Cations and Hypertension: Sodium, Potassium, Calcium, and Magnesium

Essential Hypertension

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Cations and Hypertension: Sodium, Potassium, Calcium, and Magnesium Morton H. Maxwell, MD,* and Abraham U. Waks, MDt

THE ROLE OF SODIUM IN BLOOD-PRESSURE REGULATION EPIDEMIOLOGIC STUDIES

Un acculturated Societies Hypertension is virtually nonexistent in many unacculturated societies, and blood pressure does not increase with age. 47 Observations made in nonindustrialized societies of different ethnic and genetic backgrounds in various parts of the world concluded that lack of hypertension was not attributable to malnutrition, to thin body habitus, or to stress, but was best explained by extremely low salt intake.65, 113, 118 Yladdocks compared different populations in New Guinea and found that, while in the highland no hypertension was found and blood pressure did not increase with age, in coastal communities, in which people consumed salted canned foods, blood pressure increased with age and hypertension was present. 92 Similar studies in other primitive societies confirmed a relation between blood pressure and sodium intake. ,",108,113,118,131,135 Although subjects from primitive societies with low blood pressure have a very low sodium intake, they also ingest large quantities of potassium, and are smaller, leaner, and more active physically than their industrialized counterparts, Certain epidemiologic studies have been criticized because blood-pressure measurements were not standardized and sodium intake was estimated based on dietary recall or on spot urine collections without matching age, sex, and weight. 53, 116, 133 Therefore, extrapolation from these data to the role of sodium intake in the pathogenesis of hypertension in industrialized societies remains speculative. Industrialized Societies In contrast to cross-cultural studies, studies of the correlation between habitual sodium intake and blood pressure within industrialized populations have been almost uniformly negative, Dahl and Love conducted a correlation study based *Clinical Professor of Medicine. Director, Hypertension Services, Cedars-Sinai and UCLA Medical Centers, Los Angeles, California tAssistant Clinical Professor of Medicine, Cedars-Sinai and UCLA Medical Centers, Los Angeles, California

Medical Clinics of North America-Vo!. 71, No, 5, September 1987

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upon dietary questionnaires regarding habitual salt intake. 02 They reported similar mean blood pressure in three groups whose intake of salt was characterized as low, average, or high. However, hypertension was more common in those with high salt intake. This study was widely criticized for using dietary recall as an estimate of salt intake. For example, Miall in Scotland and data from the Framingham Study found no relationship between sodium intake as estimated by 24-hour urinary sodium excretion and dietary history reported by test subjects. 33, 103 Studies of sodium excretion generally failed to find significant differences between normo- and hypertensive populations. Miall and Oldham and colleagues found similar sodium excretion levels in persons with systolic pressures greater than 200 mm Hg and those with pressures less than 150 mm Hg. 103, 107 Bing and coworkers reported no difference in urinary sodium excretion between 36 patients with hypertension and matched normotensive controls. '4 Simpson's group in New Zealand were unable to demonstrate correlations of blood pressure with sodium excretion or urinary sodium-potassium or sodium-creatinine ratio,13. The reason why no relationship was found between sodium intake and hypertension in industrialized societies may be because of the relatively high range of habitual sodium intake in these populations (100-250 mEq per day), in contrast to unacculturated societies with sodium intake of less than 50 mEq per day. In the Akita Prefecture of northern Japan, where sodium intake is extremely high (500600 mEq per day), the prevalence of hypertension is 48 per cent, and stroke is the most prominent cause of death. 138 McCarron and colleagues plotted the results of studies in 30 populations. 98 Although at the extremes of sodium intake the mean arterial pressure generally was higher in societies with high dietary sodium, for societies with sodium intake between 125 and 300 mEq per day there was no relation between mean blood pressure and dietary sodium, It is commonly believed that sodium intake in industrialized societies is high enough to raise blood pressure only in genetically susceptible salt-sensitive individuals, who represent a minority of the general population. This is the reason why correlation between blood pressure and sodium intake in the entire population is not expected. Since habitual salt intake is culturally determined, it may be anticipated that within a given population salt intakes should be similar regardless of blood pressure, As concluded by Luft and Weinberger, "It is unlikely that a high sodium intake raises the blood pressure of most people,87 If that were to be the case, blood pressure of persons within a given population should be correlated with their sodium intake, and hypertensive subjects should eat and excrete more sodium than normal subjects, Neither appears to be the case. Alternatively, it is possible that only a susceptible minority within a population will experience an increased blood pressure when exposed to a high sodium intake, Thus, if the range of sodium intake within that population is relatively small, even though the sodium intake itself is large, no correlation between arterial pressure and sodium intake would be found," SODIUM LOADING AND SODIUM RESTRICTION IN HUMANS

