When first reviewed editorially over a. The Role of Dietary Calcium in Hypertension. A Hierarchal Overview. Lawrence M.

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1 AJH 1999;12: REVIEW The Role of Dietary Calcium in Hypertension A Hierarchal Overview Lawrence M. Resnick The role of calcium in clinical hypertension can be best understood by a hierarchal model in which the blood pressure effects of a dietary signal depend on alterations of hormonal systems specific for that signal. These alterations mediate both the cellular recognition of these signals as well as the resultant clinical responses to them. In the case of both dietary calcium and dietary salt, these systems appear to include calcium regulating hormones having direct, calcium-dependent vasoactive properties, and which are linked to the activity of the renin-angiotensin system. Altered salt and calcium intake exert reciprocal linked effects on these hormone systems and on blood pressure. These reflect altered cellular calcium uptake from the extracellular space, saltinduced calcium hormones stimulating and calciuminduced suppression of these hormones inhibiting extracellular calcium uptake. Among normotensive individuals, this is associated with a reciprocal calcium-dependent suppression or stimulation of renin secretion, respectively, resulting in an offsetting decreased or increased angiotensin IImediated release of calcium into the cytoplasm from intracellular stores. Hence, no significant change in cytosolic free calcium or, consequently, in blood pressure usually results from increasing or decreasing dietary salt or calcium intake. However, whether due to genetic or other environmental factors as yet undefined, the metabolic set point of plasma renin activity in some subjects is already suppressed, or, alternatively, is unresponsive to the above hormonally mediated dietary mineral variations. Under these circumstances, increases in dietary salt will cause cytosolic free calcium and thus blood pressure to rise, whereas increased dietary calcium in these very same salt-sensitive subjects will offset the effect of salt, and lower pressure in these individuals. This analysis suggests that although increasing oral calcium intake to achieve at least current nutritional standards is entirely appropriate, uniform recommendations for all hypertensives to further increase or decrease dietary calcium or salt may be inappropriate and will obscure those for whom these maneuvers are particularly relevant. Am J Hypertens 1999;12: American Journal of Hypertension, Ltd. KEY WORDS: Calcium regulating hormones, salt, dietary calcium, cytosolic free calcium. When first reviewed editorially over a decade ago, few clinical studies had yet suggested the relevance of calcium metabolism to primary, essential hypertension in humans, and fewer than 3 to 5 clinical reports had investigated the clinical utility of calcium supplementation as a nonpharmacologic means of lowering blood pressure. 1 By contrast, at least four recently published reviews have again focused attention on the relation of calcium metabolism to blood Received November 11, Accepted November 30, From the Division of Endocrinology/Hypertension, Wayne State University Medical Center, Detroit, Michigan. Address correspondence and reprint requests to Lawrence M. Resnick, MD, Division of Endocrinology/Hypertension, Wayne State University Medical Center, 4201 St. Antoine, UHC 4H, Detroit, MI by the American Journal of Hypertension, Ltd /99/$20.00 Published by Elsevier Science, Inc. PII S (98)

2 100 RESNICK AJH JANUARY 1999 VOL. 12, NO. 1, PART 1 pressure by performing metaanalyses of over 50 published trials of oral calcium supplementation in more than 5000 subjects with hypertension, suggesting little effect or at most a small potential therapeutic role for calcium in at least some forms of hypertensive disease. 2 5 However, because the application of epidemiologic analyses in a uniform manner to a phenomenon such as hypertension that is inherently nonuniform necessarily results in a distorted, incomplete description of that phenomenon, the larger question, what is the clinical relevance of calcium to hypertension? remains poorly understood. Historically, although much of what is now thought about the relation of calcium metabolism to blood pressure (BP) is derived from these recent epidemiologic and clinical studies, it is useful nonetheless to trace the early development of these ideas. Sidney Ringer at the University of London was the first to have observed that calcium was required for cardiac muscle contraction. 6 This physiologic observation, now over a century old, was progressively, albeit intermittently, developed until the present, where calcium is now understood as a necessary component of a final common pathway in cellular physiology mediating stimulus-contraction coupling in contractile tissues, 7 stimulus-secretion coupling in hormonal and other secretory tissues, 8 and more generally cellular responsiveness in all tissues to a broad range of physiological stimuli that in the aggregate contribute to blood pressure homeostasis. 9 Similarly, the work of MacKenzie Walser at Johns Hopkins first linked another component of blood pressure regulation, renal sodium handling, to calcium homeostasis. This physiologic relation, described decades ago, 10 led to the observations by McCarron et al 11 and Strazzullo et al 12 of potentiated renal calcium excretion relative to sodium excretion in human hypertension. To what extent this represents a primary renal calcium leak, 11 or a pressure calciuresis, secondary to and merely one renal manifestation of the underlying cellular ionic mechanism of hypertension itself, 12,13 remains unresolved. Although the above advances served to link calcium metabolism to the function of specific organ systems involved in the generation and regulation of blood pressure, it was the practicing Toronto physician W.L.T. Addison, who first definitively linked calcium directly to clinical hypertension. He reported over 70 years ago that oral calcium supplementation could lower blood pressure in hypertensive individuals 15,16 (Figure 1). These results were largely ignored for more than 50 years until similar results were reported in rats by Ayachi, 17 in normotensive humans by Belizan et al, 18 and in human hypertensives by Resnick et al 19,20 and McCarron and Morris. 