Magnesium-induced Relaxation in Rat Aorta

Magnesium에 의한 흰쥐 대동맥 이완

  • Oh, Sung-suck (Bio-Safety Research Institute, Chonbuk National University) ;
  • Lee, Sang-woo (Bio-Safety Research Institute, Chonbuk National University) ;
  • Kang, Hyung-sub (Bio-Safety Research Institute, Chonbuk National University) ;
  • Kim, Jin-shang (Bio-Safety Research Institute, Chonbuk National University)
  • 오성숙 (전북대학교 생체안전성연구소) ;
  • 이상우 (전북대학교 생체안전성연구소) ;
  • 강형섭 (전북대학교 생체안전성연구소) ;
  • 김진상 (전북대학교 생체안전성연구소)
  • Accepted : 2003.06.06
  • Published : 2003.09.25


Magnesium ion ($Mg^{2+}$) is a vasodilator, but little is known about its mechanism of action on vascular system. In vitro, extracellular magnesium sulfate ($MgSO_4$) produced relaxation in phenylephrine (PE) or high KCl-precontracted isolated rat thorocic aorta with (+E) or without (-E) endothelium in a concentration-dependent manner. The $MgSO_4$-induced relaxations were not affected by removal of the endothelium. Pretreatment of +E or -E aortic rings with nitric oxide synthase (NOS) inhibitors ($20{\mu}M$ L-NNA, $100{\mu}M$ L-NAME, $1{\mu}M$ dexamethasone and $400{\mu}M$ aminoguanidine), cyclooxygenase inhibitor ($10{\mu}M$ indomethacin), guanylate cyclase inhibitors ($10{\mu}M$ ODQ and $30{\mu}M$ methylene blue) and $Ca^{2+}$ transport blocker ($10{\mu}M$ ryanodine) did not affect the relaxant effects of $MgSO_4$. $Ca^{2+}$ channel blockers ($0.3{\mu}M$ nifedipine and $0.5{\mu}M$ veropamil) completely decreased the relaxant effects of $MgSO_4$ in +E and -E aortic rings. However, in $Ca^{2+}$-free medium, $MgSO_4$-induced vasorelaxation was potentiated and this response was inhibited by nifedipine. Protein kinase C (PKC) inhibitors ($1.0{\mu}M$ staurosporine, $0.5{\mu}M$ tamoxifen and $0.1{\mu}M$ H7) or PLC inhibitor ($100{\mu}M$ NCDC) markedly decreased the relaxant effects of $MgSO_4$ in +E and -E aortic rings. In vivo, infusion of $MgSO_4$ elicited significant decreases in arterial blood pressure. After intravenous injection of nifedipine ($150{\mu}g/kg$) and NCDC (3 mg/kg), infusion of $MgSO_4$ inhibited the $MgSO_4$-lowered blood pressure markedly. However, after introvenous injection of saponin (15 mg/kg), L-NNA (3 mg/kg), L-NAME (5 mg/kg), indomethacin (2 mg/kg), methylene blue (15 mg/kg) and aminoguanidine (10 mg/kg) failed to inhibit it. These results suggest that endothelial NQ-cGMP or prostaglandin pathway is not involved in vasorelaxant or hypotensive action of $Mg^{2+}$ and that these effects are due to the inhibitory action of $Mg^{2+}$ on the $Ca^{2+}$ channel or PLC-PKC pathway, and are due to the competitive influx of $Mg^{2+}$ and $Ca^{2+}$ through the $Ca^{2+}$ channel.


