Alterations of dietary calcium intake as a therapeutic modality in essential hypertension

Alterations of calcium metabolism in hypertensive disease have been increasingly observed, although the specific manner in which these alterations contribute to the increased blood pressure remains unclear. We have studied calcium metabolism in essential hypertension and have adopted an approach based on analysis of renin system activity, which emphasizes the heterogeneity of human hypertensive disease. With this approach we have defined parallel deviations of plasma renin activity, circulating ionized calcium, and calcium-regulating hormones, which suggest a calcium deficiency in some hypertensives and, an excess of calcium in others. These deviations can be used to predict and may mediate the blood pressure sensitivity of hypertensives to dietary salt, and may also target those individuals most likely to benefit from oral calcium supplementation. Calcium itself has enhanced antihypertensive effects in low renin subjects, having lower ionized calcium and higher endogenous 1,25-dihydroxyvitamin D values, and in subjects on higher dietary salt intakes. Calcium may alter pressure, at least in part, by suppressing endogenous vitamin D metabolites and by stimulating calcitonin secretion. We hypothesize that calcium-regulating hormones participate in the physiology of the renin-angiotensin system and in the pathophysiology of human hypertension.     

Calcium metabolism and cardiovascular function after spaceflight.

To determine the influence of dietary calcium on spaceflight-induced alterations in calcium metabolism and blood pressure (BP), 9-wk-old spontaneously hypertensive rats, fed either high- (2%) or low-calcium (0.02%) diets, were flown on an 18-day shuttle flight. On landing, flight animals had increased ionized calcium (P < 0.001), elevated parathyroid hormone levels (P < 0.001), reduced calcitonin levels (P < 0.05), unchanged 1,25(OH)(2)D(3) levels, and elevated skull (P < 0.01) and reduced femur bone mineral density. Basal and thrombin-stimulated platelet free calcium (intracellular calcium concentration) were also reduced (P < 0.05). There was a tendency for indirect systolic BP to be reduced in conscious flight animals (P = 0.057). However, mean arterial pressure was elevated (P < 0.001) after anesthesia. Dietary calcium altered all aspects of calcium metabolism (P < 0.001), as well as BP (P < 0.001), but the only interaction with flight was a relatively greater increase in ionized calcium in flight animals fed low- compared with high-calcium diets (P < 0.05). The results indicate that 1) flight-induced disruptions of calcium metabolism are relatively impervious to dietary calcium in the short term, 2) increased ionized calcium did not normalize low-calcium-induced elevations of BP, and 3) parathyroid hormone was paradoxically increased in the high-calcium-fed flight animals after landing.     

The passive role of calcium in hypertension: a position statement as of August 20, 1985

Epidemiologic data suggest that calcium intake is lower in hypertensive individuals than in normotensive individuals. Moreover, hypertensive patients and rats excrete more calcium in their urine than normotensives, and laboratory studies (low ionized calcium, high parathyroid hormone (PTH)) suggest that the hypertensive is somewhat calcium depleted. However, both the low ionized calcium and elevated PTH should tend to lower pressure rather than raise it, leaving only the presumed and poorly documented natriuretic effect of calcium as a hypotensive mechanism. The evidence is better for a high sodium intake producing a conditioned deficiency of calcium by increasing calcium excretion than for a low intake of calcium raising blood pressure.     

Effect of nifedipine treatment on the renin-aldosterone system and secretion of cortisol and growth hormone in patients with essential hypertension]

The effect of treatment of hypertension with nifedipine on plasma renin activity, blood serum level of aldosterone in the course of renin test, and cortisol and growth hormone concentrations after stimulation with insulin hypoglycemia was followed during two weeks of treatment in 40 patients with essential hypertension. No significant differences in the secretion of the hormones studied, as compared to the patients with the normal arterial blood pressure, were found. After nifedipine treatment no significant changes in the secretion of aldosterone, cortisol and growth hormone were observed despite a significant fall in the arterial blood pressure while there was a moderate stimulatory effect on renin secretion. The results obtained indicate that nifedipine has only small effect on the hormonal system of patients with essential hypertension.     