21 However, the observations of an increased incidence of hypertension among FIGURE 1. Original 1924 description of the antihypertensive effect of oral calcium supplementation by the Canadian physician W.L.T. Addison. T treatment with calcium, S treatment with calcium stopped. Blood pressure values are on the y-axis. 15 subjects with the hypercalcemia of primary hyperparathyroidism, 22 and of hypotension associated with hypocalcemia 23 led some to conclude oppositely, that calcium might promote rather than ameliorate hypertension. This controversy has unfortunately not been resolved by the emergence of powerful epidemiologic techniques that have been applied to the analysis of the role of calcium in blood pressure regulation and hypertension (see below). However, the majority of epidemiologic studies performed investigating the relation of blood pressure to dietary calcium intake have agreed with the first such studies by McCarron and colleagues, 24,25 in which lower calcium intakes were associated with higher blood pressures. A HIERARCHAL ANALYSIS OF CALCIUM IN HYPERTENSION To gain perspective on the various approaches that have been taken, and the various levels at which observations have been made, it may be useful to consider more broadly their interrelation as depicted in Figures 2 and 3. In this hierarchal scheme, a central role is assigned to steady-state cell activity in mediating the influences of environmental stimuli on tissue and organ function, and ultimately in altering the clinical state of the organism as a whole. What distinguishes one individual from another the origin of the clinical heterogeneity of responses to, for example, the increased intake of dietary salt, calcium, or other mineral elements, or to sugar, carbohydrate, or fat, etc is derived from the metabolic set point of those hormone systems normally serving to regulate the

3 AJH JANUARY 1999 VOL. 12, NO. 1, PART 1 CALCIUM IN CLINICAL HYPERTENSION 101 FIGURE 2. Central role of steady-state cell activity as both the focus of environmental mineral and nutrient effects, mediated by their respective hormonal systems and as the determinant of altered tissue function and the resultant clinical state of the organism. Reproduced with permission from Resnick: Ionic disturbances of calcium and magnesium metabolism in essential hypertension, in Laragh et al: Hypertension: Pathophysiology, Diagnosis, and Management, 2nd ed. Raven Press, New York, 1995, pp disposition of those environmentally provided mineral or nutritional elements within the various intracellular compartments. Hence, the importance of systems such as the renin-angiotensin-aldosterone system, which presides over sodium and potassium homeostasis; of calcium regulating hormones, such as parathyroid hormone (PTH), vitamin D metabolites (and the newly described parathyroid hypertensive factor, PHF), which preside over calcium homeostasis; of insulin and lipoprotein species, which preside over carbohydrate and fat metabolism; and of growth hormone, cortisol, and catecholamines, which mediate responses to environmental stress, etc (Figure 2). What is interesting in this scheme is that calcium is involved in each of the above levels: environmentallyepidemiologically, as dietary calcium intake; physiologically, by stimulating or suppressing the activities of various hormonal and neurotransmitter species; and intracellularly, as free calcium in the cytoplasm and stored in various organelles, by altering cellular responsiveness to various stimuli. As a result of the above, calcium participates in a final common pathway determining metabolic, cardiovascular, neural, renal, and thrombotic activity, and as such contributes to the clinical onset of diseases such as hypertension, left ventricular hypertrophy (LVH), accelerated atherosclerosis, insulin resistance and hyperinsulinemia, the insulin resistant, type II form of diabetes mellitus, as well as the aging process itself (Figure 3). Altogether, a hypothesis has recently been put forward in which alterations of steady-state cell ion activity in all tissues, consisting at least in part of excess cytosolic free calcium and a reciprocal suppression of intracellular free magnesium, represent the common underlying basis linking the above clinical disease states, thereby explaining the origin of the syndrome complex currently termed Syndrome X. 14,26 This ionic hypothesis of cardiovascular and metabolic disease also serves to unify other current theories of hypertension, because other individual organ or tissuebased hypotheses invoking, eg, insulin resistance, central nervous dysfunction, or any of a variety of circulating putative pressor factors, merely represent tissue-specific manifestations of, and each predictable from, the more general defect in steady-state cell ion activity. HOW DOES THIS HIERARCHAL SCHEME PROVIDE US WITH A MORE INTEGRATED VIEW OF CALCIUM IN HYPERTENSION? Environmental-Epidemiologic Level Epidemiologically, a consistent inverse relationship has been observed between dietary calcium intake and blood pressure, whether the latter is expressed as absolute levels of pressure or categorically as the prevalence of hypertension. The calcium deficiency hypothesis of gestational hypertension was first proposed by Belizan et al to explain the surprisingly low incidence of preeclampsia and other pregnancy-specific forms of hypertensive disease in poor countries with a high dietary calcium intake, compared to the uniformly high incidence of gestational hypertension in equally poor countries with little access to calcium in the diet. 27 For the US population as a whole, the relation

4 102 RESNICK AJH JANUARY 1999 VOL. 12, NO. 1, PART 1 FIGURE 3. The ionic hypothesis of cardiovascular and metabolic disease, in which the multiple clinical components (bottom) of what has been termed Syndrome X, or generalized cardiovascular and metabolic disease (GCMD), each represent different clinical manifestations of altered cellular ion homeostasis (top), shared in common by all cells, but expressed differently in different tissues (middle). Reproduced with permission from Resnick: Ionic basis of hypertension, insulin resistance, vascular disease, and related disorders: mechanism of syndrome X. Am J Hypertens 1993;6:123S 134S. 14 of calcium to blood pressure was first systematically studied by McCarron and colleagues, who analyzed both local population data and the National Health and Nutrition Examination Survey (NHANES) data, observing an inverse linkage of calcium intake and hypertension to be a general phenomenon. 24,25 Although some controversy still exists, these initial observations have been confirmed by the vast majority of other epidemiologic studies performed over the past decade, and, together with early animal studies, has led to the promotion of dietary calcium deficiency as at least one potential cause of hypertension Although intriguing, and understandable in the light of subsequent physiologic and biochemical data (see below), a role for dietary calcium deficiency in clinical hypertension was not initially accepted as a viable hypothesis for a number of reasons. First, this approach seemed to detract from the enormous research and public attention given to other mineral ions, such as sodium. This monoionic approach whether emphasizing sodium, 31 calcium, 32 potassium, 33 or magnesium, 34 etc, seems to have been somewhat resolved at the epidemiologic level by further analysis of the interaction between these ionic species. Thus, a study of subjects in Montréal 35 demonstrated that dietary salt intake was indeed positively related to blood pressure the higher the salt intake, the greater the pressure but only when dietary calcium levels were clearly below minimum standards. Individuals ingesting more calcium exhibited no apparent effect of salt on blood pressure; indeed, the lowest pressures were observed among subjects having the highest combined salt and calcium intakes 35 Thus, salt might be important, but in the setting of a concomitant calcium deficit. A second reason for the initial reticence in accepting a role for dietary calcium in hypertension concerned other epidemiology-based measurements of calcium that suggested different and often opposite conclusions ie, that hypertension was a state of calcium excess rather than of calcium deficiency. Thus, blood pressure in broad-based population studies is directly related to circulating blood calcium levels. 