Sodium Loading In normotensive volunteers there was no rise in mean blood pressure after increasing sodium daily intake from 10 to 410 mEq for 4 weeks,73 The effect of varied sodium intake from 10 to 1500 mEq per day in normotensive volunteers was studied by Luft. Blood pressure was not affected at sodium intakes of less than 800 mEq per day, and even at that level of consumption not all subjects had elevated blood pressures. The blood pressure rise could be avoided or attenuated when

CATlOlXS AND HYPERTENSION

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potassium balance was maintained."' Thcse results are in accordance with population studies describcd above, implying that the effect of dietary sodium on blood pressure levels can be demonstratcd only at extremes of intake. Hypertensive subjects demonstratc variable responses to sodium loading. There was a modest rise in subjects with borderline hypertension after increasing sodium intakc from 10 to 410 mEq per day.95 Another group of 19 hypertcnsive subjects demonstrated variable response when sodium intake was increased from 9 to 249 mEq per day. Nine subjects displayed significant increases of blood pressure (salt sensitive), while the othcr ten subjects showed negligible changes in pressure (saltinsensitive). 67 In a similar study by the same group on another 11 hypertensive subjects, the salt-scnsitive subjects gained more weight, retained more sodium, and had a greater increase in cardiac output than salt-insensitive subjects. 49 Salt-sensitive subjects had lower levels of renin and aldosterone than salt-resistant subjects only while on low sodium intake. Control plasma norepinephrine levels were similar in both groups, but higher in salt-sensitive subjects after salt loading. Others have also showed that salt-sensitive hypertensive subjects suppress their plasma norepinephrine levels less than normotensive subjects in response to sodium loads. 24. 86 A relatively higher activity of the adrenergic nervous system may contribute to the relative sodium retention and increased blood pressure with sodium loads. 51 More pertinent to the relationship of sodium to hypertcnsion may be the demonstration that the blood pressure of normotensive teenagers with one hypertensive parent rose in response to increased salt intake, whereas teenagers with normotensive parents did not have a rise in their blood pressure after increasing their sodium intake. 41 Sodium Restriction Studies on the effect of moderate sodium restriction in subjects with mild hypertension reported in the 1970s claimed that it produced as great a drop in blood pressure as that achieved by the use of diuretics. These studies were short term, had a small sample size, and had many confounding variables. More recent trials are summarized in Table 1. MacGregor, Watt, and their coworkers conducted similar double-blind cross-over studies comparing low and high sodium intake. 90, 147 In both trials there was heterogeneity of subject responses, so that blood pressure might increase, decrease, or stay the same. Richards' group and Longworth's found that reduction of sodium intake by about 50 per cent resulted in no change in mean blood pressure while individual response demonstrated wide variability. 82, 122 Parfrey and associates found a small but significant reduction of mean arterial pressure on a very low sodium intake. 114 The heterogeneity in response to salt restriction may be mirrored by the blood pressure response to salt loading, in which some subjects are salt-sensitive and some are salt-resistant. It has been proposed that salt-sensitive hypertensive subjects represent a subset of subjects with essential hypertension. 67 The hypotensive response to sodium restriction is usually but not always greater in those with low plasma renin levels. Experimental Hypertension Certain forms of experimental hypertension may be induced in animals by increasing salt intake,28, 74. 78, !o2, 126 with or without the administration of mineralocorticoids or reduction of renal mass. 26 . 75 It is much easier to produce salt-induced hypertension in young rats than in adult rats. Dahl demonstrated variability in the response to salt loading in normal rats and was able to distinguish an apparent genetic basis for sodium-dependent hypertension in this species. 28, 29 Through selective breeding he developed two

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16.5/98 160/98

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Table 1. Effects of Dietary Sodium Modification in Essential Hypertension

