypomagnesemic rats exhibited mild to moderate inflammatory infiltration of mononuclear leukocytes, interstitial fibrosis, tubular atrophy, and calcium deposits. Treatment with Mg and/or ARB did not reverse the inflammatory reaction in the kidneys of hypomagnesemic rats (Fig. 3).

Figure 3

(A, B) Effects of magnesium (Mg)-deficient diet and Mg and/or angiotensin II receptor blocker (ARB) treatment on renal pathology (A, H&E, × 100; B, Masson's trichrome stain, × 100). Normal diet: inflammation (negative), fibrosis (negative), and tubular atrophy (negative). Normal diet + Mg: inflammation (negative), fibrosis (negative), and tubular atrophy (negative). Mg-free diet: inflammation (moderate), fibrosis (mild), and tubular atrophy (negative). Hypomagnesemic rats treated with Mg: inflammation (mild), fibrosis (negative), and tubular atrophy (negative). Hypomagnesemic rats treated with ARB: inflammation (moderate), fibrosis (mild), and tubular atrophy (negative). Hypomagnesemic rats treated with Mg/ARB: inflammation (moderate), fibrosis (moderate), and tubular atrophy (mild).

DISCUSSION

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.

KEY MESSAGE

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.

Acknowledgments

This work was supported by a Collaborative Research Grant of Inje University, 2007.

Notes

No potential conflict of interest relevant to this article is reported.

References

1. Touyz RM. Role of magnesium in the pathogenesis of hypertension. Mol Aspects Med 2003;24:107–136. 12537992.
2. Laurant P, Dalle M, Berthelot A, Rayssiguier Y. Time-course of the change in blood pressure level in magnesium-deficient Wistar rats. Br J Nutr 1999;82:243–251. 10655971.
3. Adrian M, Chanut E, Laurant P, Gaume V, Berthelot A. A long-term moderate magnesium-deficient diet aggravates cardiovascular risks associated with aging and increases mortality in rats. J Hypertens 2008;26:44–52. 18090539.
4. Fox C, Ramsoomair D, Carter C. Magnesium: its proven and potential clinical significance. South Med J 2001;94:1195–1201. 11811859.
5. Swaminathan R. Magnesium metabolism and its disorders. Clin Biochem Rev 2003;24:47–66. 18568054.
6. Sontia B, Touyz RM. Role of magnesium in hypertension. Arch Biochem Biophys 2007;458:33–39. 16762312.
7. Berthon N, Laurant P, Hayoz D, Fellmann D, Brunner HR, Berthelot A. Magnesium supplementation and deoxycorticosterone acetate: salt hypertension: effect on arterial mechanical properties and on activity of endothelin-1. Can J Physiol Pharmacol 2002;80:553–561. 12117304.
8. Blache D, Devaux S, Joubert O, et al. Long-term moderate magnesium-deficient diet shows relationships between blood pressure, inflammation and oxidant stress defense in aging rats. Free Radic Biol Med 2006;41:277–284. 16814108.
9. Touyz RM. Transient receptor potential melastatin 6 and 7 channels, magnesium transport, and vascular biology: implications in hypertension. Am J Physiol Heart Circ Physiol 2008;294:H1103–H1118. 18192217.
10. Shechter M, Sharir M, Labrador MJ, Forrester J, Silver B, Bairey Merz CN. Oral magnesium therapy improves endothelial function in patients with coronary artery disease. Circulation 2000;102:2353–2358. 11067788.
11. Touyz RM. Magnesium supplementation as an adjuvant to synthetic calcium channel antagonists in the treatment of hypertension. Med Hypotheses 1991;36:140–141. 1664038.
12. Saito N, Abbu GC, Konishi Y, Nishiyama S, Okada T. Magnesium, calcium and trace elements in spontaneously hypertensive rats. Clin Exp Pharmacol Physiol Suppl 1995;22:S212–S214. 9072361.
13. Makynen H, Kahonen M, Arvola P, Wuorela H, Vapaatalo H, Porsti I. Dietary calcium and magnesium supplements in spontaneously hypertensive rats and isolated arterial reactivity. Br J Pharmacol 1995;115:1455–1462. 8564205.
14. Evans GH, Weaver CM, Harrington DD, Babbs CF Jr. Dietary magnesium does not affect blood pressure in spontaneously hypertensive rats. Clin Exp Hypertens A 1989;11:619–632. 2791320.
15. Berthelot A, Esposito J. Effects of dietary magnesium on the development of hypertension in the spontaneously hypertensive rat. J Am Coll Nutr 1983;2:343–353. 6317730.
16. Touyz RM, Milne FJ. Magnesium supplementation attenuates, but does not prevent, development of hypertension in spontaneously hypertensive rats. Am J Hypertens 1999;12(8 Pt 1):757–765. 10480467.
17. Laurant P, Touyz RM. Physiological and pathophysiological role of magnesium in the cardiovascular system: implications in hypertension. J Hypertens 2000;18:1177–1191. 10994748.
18. Touyz RM, Mercure C, Reudelhuber TL. Angiotensin II type I receptor modulates intracellular free Mg2+ in renally derived cells via Na+-dependent Ca2+-independent mechanisms. J Biol Chem 2001;276:13657–13663. 11278387.
19. Nadler JL, Buchanan T, Natarajan R, Antonipillai I, Bergman R, Rude R. Magnesium deficiency produces insulin resistance and increased thromboxane synthesis. Hypertension 1993;21(6 Pt 2):1024–1029. 8505087.
20. Jin SY, Jeong HJ, Sung SH, et al. Practical standardization in renal biopsy reporting. Korean J Pathol 2010;44:613–622.
21. Resnick LM, Bardicef O, Altura BT, Alderman MH, Altura BM. Serum ionized magnesium: relation to blood pressure and racial factors. Am J Hypertens 1997;10(12 Pt 1):1420–1424. 9443780.
22. Kesteloot H, Joossens JV. Relationship of dietary sodium, potassium, calcium, and magnesium with blood pressure: Belgian Interuniversity Research on Nutrition and Health. Hypertension 1988;12:594–599. 3203963.
23. Kisters K, Tepel M, Spieker C, et al. Decreased membrane Mg2+ concentrations in a subgroup of hypertensives: membrane model for the pathogenesis of primary hypertension. Am J Hypertens 1998;11(11 Pt 1):1390–1393. 9832186.
24. 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. 9719052.
25. Laurant P, Kantelip JP, Berthelot A. Dietary magnesium supplementation modifies blood pressure and cardiovascular function in mineralocorticoid-salt hypertensive rats but not in normotensive rats. J Nutr 1995;125:830–841. 7722684.
26. Sanjuliani AF, de Abreu Fagundes VG, Francischetti EA. Effects of magnesium on blood pressure and intracellular ion levels of Brazilian hypertensive patients. Int J Cardiol 1996;56:177–183. 8894790.
27. Widman L, Wester PO, Stegmayr BK, Wirell M. The dose-dependent reduction in blood pressure through administration of magnesium: a double blind placebo controlled cross-over study. Am J Hypertens 1993;6:41–45. 8427660.
28. Cappuccio FP, Markandu ND, Beynon GW, Shore AC, Sampson B, MacGregor GA. Lack of effect of oral magnesium on high blood pressure: a double blind study. Br Med J (Clin Res Ed) 1985;291:235–238.
29. Ferrara LA, Iannuzzi R, Castaldo A, Iannuzzi A, Dello Russo A, Mancini M. Long-term magnesium supplementation in essential hypertension. Cardiology 1992;81:25–33. 1477853.
30. Lind L, Lithell H, Pollare T, Ljunghall S. Blood pressure response during long-term treatment with magnesium is dependent on magnesium status: a double-blind, placebo-controlled study in essential hypertension and in subjects with high-normal blood pressure. Am J Hypertens 1991;4:674–679. 1930849.
31. Barbagallo M, Dominguez LJ, Galioto A, Pineo A, Belvedere M. Oral magnesium supplementation improves vascular function in elderly diabetic patients. Magnes Res 2010;23:131–137. 20736142.
32. Kisters K. Oral magnesium supplementation improves borderline hypertension. Magnes Res 2011;24:17. 21421454.
33. Rosanoff A. Magnesium supplements may enhance the effect of antihypertensive medications in stage 1 hypertensive subjects. Magnes Res 2010;23:27–40. 20228010.
34. Hatzistavri LS, Sarafidis PA, Georgianos PI, et al. Oral magnesium supplementation reduces ambulatory blood pressure in patients with mild hypertension. Am J Hypertens 2009;22:1070–1075. 19617879.
35. Guerrero-Romero F, Rodriguez-Moran M. The effect of lowering blood pressure by magnesium supplementation in diabetic hypertensive adults with low serum magnesium levels: a randomized, double-blind, placebo-controlled clinical trial. J Hum Hypertens 2009;23:245–251. 19020533.
36. Ameen M, Davies JE, Ng LL. A comparison of free intracellular calcium and magnesium levels in the vascular smooth muscle and striated muscle cells of the spontaneously hypertensive and Wistar Kyoto normotensive rat. Ann N Y Acad Sci 1991;639:550–553. 1785881.
37. Laurant P, Hayoz D, Brunner HR, Berthelot A. Effect of magnesium deficiency on blood pressure and mechanical properties of rat carotid artery. Hypertension 1999;33:1105–1110. 10334795.
38. Laurant P, Berthelot A. Influence of endothelium on Mg(2+)-induced relaxation in noradrenaline-contracted aorta from DOCA-salt hypertensive rat. Eur J Pharmacol 1994;258:167–172. 8088352.
39. Touyz RM, Pu Q, He G, et al. Effects of low dietary magnesium intake on development of hypertension in stroke-prone spontaneously hypertensive rats: role of reactive oxygen species. J Hypertens 2002;20:2221–2232. 12409961.
40. Altura BM, Altura BT, Gebrewold A, Ising H, Gunther T. Noise-induced hypertension and magnesium in rats: relationship to microcirculation and calcium. J Appl Physiol 1992;72:194–202. 1537714.
41. Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988;332:411–415. 2451132.
42. Moncada S, Vane JR. The role of prostacyclin in vascular tissue. Fed Proc 1979;38:66–71. 215463.
43. Weglicki WB, Phillips TM, Freedman AM, Cassidy MM, Dickens BF. Magnesium-deficiency elevates circulating levels of inflammatory cytokines and endothelin. Mol Cell Biochem 1992;110:169–173. 1584207.
44. Briel RC, Lippert TH, Zahradnik HP. Action of magnesium sulfate on platelet prostacyclin interaction and prostacyclin of blood vessels. Am J Obstet Gynecol 1985;153:232. 3898850.
45. Ginn HE, Cade R, McCallum T, Fregley M. Aldosterone secretion in magnesium-deficient rats. Endocrinology 1967;80:969–971. 6023564.
46. Altura BM, Altura BT. Magnesium and cardiovascular biology: an important link between cardiovascular risk factors and atherogenesis. Cell Mol Biol Res 1995;41:347–359. 8867781.
47. Yanahira S, Morita M, Aoe S, et al. Effects of lactitol-oligosaccharides on calcium and magnesium absorption in rats. J Nutr Sci Vitaminol (Tokyo) 1997;43:123–132. 9151246.
48. Iseri LT, French JH. Magnesium: nature's physiologic calcium blocker. Am Heart J 1984;108:188–193. 6375330.