Vitamin D regulation of the renin-angiotensin system

The renin-angiotensin system (RAS) plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis. Epidemiological and clinical studies have long suggested an association of inadequate sunlight exposure or low serum 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] levels with high blood pressure and/or high plasma renin activity, but the mechanism is not understood. Our recent discovery that 1,25(OH)(2)D(3) functions as a potent negative endocrine regulator of renin gene expression provides some insights into the mechanism. The concept of vitamin D regulation of blood pressure through the RAS opens a new avenue to our understanding of the physiological functions of the vitamin D endocrine system, and provides a basis for exploring the potential use of vitamin D analogues in prevention and treatment of hypertension.     

Genetic variability in response to dietary calcium

Supplemental dietary calcium has been shown to reduce blood pressure in spontaneously hypertensive rats while restricted calcium diets cause an elevation in blood pressure. This latter nutrient effect has been enhanced by modest sodium restriction and is associated with a reduction in serum ionized calcium concentration. To determine whether alterations of dietary calcium and sodium have a similar influence on blood pressure in genetically normotensive rats, Fisher 344, Wistar Furth, and ACI rats were fed either a low (0.1%) calcium, low (0.25%) sodium diet or normal (1.0%) calcium, normal sodium (0.45%) diet from 4 weeks of age through 29 weeks of age. Indirect measurements of systolic blood pressure showed that only the Fisher 344 rats consistently responded to the low calcium/low sodium diets with an elevation of blood pressure. There was considerable variation in serum electrolytes across strains in the normal diets but all three strains experienced a reduction in ionized calcium and an elevation in phosphorus and magnesium on the restricted diets. In the Fisher 344 rats there were significant (p less than .05) inverse correlations among systolic blood pressure and serum ionized and total calcium concentrations and positive correlations among systolic blood pressure, phosphorus, and magnesium. There was no significant correlation between serum electrolytes and blood pressure in the other two strains. The data indicate that there is genetic variability in the blood pressure response to alterations in dietary calcium and sodium. The pattern of change in serum electrolytes across strains suggests that diet-induced alterations of serum electrolytes, specifically calcium, are not necessarily predictive of a pressor response. It would appear that some other calcium-sensitive physiological process involved in blood pressure regulation must respond differentially to calcium availability across strains.     

Effect of licorice on PTH levels in healthy women

Licorice has been considered a medicinal plant for thousands of years. Its most common side effect is hypokalemic hypertension, which is secondary to a block of 11beta-hydroxysteroid dehydrogenase type 2 at the level of the kidney, leading to an enhanced mineralocorticoid effect of cortisol. This effect is due to glycyrrhetinic acid, which is the main constituent of the root, but other components are also present, including isoflavans, which have estrogen-like activity, and are thus involved in the modulation of bone metabolism. We investigated nine healthy women 22-26 years old, in the luteal phase of the cycle. They were given 3.5 g of a commercial preparation of licorice (containing 7.6%, w/w of glycyrrhizic acid) daily for 2 months. Plasma renin activity (PRA), aldosterone, cortisol, serum parathyroid hormone (PTH), 1,25-dihydroxy Vitamin D (1,25OHD), 25-hydroxycholecalciferol (25OHD), estradiol, FHS, LH, alkaline phosphatase (ALP), calcium, phosphate and creatinine, urinary calcium and phosphate and mineralometry were measured. PTH, 25OHD and urinary calcium increased significantly from baseline values after 2 months of therapy, while 1,25OHD and ALP did not change during treatment. All these parameters returned to pretreatment levels 1 month after discontinuation of licorice. PRA and aldosterone were depressed during therapy, while blood pressure and plasma cortisol remained unchanged. CONCLUSIONS: licorice can increase serum PTH and urinary calcium levels from baseline value in healthy women after only 2 months of treatment. The effect of licorice on calcium metabolism is probably influenced by several components of the root, which show aldosterone-like, estrogen-like and antiandrogen activity.     