36 Although increased urinary loss 12 may in fact compound and aggravate a dietary calcium deficiency, one cannot account for increased calcium excretion or higher blood calcium levels on the basis of deficient calcium intake. More reasonably, higher urinary calcium excretion is an expected consequence of higher circulating calcium levels, neither being consistent with decreased dietary calcium intake. Furthermore, the direct pressor action of infused calcium, 37 the hypo-

5 AJH JANUARY 1999 VOL. 12, NO. 1, PART 1 CALCIUM IN CLINICAL HYPERTENSION 103 tension consequent to hypocalcemia, 23 and the increased prevalence of hypertension among subjects with primary hyperparathyroidism, 22 all seemed to indicate a role for increased, even excess calcium, more than for a calcium deficiency, in the pathogenesis of hypertension. The above calcium paradox, in which epidemiologically-based studies seemed to provide information in support of the apparently opposite propositions, that hypertension is a state of calcium deficiency or calcium excess (ie, being inversely associated with dietary calcium intake, but directly associated with calcium content in various body compartments), highlights the limitations inherent in the epidemiologic approach adopted by most investigators. Especially for hypertension, which is well known to be clinically heterogeneous, it is unreasonable to expect unambiguous answers from studies in which all subjects are homogeneously defined on the basis of blood pressure levels or demographic variables alone. Resolution of this apparent paradox awaited further epidemiologic, clinical, and basic studies taking into consideration the underlying physiology of calcium metabolism and blood pressure homeostasis. Thus, in epidemiologic studies where blood pressure did not seem to be strongly related to dietary calcium intake itself, pressure was directly related to circulating levels of calcium-regulating hormones, such as PTH 38 or 1,25 dihydroxyvitamin D, 39 expected physiologic consequences of altered calcium intake. Similarly, when the linkage between circulating ionized calcium levels and the activity of the renin-angiotensin system had been established 40 (see below), epidemiologic reinvestigation of the relation between blood pressure and blood ionized calcium demonstrated a direct relation between calcium and blood pressure in high renin subjects, but an opposite, inverse relation in subjects with low renin values. 41 These examples highlight the critical importance of individually variable physiologic-hormonal factors, rather than just average, static environmental influences, in defining the contribution of calcium to hypertension. Physiologic-Hormonal Level If the above epidemiologic data are correctly interpreted as supporting a role for a dietary calcium deficiency in hypertension, then one must ask, Is there any physiologic evidence that hypertensive subjects are indeed calcium deficient? This question cannot be answered solely on the basis of measured levels of calcium in body fluids. It is fundamental that before environmental signals, such as diet, can influence the clinical state of the system, they must be interpreted in the language understood by the various tissues capable of responding to these signals. For dietary minerals, such as calcium, this translating or transducing function is mediated by calcium-regulating hormones, such as PTH, calcitonin, vitamin D hormones, and newly described factors, such as parathyroid hypertensive factor (PHF), which increase or decrease tissue/cellular access to circulating calcium, thereby regulating extracellular calcium levels, and altering intracellular calcium-dependent tissue responses. Calcium Metabolism in Hypertension Steady-State Activity Despite the long-appreciated association of hypertension with hypercalcemia in primary hyperparathyroidism, lower serum ionized calcium levels were first reported in essential hypertension by McCarron in However, when considered in relation to the activity of the renin-angiotensin system, Resnick et al observed that ionized calcium levels, although within the normal range for the group as a whole, deviated in both directions away from average normotensive values. For subjects evaluated at the same level of urinary sodium excretion, serum ionized calcium levels were suppressed in low renin subjects, but were reciprocally increased in subjects with inappropriately high plasma renin activity. 40 Consistent with the above, serum ionized calcium levels in subjects with primary aldosteronism were even further suppressed than those in low renin essential hypertension, paralleling the further suppression of plasma renin activity in this disease. 43 That these statistically significant maldistributions of extracellular ionized calcium were physiologically significant as well, was determined by analyzing the activity of calcium regulating hormones in hypertension. Similar to the distribution of circulating extracellular ionized calcium, a linkage between calcium regulating hormones and renin system activity was observed. Independently of renal sodium excretion, low renin essential hypertensive subjects exhibited significantly greater PTH and 1,25 dihydroxyvitamin D (1,25 D) levels, and reciprocally lower calcitonin levels compared to normotensive or other hypertensive subjects. 44 Primary aldosteronism was associated with even higher circulating PTH levels. 43 Conversely, high renin hypertensives demonstrated the opposite calcium hormonal profile. Thus, the clinical heterogeneity of hypertension is associated with a parallel heterogeneity of calcium metabolism, linked to the activity of the renin-angiotensin system. One type of hypertension, defined on the basis of suppressed plasma renin activity, seems to display an ionic and hormonal calcium profile consistent with and appropriate for a calcium deficient state lower ionized calcium and calcitonin levels, and higher PTH and 1,25 D levels (Figure 4). Other hypertensives display a discretely different, often opposite pattern.