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strains, one salt-sensitive, the other salt-resistant. Resistant strains were also resistant to all other forms of experimental hypertension except for experimental renovascular hypertension. Transplant experiments have shown the importance of the kidney in this form of experimental hypertension. 30 When a kidney from a normotensive donor (saltresistant) was transplanted to a hypertensive (salt-sensitive) host, the blood pressure in the recipient fell to normal. Conversely, the blood pressure increased when a hypertensive kidney was transplanted into a normotensive host. In other words, the blood pressure followed the kidney. Bianchi and associates had similar results in the :\1ilan salt-sensitive strain of rats. 13 Tobian and colleagues showed that the involved kidneys of young, still normotensive, Dahl salt-sensitive rats excreted only half as much sodium as kidneys from resistant rats at equal levels of inflow pressure. '39 Sensitive Dahl rats also fail to develop hypertension on an 8 per cent salt diet if sodium retention is prevented by the administration of a thiazide diuretic. 139 The implications of these animal studies for human hypertension are uncertain. The relative amounts of salt required to induce hypertension in animals is far in excess of the usual salt content of human diets. For example, the 8-per-cent NaCI fed to salt-sensitive Dahl rats is equivalent to human consumption of 40 g of sodium daily. Even very high salt intakes do not consistently result in hypertension in all or even in most animals, implying heterogeneity of response. In the Kyoto spontaneously hypertensive rat (SHR), which is considered to be the closest counterpart to human hypertension, similar clear-cut salt sensitivity has not been demonstrated. Although experimental salt-induced hypertension does not necessarily support a primary role for sodium in the pathogenesis of human essential hypertension, the model may be applicable for a subset of genetically susceptible individuals. A genetic defect in renal sodium excretion is postulated to be present in salt-sensitive people who develop hypertension. The Pathogenic Role of Sodium in Essential Hypertension The Guy ton hypothesis is based largely on experimental studies in partially nephrectomized animals. 57 According to this theory, in early hypertension cardiac output increases in response to renal sodium retention. Then, due to general body autoregulation the peripheral resistance increases, blood pressure increases further, a diuresis ensues, and cardiac output decreases to normal-the hemodynamic change found in established hypertension. Neither the partially nephrectomized animal model, however, nor such salt-dependent forms of hypervolemic human hypertension as primary aldosteronism or chronic renal failure can be extrapolated to essential hypertension. Concordant with the autoregulation hypothesis are studies in patients with early hypertension in which a variable proportion of subjects had elevated cardiac outputs;48, 63, 125. 149 long-term follow-up studies show that as hypertension becomes established, cardiac output tends to decrease and peripheral resistance to increase,15. 38,64,88, 148 However, it must be noted that most adolescent and young subjects with hypertension do not demonstrate elevated cardiac outputs or expanded body fluid volumes. 88 The sequence of hemodynamic pattern from high cardiac output to high peripheral resistance can be explained alternatively by the development of structural changes (rrledial hypertrophy) in the peripheral vessels in response to hypertension!4 The Role of Sodium in Hypertension From the evidence, sodium retention cannot be adduced as a unifying hypothesis in the pathogenesis or perpetuation of essential hypertension. There is probably a subset of salt-sensitive individuals, however, in whom sodium intake is an

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important determinant. After the onset of established hypertension, it is likely that secondary renal abnormalities develop, increasing the proportion of salt-sensitive subjects. POTASSIUM EPIDEMIOLOGIC STUDIES

It is virtually impossible to devise a very-Iow-sodium diet that is not also very high in potassium. A plausible alternative explanation, therefore, for the low blood pressure found in some unaceulturated societies is the contribution of large amounts of potassium rather than small amounts of sodium. Blood pressure was inversely correlated with urinary potassium excretion and urinary K+/Na+ ratio in epidemiologic studies in Japan, where high-sodium diet and hypertension are widespread. 153 Another Japanese study demonstrated a decreased incidence of hypertension in a population subgroup that consumed large amounts of apples when compared to a neigh boring community with similar sodium intakes but with low potassium intakes. '27 Similar results were obtained in epidemiologic studies from the United States and Sweden, although blood pressure was correlated with urinary potassium or K+/Na+ ratio only in the normotensive subset in the Swedish study. 81, 144 146 A negative correlation between serum potassium and blood pressure was demonstrated in Japan, and a negative correlation between blood pressure and exchangeable and total body potassium in young hypertensive individuals was reported in Scotland. ;;1, 140 Other studies, however, failed to demonstrate any relationship between potassium intake and blood pressure. 9 , ,13