  1. Altura, B. T. and Altura, B. M. Endothelium-dependent relaxation in coronary arteries requires magnesium ions. Br. J. Pharmacol. 1987, 91, 449-451
  2. Altura, B. M. and Altura, B. T. Magnesium and vascular tone and reactivity. Blood Vessets. 1978, 15, 5-16
  3. Altura, B. M. and Altura, B. T. Role of magnesium in the pathogenesis of hypertension update: relationship to its actions on cardiac, vascular smooth muscle, and endothelial cells, In Hypertension: Pathophysiology, Diagnosis, and Manageinent 2nd ed. J. H. Laragh and B. M. Brenner. New York, Raven. 1995, 72, pp. 1213- 1242
  4. Altura, B. M. and Altura, B. T. Withdrawal of magnesium causes vasospasm while elevated magnesium produces relaxations of tone in cerebral arteries. Neurosci. Lett. 1980, 20, 323-327
  5. Altura, B. T. and Chand, N. Bradykinin induced relaxation of renal and pulmonary arteries is dependent upon intact endothelial cells. Br. J. Pharmacol. 1981, 74, 10-11
  6. Bara, M. and Guiet-Bara, A. Magnesium regulation of Ca2+ channels in smooth muscle and endothelial cells of human allantochorial placental vessels. Magnes Res. 2001, 14, 11-18
  7. Benham, C. D. and Tsien, R. W. A novel receptor- operated $Ca^{2+}$-permeab1e channel activated by ATP in smooth muscle. Nature. 1987, 328, 275-278
  8. Carvajal, J. A., Germain, A. M., Huidobro-Toro, J. P. and Weiner, C. P. Molecular mechanism of cGMP- mediated smooth muscle relaxation. J. Cell. Physiol. 2000, 184, 409-420
  9. Chand, N. and Altura, B. M. Acetylcholine and bradykinin relax intrapulmonary arteries by acting in endothelial cells: role in lung vascular diseases. Science. 1981, 213, 1367-1369
  10. Das, R., Kravtsov, G. M., Ballard, H. J. and Kwan, C. Y. L-NAME inhibits $Mg^{2+}$-induced rat aortic relaxation in the absence of endothelium. Br. J. Pharmacol. 1999, 128, 493-499
  11. Eisenberg, M. J. Magnesium deficiency and sudden death. Am. Heart. J. 1992, 124, 544-549
  12. Furchgott, R. F. Studies on relaxation of rabbit aorta by sodium nitrite: basis for the proposal thal the acid-activatable component of the inhibitory factor from retractor penis is inorganic nitrite and the endothelium- derived relaxing factor is nitric oxide. In: Mechanisms of vasodilatation, edited by P. M. Vanhoutte. pp. 410- 414, New York, Raven. 1988
  13. Furchgott, R. F. and Zaxadzki, J. V. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980, 288, 373-376
  14. Grubbs, R. D. and Maguire, M. E. Magnesium as a regulatory cation: criteria and evaluation. Magnesium. 1987, 6, 113-127
  15. Hazard, R. and Wurmser, L. Actions des sel de magnesium surles vasoconstricteurs renaux. Compte. Rendus. Soc. Biol. 1932, 110, 525-528
  16. Hishinuma. T., Tsukamoto, H., Suzuki, K. and Mizugaki, M. Relationship between thromboxane/ pro- stacyclin ratio and diabetic vascular complications. Pro- staglandins Leukot. Essent. Fatty. Acids. 2001, 65, 191-196
  17. Ignarro, L. and Kadowitz, P. J. The pharmacological and physiological properties of endothelium-derived relaxing factor and its similarity to nitric oxide radical. In Mechanisms of Vasodilatation, pp. 427-435, P. M. Vanhoutte, New York, Raven. 1988
  18. Iseri, L. T. and French, J. H. Magnesium: nature's physiological calcium blocker. Am. Heart J. 1984, 108, 188-193
  19. Kasai. M. and Miyamoto, H. Depolaiization induced calcium release from sarcoplasmic reticulum membrane fragments by changing ionic environrnent, FEBS Leners. 1973, 34, 299-301
  20. Ku, D. D. and Ann, H. S. Different effects af magriesium on basal and agonist-induced EDRF relaxation in canine coronary arteries. J. Cardiovasc. Pharmacol. 1991, 17, 999-1006
  21. Lee, W. M. and Severson, D. L. Signal transduction in vascular smooth muscle: diacylglycerol second messen- gers and PKC action. Am. J. Physiol. 1994, 267, C659-678
  22. Longo, M., Jain, V., Vedernikov, Y. P., Facchinetti, F., Saade, G. R. and Garfield, R. E. Endothelium dependence and gestational regulation of inhibition of vascular tone by magnesium sulfate in rat aorta. Am. J. Obst. Gynecol. 2001, 184, 971-978