6 104 RESNICK AJH JANUARY 1999 VOL. 12, NO. 1, PART 1 FIGURE 4. The inverse relation of circulating 1,25 (OH) 2 D levels to plasma renin activity in normal and essential hypertensive subjects. Reproduced with permission from Resnick et al: Calcium regulating hormones in essential hypertension: relation to plasma renin activity and sodium metabolism. Ann Intern Med 1986;105: Calcium Metabolism in Hypertension Clinical Dietary Studies Aside from these steady-state cross-sectional studies, these same renin-linked deviations in calcium metabolism could be induced dynamically by altered dietary salt or calcium intake. First, not only can dietary salt loading in at least some hypertensive individuals elevate blood pressure, but oral calcium supplementation can lower it. One of the outstanding characteristics of these dietary maneuvers is the wide splay of blood pressure responses, both depressor and FIGURE 5. Relation of the diastolic blood pressure effects ( DBP) of chronic oral calcium supplementation to average 24-h urinary sodium excretion values (UNaV) in essential hypertensive subjects. Reproduced with permission from Resnick: Role of calcium and magnesium in the therapy of human hypertension, in Laragh et al (eds): Hypertension: Pathophysiology, Diagnosis, and Management, 2nd ed. Raven Press, New York, 1989, pp pressor effects observed. This has long been known for salt, only some salt-sensitive individuals responding to higher salt intakes with a significant rise in blood pressure. This was also explicitly demonstrated in early studies of calcium supplementation given to hospitalized hypertensive subjects on metabolic balance diets, 19 when analyzed in relation to renin system activity and serum ionized calcium levels, 20 and also in longer-term outpatient studies, 45 when analyzed according to ionized calcium levels and urinary sodium excretion: the lower the renin activity or ionized calcium level, or the higher the urinary sodium excretion (reflective of dietary sodium intake), the greater the hypotensive effect of oral calcium (Figure 5). Since those preliminary reports, numerous larger clinical trials of oral calcium supplementation have been published, the majority demonstrating a hypotensive response in some, but not all subjects, whereas pressure actually rose in others. 20,46,47 Metaanalyses of these clinical trials have also recently been performed. 2 5 It appears that for at least some clinically distinct forms of hypertension, such as pregnancyinduced hypertension and preeclampsia, oral calcium supplementation lowered both systolic and diastolic blood pressure. 3 Interestingly, when all other calcium supplementation studies of normotensive and hypertensive subjects were analyzed similarly, little or no effect was observed. 2,4 Again, although these studies did not a priori distinguish different subgroups of hypertensive individuals, in the few clinical or animal studies where that was done, 19,20,45,48,49 calcium was more uniformly beneficial among low renin, salt-dependent forms of hypertension. In explaining these heterogeneous effects, it was

7 AJH JANUARY 1999 VOL. 12, NO. 1, PART 1 CALCIUM IN CLINICAL HYPERTENSION 105 FIGURE 6. The ability of high (HS) versus low (LS) dietary salt intakes to change blood pressure (% DBP) in relation to salt-induced stimulation of 1,25 (OH) 2 D (% 1,25 D), in hypertensive subjects on placebo (P) tablets. Based on data from Resnick et al. 50 interesting to note the presence of reciprocal effects of altered dietary salt and calcium intakes on calcium metabolism. Thus, salt loading to a greater or lesser degree stimulates calcium regulating hormones such as 1,25 (OH) 2 D (Figure 6), whereas calcium loading reciprocally suppresses these same calcium regulating hormone species Furthermore, the ability of salt loading to elevate pressure, and of calcium supplementation to lower it, were found to be proportional to these salt- or calcium-induced changes in calcium metabolism the greater the stimulation of, eg, 1,25 (OH) 2 D or PHF, the greater the pressor response 45,50,53 (Figure 6); conversely blood pressure falls the more calcium suppresses 1,25 (OH) 2 D. 54,55 Consistent with this observation, it was found that those individuals most responsive to the pressor effects of salt were the same individuals most likely to exhibit a hypotensive response to calcium supplementation, these subjects sharing the same low renin, lower ionized calcium, higher 1,25 D profile. 26 As such, a critical role has been suggested for at least one calcium regulating hormone, 1,25 D (and perhaps the newly recently described parathyroid hypertensive factor, PHF, as well), in mediating both the pressor effect of salt and the hypotensive action of increased calcium intake. Thus, diet-induced changes in calcium hormonal metabolism mediate the blood pressure effects of both altered dietary sodium and calcium mineral intake. Renal calcium retention and a presumed positive calcium balance may also underlie the blood pressure effects of altered potassium intake. 56,57 Cellular-Biochemical Level: How Do Dietary Salt and Calcium Really Change Blood Pressure? Given the above physiologic-hormonal considerations, it still remained unexplained why and how dietary salt- or dietary calcium-induced reciprocal changes in calcium regulating hormones and the renin-angiotensin-aldosterone system result in altered blood pressure. What was needed was an explanation of how these dietaryinduced, hormonal changes are translated at the cellular-tissue level, at which level the sensor and effector arms of the system are united, and for which calcium is critically important. Indeed, steady-state cell ion activity in general, and cytosolic free calcium in particular, is a common point of both cellular recognition and response to hormonally mediated environmental signals. Altered cellular function dependent on these ionic responses defines the ultimate clinical state (Figures 1 to 3). As has been increasingly established over the past decade, cytosolic free calcium participates as a second messenger system determining cellular responses to a wide variety of stimuli. Thus, because calcium is part of the final common pathway leading to muscle contraction (stimulus-contraction coupling), neurohormone secretion (stimulus-secretion coupling), and pressor hormonal action, the higher the level of cytosolic free calcium, the greater the smooth muscle vasoconstrictor tone, catecholamine secretion, sympathetic nervous system activity, and thus blood pressure (Figure 7). This is also true for myocardial contractility, increased platelet aggregability, insulin resistance, and altered renal cation excretion 14 ; and may directly explain the increased peripheral resistance characteristic of essential hypertension, as well as the increased cardiac ejection fraction often observed early in the course of hypertensive disease. Furthermore, the subsequent actions of catecholamines to independently increase vascular tone and blood pressure; of angiotensin II to vasoconstrict the peripheral and renal vasculature, and to stimulate aldosterone secretion; and of other potentially relevant pressor factors such as arginine vasopressin (AVP), endothelin, and PHF, are all mediated by their ability to stimulate cytosolic free calcium levels. Alto-