Clinical Studies In earlier studies, Luft and associates were able to attenuate the hypertensive effect of massive sodium loading by potassium supplementation. 8 ' Khaw and Thom reported a small but significant decrease in blood pressure in 20 young, healthy males during potassium supplementation of 64 mmol per day and unrestricted sodium intake. 72 McQuarrie and colleagues found that 200 mmol per day of KCl attenuated the hypertensive response caused by high sodium load in type I diabetics.101 Other investigators have failed to document an antihypertensive effect of a high-potassium diet in normotensive subjects or in subjects with mild hypertension. 23 , 55, 104 In these studies, the increased dietary potassium supplement was relatively small. All of the more recent controlled trials in hypertensive populations shown in Table 2 involved small numbers of subjects and were of short duration. A doubleblind, randomized, cross-over trial by MacGregor's group showed that the addition of 60 mEq per day of potassium caused a small but significant decrease in mean blood pressure in subjects with mild to moderate essential hypertension. 91 However, there was heterogeneity of response; some subjects did not respond at all. limura and coworkers, in a randomized cross-over study in which potassium intake was increased from 75 to 175 mEq per day, also showed a small but significant decrease in mean arterial pressure. 61 ,\1organ, in an open trial of only eight subjects with mild hypertension previously shown to be sensitive to sodium intake, also found a small but significant decrease in blood pressure when potassium intake was increased by 70 mEq per day.105 In this study as in the others, however, the elevated blood pressure was not reduced to normotensive range. In a randomized cross-over study by Richards and associates in which potassium intake was increased from 60 to 200 mEq for 4 to 6 weeks, there were variable responses in blood pressure, with no significant overall change. 122

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URINARY ELECTROLYTES

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In two other short-term trials no data on individual subjects were presented. Ill. l36 In both studies, increased potassium intake was associated with natriuresis. In one trial diastolic pressure was unchanged and in the other blood pressure was decreased at week 8 but not at week 4. llI. 136 In summary, the trials of dietary potassium supplementation as therapy for mild essential hypertension arc unconvincing. There are no data on compliance, risks, or side effects of potassium supplementation. The long-term results of potassium therapy are also unknown. There may be a subgroup of essential hypertensive subjects who are "potassium responders" but their clinical or biochemical characteristics have not yet been defined, although low-renin hypertensive subjects have had greater response. 61 Animal Studies A protective effect of increased potassium intake has been shown in some models of experimental hypertension, particularly in Dahl salt-sensitive rats. 4 3I.94 The Wistar-Kyoto strain of spontaneously hypertensive rats has been reported to be protected from the pressor effect of high dietary sodium by the concurrent administration of potassium. 83 In the rat model studies, the potassium loads were very large and the blood pressure responses, small and variable. Furthermore, saltsensitive forms of experimental hypertension have a limited applicability to human hypertension. MECHANISM OF ANTIHYPERTENSIVE EFFECTS OF POTASSIUM

Direct Vasodilatation Intra-arterial infusion of KCI into limbs of normotensive and hypertensive animals causes arteriolar vasodilatation ..'4. 39. 66. 76. lO9. llO This effect is antagonized by ouabain, so that the increased potassium may affect the Na+-K+ pump?7 The direct vasodilating effect of potassium can be achieved only if serum potassium is markedly elevated and, therefore, cannot explain any relationship between oral potassium loads and blood pressure in humans. Increased Sodium Excretion Potassium loading has been shown to increase water and sodium excretion in animals and in normo- and hypertensive humans. 3 • lOo 11.20.21.46. 6R. 14I. 150. 151 It is possible that the antihypertensive effect of increased potassium intake can be explained by its diuretic action. Suppression of Renin Secretion Intrarenal infusion of KCl suppresses renin secretion in the perfused kidney but not in the nonfiltering model or in the contralateral kidney. 36. 130. 141 Renin suppression has also been demonstrated in short and prolonged potassium-loading experiments in rats,43. 77. 128. 130. 141 but not in the dog unless steroid levels were kept constant by adrenalectomy and administration of fixed doses of mineraloeortieoids. Human studies have produced conflicting data. Dluhy's group and Sealey's were able to suppress renin by potassium loading only in sodium-depleted subjeets. 35 . 128 Brunner and associates achieved renin suppression unrelated to sodium balance or aldosterone secretion in 18 of 28 normo- or hypertensive subjeets. 21 Other investigators, however, have demonstrated increased rather than decreased renin secretion in response to potassium load. 5 The conflicting data regarding renin suppression as an antihypertensive mechanism of potassium loading can be elucidated as follows:

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C"TIOI\S AND HYPERTENSIO'J

1. Renin suppression requires potassium loading in amounts sufficient to significantly increase serum-potassium concentration, which is not the case when oral potassium is used. 2. A potassium load produces diuresis which may indirectly stimulate renin secretion.