The nature and role of disturbances in calcium metabolism in genetic hypertension

Abnormalities in Ca metabolism in genetic hypertension have been suggested by studies of the spontaneously hypertensive rat and of humans with essential hypertension. A state of relative Ca deficiency in genetic hypertension was previously hypothesized to explain the reduced serum ionized Ca, increased serum parathyroid hormone levels, and the association between oral Ca loading and mild reduction in blood pressure. Renal Ca leak, reduced intestinal Ca absorption, and diminished Ca intake were further postulated to account for the Ca deficient state. This hypothesis, however, is not supported by the following lines of evidence in genetic hypertension: the absence of fasting hypercalciuria owing to intrinsic tubular defects, increased net Ca absorption in vivo despite greater Ca retention before and during established hypertension, increased intracellular free Ca concentrations, the failure to aggravate the hypertension by 50% reduction in dietary Ca intake, and the failure to ameliorate the hypertension by maneuvers that augment Ca balance (parenteral Ca administration, a high Mg diet, and 1,25-dihydroxyvitamin D3 injections). The available literature may be explained by the alternative hypothesis that genetic hypertension is characterized by generalized membrane defects in Ca regulation, resulting in a relative increase in cytosolic free Ca. The mechanism (or mechanisms) and physiological consequences of the disturbances in Ca homeostasis, however, remain to be defined.     

Calcium supplementation does not alter lipid oxidation or lipolysis in overweight/obese women

Based on cell culture and studies in mice, increased dietary calcium appears to stimulate lipolysis and could possibly reduce body adiposity through hormonal influences on adipocyte calcium uptake. In this study, we investigated the effects of 1,500 mg supplemental calcium daily for 3 months on hormones regulating calcium and energy metabolism and rates of lipid oxidation and lipolysis in overweight women. Fifteen overweight (BMI > 25 kg/m(2)) premenopausal women were supplemented with 1,500 mg of calcium, as CaCO(3), per day for 3 months while maintaining their usual diets and activity levels. Baseline and endpoint measurements were obtained after the subjects consumed a standardized 25% fat diet for 4 days. Lipid oxidation was measured by indirect calorimetry, lipolysis by infusion of deuterated glycerol, and body fat by dual-energy X-ray absorptiometry. Urinary calcium, circulating levels of hormones involved in energy and lipid metabolism (insulin, leptin, and adiponectin) or calcium metabolism (25(OH)D, 1,25(OH)(2)D), and parathyroid hormone (PTH)) were also measured. Urinary levels of calcium (P = 0.005) increased and 1,25(OH)(2)D declined (P = 0.03). However other parameters, including body weight, body fat, PTH, insulin, leptin, adiponectin, 25(OH)D, as well as rates of lipid oxidation and lipolysis were not altered by calcium supplementation. Calcium supplementation for 3 months increased urinary calcium excretion, decreased circulating levels of 1,25(OH)(2)-D, but had no effect on rates of lipid oxidation or lipolysis, in these overweight women.     

The effects of fasting and refeeding on serum parathormone and calcitonin concentrations in young and old male rats.

Although fasting and refeeding reveal the existence of age-related changes in carbohydrate and lipid metabolism, the effects of aging on mineral metabolism in refed animals are unknown. We therefore investigated hormonal regulation of calcium metabolism in young (4 months) and old (26 months) male rats fasted for 48 hours and then refed for 4 or 24 hours. Serum concentrations of total and ionized calcium and parathormone were similar in control young and old rats. Serum calcitonin level was higher, and the concentrations of albumin and inorganic phosphate and alkaline phosphatase activity were lower in fed old rats. In young fasted rats, the serum ionized and total calcium was decreased, and phosphate concentration was increased. In old rats, fasting resulted in the increase of serum parathormone level. Fasting reduced serum alkaline phosphatase activity to a similar extent in both age groups. In young rats, refeeding for 24h normalized serum calcium and phosphate levels and alkaline phosphatase activity, and decreased serum concentrations of PTH and calcitonin. In old refed rats, serum calcitonin concentration was raised by 77% compared to fed or fasted animals, whereas parathormone levels were normalized. Our results indicate that old fasted or refed rats maintain normal serum calcium concentration in a different way than young animals, possibly through the increase in serum levels of parathormone and/or calcitonin. Thus, dietary manipulations such as fasting and refeeding constitute an interesting model for the investigation of the effects of aging on the hormonal regulation of serum calcium level.     