8 106 RESNICK AJH JANUARY 1999 VOL. 12, NO. 1, PART 1 FIGURE 7. Direct relation between fasting cytosolic free calcium (Ca i ) and diastolic blood pressure (DBP). Reproduced with permission from Resnick: Ionic disturbances of calcium and magnesium metabolism in essential hypertension, in Laragh et al (eds): Hypertension: Pathophysiology, Diagnosis, and Management, 2nd ed. Raven Press, New York, 1995, pp gether then, the regulation of cellular calcium metabolism is central to blood pressure homeostasis. Based on the above, the significance of dietary mineral-induced changes in calcium-regulating hormones, for example, becomes more apparent in light of the now well documented actions of, eg, 1,25 (OH) 2 Dto stimulate cellular calcium uptake and elevate cytosolic free calcium levels in cardiovascular tissues. Indeed, 1,25 D not only stimulates calcium uptake, but activates L-type calcium channels, elevates cytosolic free calcium (Ca i ) levels, and contributes to contraction in vascular smooth muscle (Figure 8) and the myocardium Parathyroid hypertensive factor (PHF) has similar calcium-uptake dependent vasoconstrictive actions on the vasculature, and inhibits renal renin release Dietary salt-induced elevations of blood pressure can thus be explained as the consequence of salt-induced changes in calcium-regulating hormones which in turn, alter Ca i levels in cardiovascular and pressor hormone-related tissues, directly resulting in the vasoconstriction and potentiated sympathetic nerve activity we associate with salt-sensitive hypertension. The ability of chronic dietary salt loading to elevate blood pressure in proportion to its ability to alter intracellular Ca i, ph, and free magnesium levels, has been well documented (Figure 9). Conversely, by reversing or preventing these salt-induced calcium-hormonal changes, dietary calcium supplementation may lower Ca i in these tissues, reversing or preventing the cardiovascular effects of salt loading. 75,76 The ability of dietary calcium supplementation to result in lower intracellular free calcium levels concomitantly with its ability to lower blood pressure has recently been reported. 76 The above scheme emphasizing the coordinate regulation of calcium and sodium metabolism also explains why, epidemiologically, among calcium replete individuals, blood pressure appeared unrelated to dietary salt intake, 35 because little stimulation of, eg, 1,25 D, would be expected under calcium replete, 1,25 D suppressed circumstances. On the other hand, other individuals would be salt-sensitive, if, by virtue of chronic low dietary calcium intake, an exaggerated calcium-hormonal response (or minimal renin suppression, see below) followed salt loading, because this would result in calcium hormone-mediated elevations of Ca i and a subsequent pressor response. The latter circumstances are, interestingly, common among salt-sensitive, black populations in the United States, 77 and among pregnant women in the third trimester, in whom calcium supplementation may lower blood pressure and prevent preeclampsia. 3,78 FIGURE 8. Whole cell patch clamp electrophysiologic measurements in vascular smooth muscle demonstrating stimulation of L-type calcium channel activity by 1,25 (OH) 2 D. Reproduced from Shan et al: 1,25 Dihydroxyvitamin D as a cardiovascular hormone: effects of calcium current and cytosolic free calcium in vascular smooth muscle cells. Am J Hypertens 1993;6:

9 AJH JANUARY 1999 VOL. 12, NO. 1, PART 1 CALCIUM IN CLINICAL HYPERTENSION 107 FIGURE 9. Relation of blood pressure and intracellular ion responses to chronic dietary salt loading in salt-sensitive and salt-insensitive essential hypertensive subjects. Reproduced with permission from Resnick: Intracellular ionic consequences of dietary salt loading in essential hypertension: relation to blood pressure and effects of calcium channel blockade. J Clin Invest 1994;94: OTHER DIETARY NUTRIENT-HORMONAL SYSTEMS CAN CHANGE BLOOD PRESSURE: THE ROLE OF CELLULAR CALCIUM METABOLISM IN HYPERGLYCEMIC AND INSULIN RESISTANT STATES Environmental maneuvers in addition to alterations of dietary salt, calcium, and other mineral ion content may also have profound blood pressure and vascular effects. Recently, the ability of diets high in sugar content to elevate blood pressure in a variety of animal models has been reported. The association of this carbohydrate-induced hyperinsulinemia with essential hypertension in which hyperinsulinemia and insulin resistance are also present, has furthered the presumption that insulin per se, in the context of insulin resistance, contributes to the hypertensive state. 79 Our group has attempted to understand the origin of these insulin-metabolic lesions in cellular ionic terms, and has incorporated insulin resistance and hyperinsulinemia into the overall ionic hypothesis mentioned above (Figure 3). The ionic basis of insulin resistance- and glucoserelated effects on blood pressure derives from data in which cells are exposed to insulin or glucose. Oral glucose loading in vivo and hyperglycemia in vitro consistently results in a characteristic elevation in cytosolic free calcium and reciprocal suppression of intracellular free magnesium in peripheral red cells as well as vascular smooth muscle cells 80,81 (Figure 10). This altered ion profile exactly matches the steadystate alterations observed in cells from fasting hypertensive subjects, 82 is an effect specific for glucose, and is dose-dependent, starting at glucose concentrations above 10 mmol/l (180 mg%), approximately the renal threshold for glycosuria. Thus, we believe the vasoconstriction associated with chronic hyperglycemic states, such as type II diabetes mellitus, may be a direct consequence of glucose toxicity, mediated by the same underlying cellular calcium ionic alterations operative in essential hypertension, and consisting at least in part of increased cytosolic free calcium levels. Similarly, insulin resistance itself appears to be an ionic phenomenon. In vitro, insulin, independently of glucose, elevates both cytosolic free calcium and free magnesium levels. This is also true in circulating red blood cells, 83 in adipocytes, 84 and in vascular smooth muscle cells. 85 Interestingly, when comparing the ionic effects of insulin in cells from normotensive versus essential hypertensive subjects, two observation were made. First, insulin s ionic actions were blunted in hypertensive cells. Second, the ability of insulin to elevate either divalent cation closely followed the basal ion content of the cell. Thus, the lower the cytosolic free calcium, and the higher the basal free magnesium level, ie, the more normal the initial ion content, the more responsive were the cells to insulin. It thus seems that the initial ionic deviations characteristic of hypertension, induced by dietary salt loading in salt-sensitive hypertension, and equally by hyperglycemia, makes cells insulin resistant. This has been supported by other studies in which reversible increases and decreases in cellular calcium content were associated with a parallel resistance to other, nonionic actions of insulin as well Lastly, this cellular calcium-related alteration of hormone responsiveness is not specific for insulin, or even for hor-