Other antihypertensive mechanisms of increased potassium may be attributed to its effect on the central or peripheral nervous system or to increased urinary kallikrein. 18. 19. 52. 58. 9:) Potassium loading has been shown to be antihypertensive, but clinical results are not convincing and suggest little or no role for potassium in .the pathogencsis or treatment of human hypertension. CALCIUM Contraction of smooth muscle and, therefore, peripheral vascular resistance depends on and is initiated by an increase in intracellular cytosolic calcium concentration. It is not surprising, therefore, that there is interest in the role of calcium in the etiology, pathophysiology, and treatment of hypertension. Calcium Intake and Hypertension Epidemiologic studies examining the relation between intake of calcium-rich dairy products and blood pressure in various populations are controversial. Analysis of the data from 1971-1974 National Health and Nutrition Examination Survey (NHANES I) by McCarron and associates revealed an inverse relation between dietary intake of calcium and blood pressure. 100 Harlan and coworkers, however, interpreted these same data as showing a much more tenuous relation that did not hold for all subgroups of the population. 59 A third analysis by Gruchow and colleagues detected such a relation in black populations only.56 Additional support for an inverse relation between dietary calcium intake and blood pressure has been provided by several other population studies. 1. 50. 60. 119 All of these studies are open to certain criticisms. The methods of dietary recall vary in accuracy and reliability. Differences in other nutrients and ions that could affect blood pressure independently of calcium, such as potassium, could not be eliminated in these population studies. Feinstein showed that the correlations between calcium intake and blood pressure are weak and reach statistical significance in several of these studies only because the population sample sizes were so large. 42 A recent analysis was conducted by the NHANES official investigators. 129 Contrary to McCarron's conclusions, their analysis based on the same data combined with the more recent NHANES II (approximately 40,000 subjects), concluded that there was no association between calcium intake and blood pressure. 100 It is interesting to note that Finland, which has one of the highest prevalences of hypertension in the world, has one of the highest calcium consumptions as well. 117 Serum Calcium Several studies analyzing serum calcium levels in normotensive and hypertensive populations and individuals give conflicting results. Several large studies including more than 10,000 participants have demonstrated a significant increase in systolic and diastolic blood pressure with rising levels of total serum calcium. 22. 71. 123 Strazzulo and coworkcrs, however, found no difference in total or ionized calcium concentrations between 55 patients with hypertension and a matched normotensive group.137 McCarron, on the other hand, has reported that hypertensive subjects had lower mean serum ionized calcium levels than did control subjects. 97 Resnick and associates found low ionized calcium only in low-renin hypertensive patients. 121 Folsom and associates reported a small, insignificant decrease in ionized calcium in hypertensive men but not in hypertensive women. 45 To conclude, most of the data based on large population studies supports a

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positive association between serum calcium and blood pressure. Because there is a correlation between total and ionized calcium in persons with normal serum albumin, a negative correlation between ionized calcium and hypertension seems unlikely and has yet to be confirmed in further studies. Calcium Loading and Blood Pressure Intravenous calcium administration results in increased blood pressure and systemic vascular resistance in normotensive subjects and in patients with hypertension. 12,96,