The lack of relationships between vitamin D3 metabolites and calcium-binding protein in the eggshell gland of laying birds

The relationship of the metabolism of vitamin D3 and calcium-binding protein (CaBP) to calcium transport by the eggshell gland (ESG) was assessed in chickens. Plasma or ESG 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) and ESG CaBP were no different between periods of ESG inactivity and of shell calcification. A severe dietary calcium deficiency resulted in increased kidney 25-hydroxycholecalciferol-1-hydroxylase activity (542%), plasma and ESG 1,25(OH)2D3 concentrations (193 and 274%, respectively), but in decreased ESG CaBP (34%), associated with the production of poorly calcified eggs. Significant correlations were found between 25 hydroxycholecalciferol-1-hydroxylase, plasma 1,25(OH)2D3 and ESG 1,25(OH)2D3, but not between ESG 1,25(OH)2D3 and CaBP. Hens with a low shell density had a significantly lower (55%) ESG CaBP than those with high shell density, without any significant change in ESG 1,25(OH)2D3. Significant correlations were found between ESG CaBP and shell calcium. Total receptors for 1,25(OH)2D3 were lower in ESG than in the intestine. The results suggest that CaBP level and calcium transport in the ESG are not regulated by 1,25(OH)2D3.     

Salt-induced hypertension in WKY rats: Prevention by α-lipoic acid supplementation

There is strong evidence that points to excess dietary salt as a major factor contributing to the development of hypertension. Salt sensitivity is associated with glucose intolerance and insulin resistance in both animal models and humans. In insulin resistance, impaired glucose metabolism leads to elevated endogenous aldehydes which bind to vascular calcium channels, increasing cytosolic [Ca²⁺]_i and blood pressure. In an insulin resistant animal model of hypertension, spontaneously hypertensive rats (SHRs), dietary supplementation with lipoic acid lowers tissue aldehydes and plasma insulin levels and normalizes blood pressure. The objective of this study is to examine the effects of a high salt diet on tissue aldehydes, cytosolic [Ca²⁺]_i and blood pressure in WKY rats and to investigate whether dietary supplementation with lipoic acid can prevent a salt induced increase in blood pressure. Starting at 7 weeks of age, WKY rats were divided into three groups of six animals each and treated for 10 weeks with diets as follows: WKY-normal salt (0.7% NaCl); WKY-high salt (8% NaCl); WKY-high salt + lipoic acid (8% NaCl diet + lipoic acid 500 mg/Kg feed). At completion, animals in the high salt group had elevated systolic blood pressure, platelet [Ca²⁺]_i, and tissue aldehyde conjugates compared with the normal salt group and showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. Dietary -lipoic acid supplementation in high salt-treated WKY rats normalized systolic blood pressure and cytosolic [Ca²⁺]_i and aldehydes in liver and aorta. Kidney aldehydes and renal vascular changes were attenuated, but not normalized.     

Effects of chronic dietary salt loading on the renin angiotensin and adrenergic systems of rainbow trout (Oncorhynchus mykiss)