10 108 RESNICK AJH JANUARY 1999 VOL. 12, NO. 1, PART 1 FIGURE 10. Cytosolic free calcium response to hyperglycemia in an isolated vascular smooth muscle cell. Reproduced with permission from Barbagallo et al: Glucose-induced alterations of cytosolic free calcium in cultured rat tail artery vascular smooth muscle cells. J Clin Invest 1995;95: mone action, but may reflect a more general property of cells, in which cellular calcium content determines cell responsiveness to a wide variety of extracellular stimuli. Thus, the cellular ionic effects of glucose itself differs according to the basal cellular ion content, with lower free magnesium and greater cytosolic calcium levels significantly blunting the effect of glucose (unpublished observations). Altogether then, cellular free calcium levels seem to be critical not only in mediating dietary and hormonal signals, but at determining the level of cell responsiveness to those stimuli. Calcium is thus a central actor in the sensor as well as the effector arms of cellular physiology. THE COORDINATE REGULATION OF INTRACELLULAR AND EXTRACELLULAR CALCIUM: WHY DON T WE ALL HAVE HYPERTENSION? The development by Laragh of the vasoconstrictionvolume analysis of hypertension 89 has allowed us not only to better understand blood pressure homeostasis, but also to define and analyze in a physiologic manner the heterogeneity of clinical hypertensive disease. In this formulation, the excess peripheral resistance characteristic of all essential hypertension is derived, to a greater or lesser extent, from inappropriate contributions of sodium-volume factors and renin-angiotensin system mediated vasoconstrictor factors. For a given individual, the relative contributions of these factors can be clinically identified by measurement of the plasma renin activity in relation to dietary salt intake. According to this scheme, in normal individuals dietary salt loading does not raise blood pressure because the excess sodium intake, sensed at the renal level, suppresses renin secretion, and thus lowers circulating angiotensin II levels. Hence, the contribution of increased sodium-volume status to blood pressure is normally offset by a reciprocal withdrawal of angiotensin II-mediated vasoconstrictor tone, but the blood pressure remains the same. Conversely, hypotension does not normally result from a decreased dietary salt intake, due to reciprocal stimulation of renin system activity in parallel with and compensatory to the decreased volume consequent to the low salt diet. In this physiologic formulation, blood pressure rises outside the normal range only from inappropriate stimulation or lack of appropriate suppression of one or the other arm of the system. Thus, a high dietary salt intake in the presence of low or nonsuppressible renin secretion (the nephron heterogeneity hypothesis) 90 will raise pressure in salt-related forms of hypertensive disease, whereas excessive renin activity with normal or even low dietary salt intakes may lead to renin-dependent hypertension. This physiologic, vasoconstriction-volume analysis of hypertension can now be reformulated in cellular calcium ionic terms, 91 allowing us to understand the blood pressure consequences of altered dietary salt or calcium intake as the result of their reciprocal hormone-mediated effects on Ca i (Figure 11). In analogy with the bipolar analysis of sodium-volume versus renin-dependent vasoconstriction, this cellular calcium-derived model is based on a parallel, bipolar analysis of extracellular versus intracellular contributions to the maintenance of cytosolic free calcium levels, in which a) smooth muscle tone, myocardial contractility, and blood pressure itself are directly proportional to ambient Ca i levels, b) angiotensin II-mediated cellular effects are associated with primary actions to release intracellular stored calcium into the cytoplasm, 92 and c) the ability of calcium-regulating hormones such as 1,25 (OH) 2 D to raise Ca i depend on cellular calcium uptake from the extracellular space. Hence, the extracellular versus intracellular source of

11 AJH JANUARY 1999 VOL. 12, NO. 1, PART 1 CALCIUM IN CLINICAL HYPERTENSION 109 Ca i determines the relative blood pressure contribution of sodium-volume versus renin-angiotensin II dependent factors. These interrelated, alternate sources of cytosolic free calcium extracellular versus intracellular thus form the basis of an equivalent, cellular-ionic description of Laragh s volume-vasoconstriction analysis of hypertension. How does this calcium-based scheme work? Stated in cellular terms, going on a high salt diet, as described above, stimulates calcium regulating hormone-related factors, which potentiate cellular Ca uptake from the extracellular space. This same intracellular calcium entry also reciprocally and simultaneously suppresses renal renin secretion, because almost uniquely to that tissue, higher Ca i in the juxtaglomerular apparatus inhibits renin release. 93 The lower angiotensin II levels resulting from lower renin activity would decrease cellular calcium release from intracellular stores. The net effect is thus no net change in Ca i, just a shift in its source. Thus, in normal people, high salt diets do not significantly change blood pressure. Hypertension would result from excessive salt-induced elevations in calcium-regulating hormones in a setting of low renin activity or of an inadequate suppression of renin activity. This is exactly what would be expected of a calcium deficient individual, having basal steadystate elevations of PTH and 1,25(OH) 2 D the calcium hormonal profile of low renin essential hypertension (see above). Conversely, sodium volume depletion or increased dietary Ca would reverse the above process or lower blood pressure, by suppressing calcium-regulating hormones, such as 1,25 (OH) 2 D. This would result in less dependence of cytosolic free calcium on extracellular Ca entry, and reciprocally more on angiotensin II-induced Ca release from intracellular stores. Again, if the two hormonal systems, renin-angiotensin versus FIGURE 11. General hypothesis in which dietary mineral elements such as salt and calcium result in altered blood pressure to the extent that they alter the activities of their regulating hormone systems, the renin-angiotensin system, and calcium regulating hormones, respectively. These hormones in turn, regulate cytosolic free calcium and magnesium activity by virtue of their actions on intracellular calcium release and extracellular calcium entry. Reproduced with permission from Resnick: Uniformity and diversity of calcium metabolism in hypertension: a conceptual framework. Am J Med 1987; 82(suppl 1B): calcium