112, 142, 152

Oral calcium loading in normotensive and hypertensive subjects, however, has been reported to cause either a minor decrease or no change in blood pressure. Belizan and associates studied 30 young normotensive subjects who supplemented their diet with 25 mmol of calcium per day for 22 weeks, and reported a 5 per cent to 9 per cent decrease in supine diastolic pressure. 7 The same group also reported a small blood pressure decrease in 36 pregnant women who were taking a supplement of 2 g of calcium per day.8 Johnson and coworkers 62 conducted a 4-year study in 81 normotensive and 34 hypertensive subjects, some of whom were taking a daily supplement of l.5 g of calcium, and found no significant differences in blood pressure between the supplemented and the unsupplemented normotensive women; in contrast, the calcium-supplemented hypertensive women showed a 13 mm Hg decrease in systolic pressure compared with the 7 mm Hg decrease in the control hypertensive group. Lyle's group reported small (2-3 mm Hg) but consistent reduction of mean arterial pressure in a group of 75 normotensive men, supplemented by 1500 mg per day of calcium, compared with a control group.89 Grobee and Hofman reported that mild hypertensives given 1 g per day of calcium experienced a decrease in diastolic blood pressure at 6 and 12 weeks of 3.1 and 2.4 mm Hg, respectively, compared with a group taking placebo. 54 McCarron's group, in a double-blind study, reported no change in blood pressure of 32 normotensive subjects after 8 weeks of calcium supplementation, but in 48 hypertensive subjects mean supine blood pressure decreased by 3.8/2.3 mm Hg.99 Analysis of individual responses showed that about 50 per cent of the hypertensives and 17 per cent of the normotensive group demonstrated a hypotensive response to calcium supplementation. Therefore, calcium supplementation may affect only a subgroup of the hypertensive population. Resnick and Laragh found that responders are those with low ionized calcium. 120 To conclude, it is possible that calcium supplementation may be a weak antihypertensive agent for a subgroup of the hypertensive population. The possible benefit of its use must be weighed against the risk of a higher incidence of kidney stones. MAGNESIUM

Magnesium is the second most prevalent intracellular cation. It may play a . role in the control (and possibly in the pathogenesis) of hypertension. EPIDEMIOLOGIC STUDIES

There are no direct data on the relation between magnesium intake and the prevalence of hypertension in humans. Sangal and Beevers found an inverse relation between serum magnesium and blood pressure in 73 Danish men and women aged 60. 124 Similar relations were reported by others.2, 115 An inverse relation between urinary magnesium and diastolic blood pressure was seen in a subsample of the

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Belgian population. 70 These data contradicted earlier reports that hypertension, in the absence of overt renal disease, was associated with increases in serum magnesium levels. 14:l ]\io relation between magnesium excretion and blood pressure was seen in a Korean population or in the NHANES I data. 59. rm Studies by Resnick and colleagues revealed a negative correlation between plasma renin activity and serum magnesium levels in patients with essential hypertension (i. e., low-renin essential hypertensive subjects had higher scrum magnesium levels). 121 Because renal tubular reabsorption of magnesium is almost complete during low magnesium intake, it is difficult to imagine that decreased magnesium intake will lead to magnesium deficiency severe enough to be reflected by hypomagnesemia and hypertension in a significant proportion of a population. Magnesium Loading Magnesium has long been known to have a blood pressure-lowering effect, especially in the treatment of eclampsia and pre-eclampsia. There are almost no data on the hypotensive effect of increased dietary magnesium in essential hypertension. Dyckner and Wester conducted a study on 20 patients with hypertension or congestive heart failure who had long-term treatment with diuretics. 37 Magnesium supplementation resulted in a significant (2118 mm Hg) decrease in blood pressure. Cappuccio and coworkers, however, found no change in blood pressure in a randomized, cross-over study in 17 hypertensive subjects treated with 15 mmol per day of magnesium aspartate hydrochloride. 25 To conclude, there are no data to define the etiologic role of magnesium deficiency in human hypertension or to support the use of magnesium supplementation as antihypertensive therapy in essential hypertension. CONCLUSIONS In summary, there is no compelling evidence that too little or too much dietary sodium, potassium, calcium, or magnesium is responsible for the genesis of essential hypertension, or that changes in the intake of any of these cations will consistently lower elevated blood pressure to normal levels. This is not to suggest that alterations in cation metabolism or intake may not be important in certain hypertensive subpopulations. Even though the mean blood pressure change after a change in dietary cation intake in a study group may be minimal, changes in individual patients are often substantial, demonstrating the heterogeneity of essential hypertension.67,

90, 91, 99, 120

Because of the long-standing belief in a putative role for high salt intake in hypertension, the experimental, clinical, and epidemiologic studies on sodium and blood pressure number in the thousands. Yet, only two firm conclusions emerge. The first is that intracellular sodium concentration in white and red blood cells (and presumably vascular smooth muscle cells) is significantly higher in hypertensive animals and humans than in normotensive controls. 16 The second is that there is a sizable subgroup of patients with essential hypertension whose blood pressure is salt sensitive. 67 The mechanisms are speculative. Despite a plethora of reports on cellular sodium-potassium exchange, no consistent abnormality has been described. 16 There is even less agreement on perturbations of or effects of changing the other cations, potassium, calcium, and magnesium. Interpretation of data in this area is complicated by lags in methodology (e.g., measuring cytosolic calcium concentration) leading to gaps in information, and the known interrelations between these cations. For example, sodium and calcium compete for reabsorption in the proximal tubule, so that increasing the filtered load of either causes increased excretion of the other. 145 One might speculate, therefore, that increased calcium

