Medical Hypotheses MtdicalHyporkrrr (1991) 36. 14&141 0 Longman Group UK Ltd 1991
Magnesium Supplementation as an Adjuvant to Synthetic Calcium Channel Antagonists in the Treatment of Hypertension R.M. TOUYZ Department of Medicine, University of the Witwatersrand Johannesburg, South Africa
Medical School, 7 York Road, Parktown 2193,
Abstract - Magnesium (M? *+) has antagonistic properties to calcium (Ca*+) and has been termed the physiologic Ca + blocker. Synthetic Ca *+ channel blockers are extensively used as anti-hypertensive agents. It is hypothesised that when administered in combination synthetic Ca*+ channel blockers and Mg are synergistic in the treatment of hypertension.
Introduction The association between Mg2+ metabolism and blood pressure regulation was suggested over six decades ago, when Mg2+ salts were administered as a blood pressure lowering agent in malignant hypertension (1). Since then, experimental research has confirmed that Mg*’ deficiency alters vascular smooth muscle tone resulting in increased blood pressure (2, 3). The role of Mg*+ in the pathoaetiology of essential hypertension is probably related to its effects on the other cations and particularly Ca2+. Intracellular Ca2’ concentration is one of the major determinants of vascular smooth muscle tone and contractility (4). C tosolic Ca*+ overload with abnormal cellular Ca1+ metabolism has been reported in essential hypertension (5, 6). Since Ca2+ and Mg2+ are both divalent cations, many of their cellular metabolic processes are interrelated. Magnesium, the second most common intracellular
1. 2. 3. 4.
cation, is vital for many enzymatic
Date received31 December 1990 accepwJ 26 khmary IYYI
_ Uare
processes, including that involved in Ca2+ movement across and within the cell membrane of cardiac and vascular tissues (7). Calcium is essential for all neuromuscular activity, including impulse formation of nodal tissues and muscular contraction of vascular tissues and myocardium (8). Calcium enters cells either via passive movement, or through a variety of Ca2* channels. Magnesium modulates the activity of the Ca2+ ion and has been described as the endogenous Ca2+ channel blocker for the following reasons (9, 10):
140
Mg*+ blocks entry of Ca2’ via the receptor op erated channels of vascular smooth muscle cells; Within the cell, Mg2+ inhibits Ca*+ release and drives Ca2+ into sarcoplasmic reticulum; Mg2+ competes with Ca2+ over nonspecific binding sites on the plasma membrane; Mg*+ can block the slow Ca2+ channels.
SYKI?IETIC Ca*+ CHANNEL BLOCKERS AND MG IN TREATMENT OF HYPERTENSION
Consequently, Mg2+ seems to control certain neuromuscular functions by reducing the availability of Ca2’ ions. It could serve as an important therapeutic tool in cardiovascular disease. Synthetic Ca2+ channel antagonists exert their antihypertensive effects by reducing $e availabflity of intracellular Ca2+ by blocking Ca + influx (11) These drugs react with specific membrane receptor binding sites which modulate Ca2’ influx by causing conformational changes of the channel proteins (12). Two types of Ca2+ channels have been identified in vascular smooth muscle cells including a fast deactivating channel of the T-type and slow Ca2’ channels of the L-type (13). Mg2+ blocks the slow channels which are (character&d by having a high threshold and high affinity towards dihydropyridine derivatives. The net result of blocking Ca2+ channels by Mg2+ or synthetic Ca2’ channel antagonists, is vasodilation, with consequent reduction in blood pressure. Hypothesis
and discussion
With the knowledge that Mg2+ is the physiologic Ca2+ blocker and that Ca2’ blockers results in relaxation of vascular cells, the proposal is made that the hypotensive therapeutic effect of synthetic Ca2+channel antagonists given concommitantly with Mg2+ would be synergistic. A number of beneficial effects would derive from the combination of Mg2+ with synthetic Ca2+-channel blockers, including reduced therapeutic doses of Ca2+-channel antagonists, decreased side.-effects of the drug, smooth blood pressure control and improved prognosis in patients with hypertens,ion and ischaemic heart disease or arrhythmias. In order to test this hypothesis, a long-term, double blind placebo-controlled study is necessary. Such a study is currently being conducted.