hormones, change symmetrically and proportionately, renin stimulation from decreased extracellular calcium entry into juxtaglomerular cells being associated with a parallel calcium hormone suppression, then Ca i levels in smooth muscle, heart, adrenal gland, central nervous system, etc, sites stay the same, and blood pressure also remains normal on low salt diets. However, blood pressure would be expected to fall with low salt diets or with high calcium intakes exactly in those individuals characterized by the suppression of calcium hormone-dependent extracellular calcium entry in the absence of any reciprocal stimulation of renin activity or angiotensin II ie, in the low renin, salt-sensitive patient. SUMMARY What emerges from this type of analysis is an increasing appreciation of how neither the relation of calcium metabolism to hypertension, nor the blood pressure effects of calcium supplementation can be adequately understood on the basis of past or future studies that do not take into account the underlying heterogeneity of human hypertension. This heterogeneity, in turn, reflects physiologic differences among different subjects in circulating levels of calcium-regulating hormones, of the renin-angiotensin system, and presumably of other humoral regulators of cellular calcium metabolism. Alterations of dietary calcium, of its allied mineral elements, such as sodium chloride, potassium, and magnesium, and of other nutrients, such as sugar, can each directly, or via diet-induced changes in the above hormonal systems, shift the distribution of calcium between circulating-extracellular, intracellular-cytosolic, and intracellular storage sites (Figure 11). Whether blood pressure changes in response to these maneuvers thus depends on the metabolic setpoint of these humoral systems, differing considerably

12 110 RESNICK AJH JANUARY 1999 VOL. 12, NO. 1, PART 1 among different individuals for any level of blood pressure. This approach argues strongly in favor of a more physiologic profiling of hypertensive individuals prior to dietary recommendations. Furthermore, expensive, large scale clinical trials of dietary mineral therapies in hypertension will continue to obscure relevant clinical information and cannot provide a guide to patient care if they fail to investigate hypertensive subjects that are not a priori identified on the basis of these underlying physiologic differences. From a practical point of view, this cellular-physiologic approach also highlights the futility and inappropriateness of treatments based on uniform, fixed algorithms for dietary sodium, calcium, or other minerals in hypertension, which may ultimately be less cost effective than their simplicity would suggest. At the same time, however, achieving at least minimum, current Recommended Dietary Allowance (RDA) standards for adequate oral calcium intake is quite reasonable, and may have significant blood pressure effects among those individuals whose present avoidance of calcium-containing foods make them prone not only to salt-sensitive hypertensive disease, but also to other calcium-related diseases such as osteoporosis. REFERENCES 1. Resnick LM: Calcium and hypertension the emerging connection. Ann Int Med 1985;103: Bucher HC, Cook RJ, Guyatt GH, et al: Effects of dietary calcium supplementation on blood pressure. A meta-analysis of randomized controlled trials. JAMA 1996;275: Bucher HC, Guyatt GH, Cook RJ, et al: Effect of calcium supplementation on pregnancy-induced hypertension and preeclampsia. A meta-analysis of randomized controlled trials. JAMA 1996;275: Allender PS, Cutler JA, Follmann D, et al: Dietary calcium and blood pressure: a meta-analysis of randomized controlled trials. Ann Intern Med 1996;124: Griffith LE, Guyatt GH, Cook RJ, et al: The influence of dietary and non-dietary calcium supplementation on blood pressure: an updated meta-analysis of randomized controlled trials. Am J Hypertens 1999;12: Ringer S: A third contribution regarding the infusion of the inorganic constituents of the blood on the ventricular contraction. J Physiol (London) 1883;4: Kuriyama H, Uyshi I, Sueuk H, et al: Factors modifying contraction-relaxation cycle in vascular smooth muscles. Am J Physiol 1982;243:H641 H Jordan RM, et al: General principles of endocrinology, in Kohler PO (ed): Clinical Endocrinology. John Wiley & Sons, New York, 1986, pp Erne P, Bolli P, Burgissen E, Buhler F: Correlation of platelet calcium with blood pressure: effect of antihypertensive therapy. N Engl J Med 1984;319: Walser M: Calcium clearance as a function of sodium clearance in the dog. Am J Physiol 1961;200: McCarron D, Pingree P, Rubin R, et al: Enhanced parathyroid function in essential hypertension: a homeostatic response to a urinary calcium leak. Hypertension 1980;2: Strazzullo P, Nunziata V, Cirillo M, et al: Abnormalities of calcium metabolism in essential hypertension. Clin Sci 1983;65: Barbagallo M, Resnick LM, Sosa RE, et al: Renal divalent cation excretion in secondary hypertension. Clin Sci 1992;83: Resnick LM: Ionic basis of hypertension, insulin resistance, vascular disease, and related disorders: mechanism of Syndrome X. Am J Hypertens 1993;6:123S 134S. 15. Addison W: The use of calcium chloride in arterial hypertension. Can Med Assoc J 1924;14: Addison W, Clark H: Calcium and potassium chloride in the treatment of arterial hypertension. Can Med Assoc J 1925;15: Ayachi S: Increased dietary calcium lowers blood pressure in the sponteneous hypertensive rat. Metabolism 1979;28: Belizan M, Villar J, Pineda O, et al: Reduction of blood pressure with calcium supplementation in young adults. JAMA 1983;249: Resnick L, Sealey J, Laragh J: Short and long-term oral calcium alters blood pressure (BP) in essential hypertension (abst). Fed Proc 1983;42: Resnick L, Nicholson J, Laragh J: Calcium metabolism and essential hypertension-relation to altered renin system activity. Fed Proc 1986;45: McCarron D, Morris C: Blood pressure response to oral calcium in persons with mild to moderate hypertension: a randomized, double-blind, placebo-controlled crossover trial. Ann Int Med 1985;103: Brinton GS, Jubiz W, et al: Hypertension in primary hyperparathyroidism: the role of the renin-angiotensin system. J Clin Endocrinol Metab 1975;41: Clowes GHA Jr, Simeone FA: Acute hypocalcemia in surgical patients. Ann Surg 1957;145: McCarron D, Morris C, Cile C. Dietary calcium in human hypertension. Science 1982;217( ). 25. McCarron D, Morris C, Henry J, Stanton J: Blood pressure and nutrient intake in the United States. Science 1984;224: Resnick L: Hypertension and abnormal glucose homeostasis: possible role of divalent ion metabolism. Am J Med 1989;87(suppl 6A):17S 22S. 27. Belizan JM, et al: The relationship between calcium intake and edema-, proteinuria-, and hypertension-gestosis: an hypothesis. Am J Clin Nutr 1980;33: Ackley S, Barrett-Connor E, Suarez L: Dairy products, calcium, and blood pressure. Am J Clin Nutr 1983;38: Gruchow H, Sobocinski H, Barbariak J: Threshold effects of dietary calcium on blood pressure. J Hypertens 1986;4(suppl 5):S355 S357.