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intake may lower blood pressure by causing a subtle diuresis of sodium. Potassium loading may also result in sodium diuresis. '54 Dietary sources of calcium and magnesium are also rich in potassium. 40 The increased intracellular sodium concentration in hypertension may be a factor in trapping free calcium within the cell, which then increases vascular tone. '7 Magnesium has been referred to as the mimic! antagonist of calcium. 80 The interactions between these two divalent cations are extremely complicated and imperfectly understood. Essential hypertension is a multifactorial disorder that will undoubtedly continue to elude simplistic or unitary theories of etiology and treatment. After reviewing the evidence for nonpharmacologic approaches to the control of high blood pressure, including changes in diertary cation intake, a recent National Institutes of Health consensus committee could only recommend weight control, alcohol restriction, and sodium restriction as adjuncts to therapy with antihypertensive drugs. 106 The data on potassium, calcium, and magnesium were deemed to be insufficient for any current recommendations. With this we agree.

REFERENCES 1. Ackley S, Barrett-Connor E, Suarez L: Dairy products, calcium, and blood pressure. Am J Clin Nutr 38:457, 1983 2. Albert DG, Morita Y, lseri LT: Serum magnesium and plasma sodium levels in essential vascular hypertension. Circulation 17:761, 1958 3. Bassett SH, Elden CA, McCaa WS: The mineral exchange of man. n. J Nutr 5:1, 1932 4. Battarbee HD, Funch DP, Dailey JW: The effect of dietary sodium and potassium upon blood pressure and catecholamine excretion in the rat. Proc Soc Exp BioI Med 161:32, 1979 5. Bauer JH, Gaunter W: Effect of potassium chloride on plasma renin activity and plasma aldosterone during sodium restriction in normal man. Kidney lnt 15:286, 1979 6. Beard TC, Cooke HM, Gray WR, et al: Randomized controlled trial of a no-addedsodium diet for mild hypertension. Lancet 2:455, 1982 7. Belizan JM, Villar J, Pineda 0, et al: Reduction of blood pressure with calcium supplementation in young adults. JAMA 249:1161, 1983 8. Belizan JM, Villar J, Salazar A, et al: Preliminary evidence of the effect of calcium supplementation on blood pressure in normal pregnant women. Am J Obstet Gynecol 146:175, 1983 9. Berenson GS, Voors AW, Dalferes ER, et al: Creatinine clearance, electrolytes, and plasma renin activity related to the blood pressure of white and black children-The Bogalusa Heart Study. J Lab Clin Med 93:535, 1979 10. Berliner RW: Ion exchange mechanisms in the nephron. Circulation 21:892, 1960 11. Berliner RW, Kennedy TJ, Hilton JG: Renal mechanisms for excretion of potassium. Am J Physiol 162:348, 1950 12. Bianchetti MG, Beretta-Piccoli C, Weidman P, et al: Calcium and blood pressure regulation in normal and hypertensive subjects. Hypertension 5:57, 1983 13. Bianchi G, Baer PG, Fox U, et al: Changes in renin, water balance, and sodium balance during development of high blood pressure in genetically hypertensive rats. Circ Res _ 36-37(Suppl 1): 153, 1975 14. Bing RF, Thurston H, Swales JD: Salt intake and diuretic treatment of hypertension. Lancet 2:121, 1979 15. Birkenhager WH, Schalekamp MADH, Kraus KH, et al: Consecutive hemodynamic pattern in essential hypertension. Lancet 1:560, 1972 16. Blaustein MP: Sodium transport and hypertension. Where are we going? Hypertension 6:445, 1984 17. Blaustein MP, Hamlyn JM: Sodium transport inhibition, cell calcium, and hypertension. The natriuretic hormone/N a + -Ca2+ exchange/hypertension hypothesis. Am J Med 77:4A:45, 1984 18. Bogdanski DF, Blaszkowski TP, Tissary AH: Mechanisms of biogenic amine transport

CATIONS AND HYPERTENSION

19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48.

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