141
References 1. Blackfan KD, Hamilton B. Uremia in acute glomerular nephritis. The cause and treatment in children. Boston Medical and Surgical Journal 193: 617-628, 1925. 2. Altura BM, Altura BT, Carella A. Magnesium deficiencyinduced spasms of umbilical vessels: relation to preeeclampsia, hypertension, growth retardation. Science 221: 376378. 1983. 3. Altura BM, Altura BT, Gebrewold A. Magnesium deficiency and hypertension: correlation between magnesium deficient diets and microcirculatory changes in situ. Science 223: 1315-1317, 1984. 4. Ishikawa T, Hidaka H. Molecular pharmacology of calcium, calmodulindependent myosin phosphorylation in vascular smooth muscle. American Journal of Hypertension 3: 2315-2345, 1990. 5. Eme P, Bolli P, Burgisser E. Buhler FR. Correlation of platelet calcium with blood pressure. Effect of antihypertensive tber;;;4,New England Journal of Medicine. 310: 1084-1088. 6. Rao RM, Young EW, McCarron DA. Disregulation of cell calcium and calcium-binding proteins in experimental hypertension. Advanced Experimenral Medical Biology 255: 505-514. 1989. I. Altura BNM, Altura BT. Magnesium-calcium interrelationships in vascular smooth muscle. Magnesium Bulleten 8: 338-350, 1986. 8. Aikawa JK. Biochemistry and physiology of Mg’+. World Review of Nutrition and Diet 28: 112. 1978. 9. Portelli C. The synergism and antagonism of cations. Physiologie 19: 229-234, 1982. 10. Stephenson EW, Podolsky RJ. Regulation by magnesium of intracellular calcium movement in skinned muscle fibers. Journal of General Physiology 69: 1-6, 1977. 11. Braunwald E. Mechanisms of action of calcium-channelblocking agents. New England Journal of Medicine 302: 1618-1629. 1982. 12. Godfraind T. Mechanisms of action of calcium entry blockers. Federation Proceedings 40: 2866-2871. 1981. 13. Bean BP. Classes of calcium channels in vertebrate cells. Annual Review of Physiology 51: 367-384, 1989.
Magnesium Supplementation as an Adjuvant to Synthetic Calcium Channel Antagonists in the Treatment of Hypertension R.M. TOUYZ Department of Medicine, University of the Witwatersrand Johannesburg, South Africa
Medical School, 7 York Road, Parktown 2193,
Abstract - Magnesium (M? *+) has antagonistic properties to calcium (Ca*+) and has been termed the physiologic Ca + blocker. Synthetic Ca *+ channel blockers are extensively used as anti-hypertensive agents. It is hypothesised that when administered in combination synthetic Ca*+ channel blockers and Mg are synergistic in the treatment of hypertension.
Introduction The association between Mg2+ metabolism and blood pressure regulation was suggested over six decades ago, when Mg2+ salts were administered as a blood pressure lowering agent in malignant hypertension (1). Since then, experimental research has confirmed that Mg*’ deficiency alters vascular smooth muscle tone resulting in increased blood pressure (2, 3). The role of Mg*+ in the pathoaetiology of essential hypertension is probably related to its effects on the other cations and particularly Ca2+. Intracellular Ca2’ concentration is one of the major determinants of vascular smooth muscle tone and contractility (4). C tosolic Ca*+ overload with abnormal cellular Ca1+ metabolism has been reported in essential hypertension (5, 6). Since Ca2+ and Mg2+ are both divalent cations, many of their cellular metabolic processes are interrelated. Magnesium, the second most common intracellular
1. 2. 3. 4.
cation, is vital for many enzymatic
Date received31 December 1990 accepwJ 26 khmary IYYI
_ Uare
processes, including that involved in Ca2+ movement across and within the cell membrane of cardiac and vascular tissues (7). Calcium is essential for all neuromuscular activity, including impulse formation of nodal tissues and muscular contraction of vascular tissues and myocardium (8). Calcium enters cells either via passive movement, or through a variety of Ca2* channels. Magnesium modulates the activity of the Ca2+ ion and has been described as the endogenous Ca2+ channel blocker for the following reasons (9, 10):
140
Mg*+ blocks entry of Ca2’ via the receptor op erated channels of vascular smooth muscle cells; Within the cell, Mg2+ inhibits Ca*+ release and drives Ca2+ into sarcoplasmic reticulum; Mg2+ competes with Ca2+ over nonspecific binding sites on the plasma membrane; Mg*+ can block the slow Ca2+ channels.