Previous studies have demonstrated that chronic dietary salt loading causes hypertension and a decreased sensitivity of the systemic vasculature to α-adrenergic stimulation and other hypertensive stimuli (e.g. hypercapnia) in rainbow trout (Oncorhynchus mykiss). This reduced sensitivity to hypertensive stimuli is consistent with a possible blunting of homeostatic responses normally aimed at raising blood pressure. To test this idea, we examined the consequences of long-term salt feeding and the associated hypertension on the interactive capacities of the renin angiotensin system (RAS) and adrenergic systems to elevate blood pressure in trout. Secretion of catecholamines in response to a range of doses of homologous ANG II in vivo and in situ (using a perfused posterior cardinal vein preparation) was reduced in the salt-fed fish. The reduced sensitivity to ANG II could not be explained by alterations in stored catecholamine (adrenaline or noradrenaline) levels or the general responsiveness of the chromaffin cells to depolarizing stimuli (60 mmol/l KCl). Despite the decreased responsiveness of the chromaffin cells to ANG II, plasma catecholamines were increased to a greater extent in the salt-fed fish during acute hypoxia (a condition that activates the RAS). Interestingly, the pressor effects of ANG II in vivo were actually heightened in the salt-fed fish. The increased pressor response to exogenous ANG II was likely attributable to its direct interaction with vascular ANG II receptors because the effect persisted even after blockade of α-adrenergic receptors. Treating fish with the vascular smooth muscle relaxant papaverine caused similar reductions in blood pressure and increases in plasma ANG II levels regardless of diet. Similarly, inhibition of angiotensin converting enzyme with lisinopril reduced blood pressure equally in control and salt-fed fish. These results indicate that, while long-term dietary salt loading blunts the response of trout chromaffin cells to ANG II, the RAS itself appears to be unaffected. Indeed, the capacity of ANG II to elevate blood pressure is not compromised nor do fish exhibit a reduced capacity to mount an acute humoral adrenergic stress response during acute hypoxia.     

Dietary lipoic acid supplementation attenuates hypertension in Dahl salt sensitive rats

There is strong evidence that excess dietary salt (NaCl) is a major factor contributing to the development of hypertension. Salt sensitive humans and rats develop hypertension even on a normal salt diet. Salt sensitivity is associated with glucose intolerance and insulin resistance in both humans and animal models, including Dahl salt sensitive (DSS) rats. In insulin resistance, impaired glucose metabolism leads to elevated endogenous aldehydes. These aldehydes bind sulfhydryl groups of membrane proteins, altering calcium channels, increasing cytosolic free calcium ([Ca²⁺]_i) and blood pressure. Treatment with lipoic acid, an endogenous sulfur-containing fatty acid, normalizes insulin resistance and lowers tissue aldehyde conjugates, cytosolic [Ca²⁺]_i, and blood pressure in spontaneously hypertensive rats (SHR). The objective of this study was to investigate the effects of a normal salt diet on tissue aldehyde conjugates, cytosolic [Ca²⁺]_i and blood pressure in DSS rats and to determine whether lipoic acid supplementation prevents the increase in blood pressure and biochemical changes. Starting at 7 weeks of age, DSS rats were divided into three groups of six animals each and treated for 6 weeks with diets as follows: DSS-low salt, 0.4% NaCl; DSS-normal salt, 0.7% NaCl, and; DSS-normal salt + lipoic acid, 0.7% NaCl + lipoic acid 500 mg/kg feed. At completion, animals in the normal salt group had elevated systolic blood pressure, cytosolic [Ca²⁺]_i and tissue aldehyde conjugates as compared to the low salt group. They also showed smooth muscle cell hyperplasia in small arteries and arterioles of the kidney. Dietary lipoic acid supplementation attenuated the increase in systolic blood pressure and associated biochemical and histopathological changes.     

Nitrendipine and other calcium entry blockers (calcium antagonists) in hypertension

Nitrendipine is a calcium antagonistic 1,4-dihydropyridine derivative with a pronounced antihypertensive activity in animal experiment. Similar to other calcium entry blockers, nitrendipine decreases blood pressure by lowering the elevated peripheral vascular resistance. However, its long-term effect differs from that of vasodilators such as hydralazine and minoxidil. In contrast to vasodilators, nitrendipine reduces heart hypertrophy in various forms of experimental hypertension in rats. Nitrendipine is highly effective in normalizing blood pressure, reducing heart hypertrophy, and preventing mortality in salt-related hypertension (two-kidney renal hypertension, salt-induced hypertension in Dahl rats), which are rather refractory to the effect of vasodilators. Nitrendipine reduces renovascular resistance in spontaneously hypertensive rats but has no effect on that of normotensive rats. In conscious renal hypertensive dogs, nitrendipine decreases blood pressure more than does hydralazine. The reflex tachycardia is more pronounced after hydralazine than after nitrendipine; blood pressure decrease is greater and the duration of the effect is longer than that of nifedipine. Nitrendipine is thus predicted as an effective drug for antihypertensive monotherapy.     