  23. Malarkey, K., Aidulis, D., Belham, C. M., Graham, A., McLees, A., Paul, A. and Plevin, R. Cell signaling pathways involved in the regulation of vascular smooth muscle contraction and relaxation. In Garland, C.J., Angus, I.A. (Eds.), Pharmacology of Vascular Smooth Muscle. Oxford Univ. Press, pp. 160-183, New York. 1996
  24. Matsunaga, H., Ling, B. N. and Eaton, D. C. $Ca^{2+}$ permeable channel associated with platelet-derived growth factor receptor in mesangial cells. Am. J. Physiol. 1994, 267, C456-465
  25. Moncada, S., Palmer, R. M. J. and Higgs, E. A. Nitric oxide: Physiology, pathophysiology and pharma- cology. Pharmacol. Rev. 1991, 43, 109-142
  26. Mordes, J. P. and Wacker, W. E. C. Excess magnesium. Pharmacol. Rev. 1978, 29, 273-300
  27. Nakajima, T., Hazama, H., Hamada, E., Wu, S. N., Igarashi, K., Yamashita, T., Seyama, Y., Omata, M. and Kurachi, Y. Endothelin-l and vasopressin activate $Ca_{(2+)}$-permeab1e non-selective cation channels in aortic smooth muscle cells: mechanism of receptor- mediated Ca2+ influx. J. Mol. Cell Cardiol. 1996, 28, 707-722
  28. Nakajima, T., Iwasawa, K., Hazama, H., Asano, M.,Okuda, Y. and Omata, M. Extracellular M& inhibitsreceptor-mediated $Ca^{2+}$-permeable non-selective cationcurrents in aortic smooth muscle cells. Eur. J. Phamacol.1997, 320, 81-86
  29. Noguera, M. A., Chulia, S., Ivorra, M. D. and D'Ocon, M. P. Effect of divalent cations on KCl- and nora- drenaline-induced contractile responses in rat aorta after nifedipine treatment. Gen. Pharmacol. 1999, 33, 43-50
  30. Noguera, M. A. and D'Ocon, M. P. Modulatory role of magnesium on the contractile response of rat aorta to several agonists in normal and calcium-free medium. J. Pharm. Pharmacol. 1993, 45, 697-700
  31. Parfenova, H. and Leffer, C. W. Functional study on vasodilator effects of prostaglandin E2 in the newborn pig cerebral circulation. Eur. J. Pharmacol. 1995, 278, 133-142
  32. Rude, G. K. Physiology of magnesium metabolism and the important role of magnesium in potassium deficiency. Am. J. Cardiol. 1989, 63, 31G-34G
  33. Ruegg, U. T., Wallnofer, A., Weir, S. and Cauvin, C. Receptor-operated calcium-permeable channels in vascular smooth muscle. J. Cardiovasc. Pharmacol. 1989, 6, S49-58
  34. Saris, N. E., Mervaala, E., Karppanen, H., Khawaja, J. A. and Lewenstam, A. Magnesium. An update on physiological, clinical and analytical aspects. Clin. Chim. Acta. 2000, 294, 1-26
  35. Sjogren, A., Edvinsson, L. and Fallgren, B. Magnesium deficiency in coronary artery disease and cardiac arrhythmias. J. Intern. Med. 1989, 226, 213-222
  36. Van Renterghem, C., Romey, G. and Lazdunski, M. Vasopressin modulates the spontaneous electrical activity in aortic cells (line A7r5) by acting on three different types of ionic channels. Proc. Natl. Acad. Sci. 1988, 85, 9365-9369
  37. Yang, Z. W., Altura, B. T. and Altura, B. M. Low extracellular Mg2+ contraction of arterial muscle: role of protein kinase C and protein tyrosine phosphorylation. Eur. J. Pharmacol. 1999, 378, 273-281
  38. Yang, Z. W., Gebrewold, A., Nowakowski, M., Altura, B. T. and Altura, B. M. MgU-induced endothelium- dependent relaxation of blood vessels and blood pressure lowering: role of NO. Am. J. Physiol. Regul Integr. Comp. Physiol. 2000, 278, R628-R639
  39. Zhang, A., Cheng, T. P. and Altura, B. M. Magnesium regulates intracellular free ionized calcium concentration and cell geometry in vascular smooth muscle cells. Biochim. Biophys. Acta. 1992, 1134, 25-29
  40. Zhang, A., Fan, S. H., Cheng, T. P., Altura, B. T., Wong, R. K. and Altura, B. M. Extracellular $Mg^{2+}$ modulates intracellular $Ca^{2+}$ in acutely isolated hippocampal CAl pyraniidal cells of the guinea-pig. Brain. Res. 1996, 728, 204-208
  41. Zhang, A. M., Altura, B. T. and Altura, B. M. Endothelial-dependent sexual dimorphism in vascular smooth muscle: role of $Mg^{2+}$ and $Na^+$. Br. J. Pharmacol. 1992, 105, 305-310