Article information Continued

Figure 1

(A) Changes in systolic blood pressure during magnesium (Mg) deficiency, (B) Mg and/or angiotensin II receptor blocker (ARB) treatment, and (C) reduction of systolic blood pressure after Mg/ARB treatment. Values are presented as means ± SD. ap < 0.05 vs. normal diet group, bp < 0.05 vs. 14 weeks.

Figure 2

(A) Change in serum angiotensin II during magnesium (Mg) deficiency and (B) Mg and/or angiotensin II receptor blocker (ARB) treatment. (C) Change in aldosterone level during Mg deficiency and (D) Mg and/or ARB treatment. Values are presented as means ± SD. ap < 0.05 vs. other group, bp < 0.05 vs. 14 weeks.

Figure 3

(A, B) Effects of magnesium (Mg)-deficient diet and Mg and/or angiotensin II receptor blocker (ARB) treatment on renal pathology (A, H&E, × 100; B, Masson's trichrome stain, × 100). Normal diet: inflammation (negative), fibrosis (negative), and tubular atrophy (negative). Normal diet + Mg: inflammation (negative), fibrosis (negative), and tubular atrophy (negative). Mg-free diet: inflammation (moderate), fibrosis (mild), and tubular atrophy (negative). Hypomagnesemic rats treated with Mg: inflammation (mild), fibrosis (negative), and tubular atrophy (negative). Hypomagnesemic rats treated with ARB: inflammation (moderate), fibrosis (mild), and tubular atrophy (negative). Hypomagnesemic rats treated with Mg/ARB: inflammation (moderate), fibrosis (moderate), and tubular atrophy (mild).

Table 1

Serum biochemical parameters in each diet group during induction of hypomagnesemia and treatment of hypomagnesemic rats

Table 1

Values are presented as means ± SD.

ap < 0.05 vs. baseline.

bp < 0.05 vs. 14 weeks.