The dissociation between the plasma levels of aminopeptidases A and B in spontaneously hypertensive rats

We performed a longitudinal study for 20 weeks on spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKR) to determine the relationship between peptide metabolism and the age-dependent increase in blood pressure. In both SHR and WKR, the plasma level of aminopeptidase A (AP-A) clearly showed an age-dependent decrease. The plasma level of aminopeptidase B paralleled that of AP-A in WKR, but such an age-dependency was not observed in SHR, thus showing a dissociation between the two aminopeptidases. With age in both strains, the level of angiotensin-converting enzyme tended to decrease, while that of kallikrein activity tended to increase. In addition to these findings, a multivariate study testing the relationship of blood pressure to these enzyme activities, as well as to plasma levels of angiotensin I and renin activity, suggested abnormalities in the networks of proteolytic enzymes and in the peptide metabolism surrounding the renin-angiotensin system in SHR. These abnormalities may play some important roles in pathophysiological mechanisms of hypertension in SHR.     

Induced changes in the affinity of 1,25-dihydroxyvitamin D3 receptors in chick intestine

The contents of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in plasma and intestinal mucose were increased by dietary calcium and by dietary phosphorus restriction. The concentration of intestinal occupied receptors for 1,25(OH)2D3 was higher in calcium-restricted birds. The affinity (association constant) of intestinal receptors for 1,25(OH)2D3 was lower in phosphorus-restricted chicks, as compared to control or calcium-restricted chicks. The number of binding sites were not influenced by dietary calcium or phosphorus restriction.     

Suppression of renin secretion by propranolol in salt-depleted dogs

d, 1-propranolol was infused into salt-depleted, conscious dogs at two dosages: 1 mg/kg followed by 0.60 ? 0.67 mg/kg/hr, and 5 mg/kg followed by 1.57 ? 1.76 mg/kg/hr. At both dosages, propranolol decreased plasma renin activity (PRA), plasma aldosterone concentration, and heart rate significantly. Renin substrate concentration remained unchanged. PRA was suppressed with the higher dosage but not with the lower dosage, to values found with dietary salt loading. Mean arterial blood pressure (MABP) remained unchanged with the low-dose infusions, but decreased significantly with the high-dose infusions. The data suggest that the mechanism(s) for the increase in PRA with low-salt diets is sensitive to propranolol and that the effect of propranolol on MABP is dependent on the salt intake and on the dose administered.     

Relevance of Salt,Water, and Renin to Hypertension in Chronic Renal Failure

Blood pressure control was examined in 75 patients with end-stage renal failure treated by regular twice-weekly haemodialysis. Dietary sodium was restricted and extracellular fluid was removed by ultrafiltration until blood pressure was normal or signs of salt depletion were observed. Failure of these measures constituted an indication for nephrectomy. Of the 75 patients, 18 were never hypertensive, 46 had hypertension which could be corrected by salt and water depletion, and 11 had persistent hypertension which could not be controlled in this way. Nine of these 11 patients underwent bilateral nephrectomy; in each of the seven in whom the post operative result could be evaluated the blood pressure returned rapidly to normal.Plasma renin activity, measured in 34 subjects, was raised above normal in six out of nine patients whose blood pressure could not be controlled by salt and water depletion and in one of the 11 patients whose blood pressure could be so controlled, but was within the normal range in all nine normotensive patients. The mean level of plasma renin activity in the first group was significantly higher than that of each of the other two groups.There was a significant correlation between hypertension during dialysis and after transplantation, suggesting that, in addition to renin, there is a non-renal factor which predisposes certain patients to hypertension in the presence of salt and water excess.