SYKI?IETIC Ca*+ CHANNEL BLOCKERS AND MG IN TREATMENT OF HYPERTENSION
Consequently, Mg2+ seems to control certain neuromuscular functions by reducing the availability of Ca2’ ions. It could serve as an important therapeutic tool in cardiovascular disease. Synthetic Ca2+ channel antagonists exert their antihypertensive effects by reducing $e availabflity of intracellular Ca2+ by blocking Ca + influx (11) These drugs react with specific membrane receptor binding sites which modulate Ca2’ influx by causing conformational changes of the channel proteins (12). Two types of Ca2+ channels have been identified in vascular smooth muscle cells including a fast deactivating channel of the T-type and slow Ca2’ channels of the L-type (13). Mg2+ blocks the slow channels which are (character&d by having a high threshold and high affinity towards dihydropyridine derivatives. The net result of blocking Ca2+ channels by Mg2+ or synthetic Ca2’ channel antagonists, is vasodilation, with consequent reduction in blood pressure. Hypothesis
and discussion
With the knowledge that Mg2+ is the physiologic Ca2+ blocker and that Ca2’ blockers results in relaxation of vascular cells, the proposal is made that the hypotensive therapeutic effect of synthetic Ca2+channel antagonists given concommitantly with Mg2+ would be synergistic. A number of beneficial effects would derive from the combination of Mg2+ with synthetic Ca2+-channel blockers, including reduced therapeutic doses of Ca2+-channel antagonists, decreased side.-effects of the drug, smooth blood pressure control and improved prognosis in patients with hypertens,ion and ischaemic heart disease or arrhythmias. In order to test this hypothesis, a long-term, double blind placebo-controlled study is necessary. Such a study is currently being conducted.
141
References 1. Blackfan KD, Hamilton B. Uremia in acute glomerular nephritis. The cause and treatment in children. Boston Medical and Surgical Journal 193: 617-628, 1925. 2. Altura BM, Altura BT, Carella A. Magnesium deficiencyinduced spasms of umbilical vessels: relation to preeeclampsia, hypertension, growth retardation. Science 221: 376378. 1983. 3. Altura BM, Altura BT, Gebrewold A. Magnesium deficiency and hypertension: correlation between magnesium deficient diets and microcirculatory changes in situ. Science 223: 1315-1317, 1984. 4. Ishikawa T, Hidaka H. Molecular pharmacology of calcium, calmodulindependent myosin phosphorylation in vascular smooth muscle. American Journal of Hypertension 3: 2315-2345, 1990. 5. Eme P, Bolli P, Burgisser E. Buhler FR. Correlation of platelet calcium with blood pressure. Effect of antihypertensive tber;;;4,New England Journal of Medicine. 310: 1084-1088. 6. Rao RM, Young EW, McCarron DA. Disregulation of cell calcium and calcium-binding proteins in experimental hypertension. Advanced Experimenral Medical Biology 255: 505-514. 1989. I. Altura BNM, Altura BT. Magnesium-calcium interrelationships in vascular smooth muscle. Magnesium Bulleten 8: 338-350, 1986. 8. Aikawa JK. Biochemistry and physiology of Mg’+. World Review of Nutrition and Diet 28: 112. 1978. 9. Portelli C. The synergism and antagonism of cations. Physiologie 19: 229-234, 1982. 10. Stephenson EW, Podolsky RJ. Regulation by magnesium of intracellular calcium movement in skinned muscle fibers. Journal of General Physiology 69: 1-6, 1977. 11. Braunwald E. Mechanisms of action of calcium-channelblocking agents. New England Journal of Medicine 302: 1618-1629. 1982. 12. Godfraind T. Mechanisms of action of calcium entry blockers. Federation Proceedings 40: 2866-2871. 1981. 13. Bean BP. Classes of calcium channels in vertebrate cells. Annual Review of Physiology 51: 367-384, 1989.