13 AJH JANUARY 1999 VOL. 12, NO. 1, PART 1 CALCIUM IN CLINICAL HYPERTENSION Reed D, McGee D, Yamo K, Hankin J: Diet, blood pressure, and multicolinearity. Hypertension 1985;7: MacGregor GA: Sodium is more important than calcium in essential hypertension. Hypertension 1985;7: McCarron DA: Is calcium more important than sodium in the pathogenesis of essential hypertension? Hypertension 1985;7: Tobian L: The Jeremiah Metzger Lecture: High potassium diets strongly protect against stroke deaths and renal disease: a possible legacy from prehistoric man. Trans Am Clin Climatol Assoc 1985;97: Altura BM, Altura BT, et al: Magnesium deficiency and hypertension: correlation between magnesium-deficient diets and microcirculatory changes in situ. Science 1984;223: Hamet P, Daignault-Gelinas M, Lambert J, et al: Epidemiological evidence of an interaction between calcium and sodium intake impacting on blood pressure: A Montreal Study. Am J Hypertens 1992;5: Kesteloot H, Geboers J: Calcium and blood pressure. Lancet 1982;i: Weidmann P, Massry SG, Coburn JW, et al: Blood pressure effects of acute hypercalcemia: studies in patients with chronic renal failure. Ann Intern Med 1972; 76: Grobbee D, Hofman A: Effect of calcium supplementation on diastolic blood pressure in young people with mild hypertension. Lancet 1986;ii: Sowers MF: Relationship between 1,25-dihydroxyvitamin D and blood pressure in a geographically defined population. Am J Clin Nutr 1988;48: Resnick L, Laragh J, Sealey J, Alderman M: Divalent cations in essential hypertension: relations between serum ionized calcium, magnesium, and plasma renin activity. N Engl J Med 1983;309: Hunt SC, Williams RR, et al: Different plasma ionized calcium correlations with blood pressure in high and low renin normotensive adults in Utah. Am J Hypertens 1991;4: McCarron D: Low serum concentrations of ionized calcium in patients with hypertension. N Engl J Med 1982;307: Resnick L, Laragh J: Calcium metabolism and parathyroid function in primary aldosteronism. Am J Med 1985;78: Resnick L, Muller F, Laragh J: Calcium regulating hormones in essential hypertension: relation to plasma renin activity and sodium metabolism. Ann Intern Med 1986;105: Resnick L: Uniformity and diversity of calcium metabolism in hypertension: a conceptual framework. Am J Med 1987;82(suppl 1B): Zoccali C, Mallamaci F, Delfino D, et al: Does calcium have a dual effect on arterial pressure: response to 1,25 dihydroxyvitamin D 3 and calcium supplements in essential hypertension. J Hypertens 1987;5(suppl 5):S267 S Meese RB, Gonzales DG, Casparian JM, et al: The inconsistent effects of calcium supplements upon blood pressure in primary hypertension. Am J Med Sci 1987; 254: Resnick L, Sosa R, Corbett M, et al: Effects of dietary calcium on sodium volume vs. renin-dependent forms of experimental hypertension. Trans Assoc Amer Physicians 1986;99: McCarron D, Lucas P, Schneidman R, Druecke T: Blood pressure development of the spontaneously hypertensive rat following concurrent manipulation of dietary Ca and Na: relation to intestinal Ca fluxes. J Clin Invest 1985;76: Resnick L, Nicholson J, Laragh J: Alterations in calcium metabolism mediate dietary salt sensitivity in essential hypertension. Trans Assoc Amer Physicians 1985;98: Zemel M, Gualdoni S, Walsh M, et al: Effects of sodium and calcium on calcium metabolism and blood pressure regulation in hypertensive black adults. J Hypertens 1986;4 (suppl 5):S364 S Hughes G, Oexmann M, Margolius H, et al: Normal vitamin D and mineral metabolism in essential hypertension. Am J Med Sci 1988;296: Resnick LM, Lewanczuk RZ, Laragh JH, Pang PKT: Parathyroid hypertensive factor-like activity in human essential hypertension: relationship to plasma renin activity and dietary salt sensitivity. J Hypertens 1993;11: Resnick L: Role af calcium and magnesium in the therapy of human hypertension, in Laragh J, Brenner B (eds): Hypertension: Pathophysiology, Diagnosis, and Management, Vol 2. Raven Press, New York, 1989, pp Ogihara T, Saito H, Tabuchi Y, et al: The hypotensive effect of long-term oral calcium loading in elderly hypertensive patients: the importance of endogenous vitamin D suppression. J Hypertens 1986;4(suppl 6): S685 S Lawton WJ, Fitz AE, Anderson EA, et al: Effect of dietary potassium on blood pressure, renal function, muscle sympathetic nerve activity, and forearm vascular resistance and flow in normotensive and borderline hypertensive humans. Circulation 1990;81: Lemann J Jr, Pleuss JA, Gray RW, et al: Potassium administration increases and potassium deprivation reduces urinary calcium excretion in healthy adults. Kidney Int 1991;39: Kawashima O: Receptor for 1,25 dihydroxyvitamin D in a vascular smooth muscle cell line derived from rat aorta. Biochem Biophys Res Commun 1987;146: Merke J, Hofmann W, Goldenschmidt D, Ritz E: Demonstration of 1,25 (OH) 2 vitamin D 3 receptors and actions in vascular smooth muscle cells in vitro. Calcif Tissue Int 1987;41: Bukoski R, Xue H, McCarron D: Effect of 1,25(OH) 2 vitamin D3 and ionized calcium on 45 Ca uptake by primary cultures of aortic myocytes of spontaneously hypertensive and Wistar Kyoto normotensive rats. Biochem Biophys Res Commun 1987;146: Bukoski RD, Xue H: On the vascular inotropic action of 1,25-(OH) 2 vitamin D 3. Am J Hypertens 1993;6: