(Hypertension. 1997;29:531.)
© 1997 American Heart Association, Inc.
State-of-the-Art-Lecture |
Oral Calcium Supplementation Reduces Intraplatelet Free Calcium Concentration and Insulin Resistance in Essential Hypertensive Patients
From the Hypertension Unit, Departments of Internal Medicine and Nephrology (E.P.), Hospital Clínic, University of Barcelona, Spain.
Correspondence to Alejandro de la Sierra, MD, Hypertension Unit, Department of Internal Medicine, Hospital Clínic, Villarroel 170, 08036-Barcelona, Spain. E-mail iserte{at}medicina.ub.es
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Abstract |
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We evaluated the effect of oral calcium supplementation on blood pressure, calcium metabolism, and insulin resistance in essential hypertension. After receiving a standard diet with 500 mg of calcium per day during a 4-week period, 20 nondiabetic, essential hypertensive patients were randomized in a double-blind fashion to receive oral calcium supplementation (1500 mg of calcium per day) or placebo for 8 weeks. At the end of the 4-week period of low-calcium diet and after the 8-week period of intervention, we measured blood pressure (by both office and 24-hour ambulatory blood pressure monitoring), calcium-regulating hormones [urinary hydroxyproline and serum osteocalcin, parathormone, and 1,25(OH)2-vitamin D3], intra-platelet free calcium concentration, fasting plasma glucose and insulin levels, and the insulin-sensitivity index (euglycemic-hyperinsulinemic clamp). Compared with patients maintained at low calcium intake, essential hypertensive patients under oral calcium supplementation significantly reduced serum osteocalcin (from 22.2±1.9 to 17.9±2.0 µg/L; P=.0015), parathormone (from 4.20±0.38 to 3.30±0.36 pmol/L; P=.0003), and 1,25(OH)2-vitamin D3 (from 98.0±11.0 to 61.6±5.7 pmol/L; P=.0062). Likewise, we found a significant reduction in intraplatelet free calcium concentration (from 35.9±1.2 to 26.5±0.8 nmol/L; P=.0005) and fasting plasma insulin levels (from 71.8±5.9 to 64.6±6.2 pmol/L; P=.05) and a significant increase in the insulin-sensitivity index (from 2.89±0.77 to 4.00±0.95 mg·kg-1·-1; P=.0007). None of these parameters were significantly modified in patients maintained at low calcium intake. Office and 24-hour mean values of systolic and diastolic blood pressure did not change after 8 weeks of oral calcium supplementation or placebo.
Key Words: calcium, dietary • calcium supplements • intracellular free calcium • insulin resistance • hypertension
Abbreviations: ABPM = ambulatory blood pressure monitoring • BP = blood pressure • DBP = diastolic blood pressure • Fura 2-AM = Fura 2-acetoxymethylester • HBS = HEPES-buffered saline • PRP = platelet-rich plasma • SBP = systolic blood pressure
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Introduction |
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Epidemiological studies have demonstrated an inverse relationship between dietary calcium intake and BP,1–3 suggesting that supplemental dietary calcium may lower BP. A recent review of these evidences4 indicates a moderate effect of calcium supplementation on BP.
Essential hypertension is associated with increased calcium concentration in several cell types.5–7 In animal models with experimental hypertension,8–10 calcium supplementation leads to a decrease in intracellular calcium, which is postulated as one of the mechanisms of the BP fall. Furthermore, in black hypertensive patients, it has been reported that high calcium intake prevents the increase in intracellular calcium promoted by a high salt diet.11
Several studies have demonstrated the existence of some degree of insulin resistance and/or hyperinsulinemia in patients with essential hypertension and an inverse relation between BP and insulin-mediated glucose disposal.12,13 An important relationship is likely to exist between alterations in intracellular calcium metabolism, insulin resistance, and hypertension.14 There are several data suggesting that "optimal" levels of intracellular free calcium concentration are necessary for maximal cellular action of insulin.15,16 The increased intracellular calcium content reported in essential hypertension might affect insulin action in muscle cells, since it is partially responsible for insulin resistance.16 Therefore, it could be speculated that the expected reduction in intracellular calcium induced by oral calcium supplementation could improve cellular insulin metabolism and partially correct insulin resistance.
Based on these considerations, the aim of the present study was to analyze the effect of oral dietary calcium supplementation on BP, calcium metabolism, and intra-platelet free calcium concentration, as well as on insulin sensitivity, in essential hypertensive patients.
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Methods |
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Patient Selection
Twenty previously untreated, mild-to-moderate essential hypertensive patients (12 men and 8 women) aged 25 to 56 years old (mean±SEM, 44.6±8.3 years) were consecutively recruited from the Hypertension Unit of the Hospital Clinic, Barcelona, Spain. The diagnosis of essential hypertension was considered on the basis that no known cause of high BP could be detected after complete clinical, biochemical, and radiological examination. None of the patients had renal impairment, papilloedema, or evidence of cardiac failure or coronary or cerebrovascular diseases. Patients with a definite diagnosis of diabetes mellitus or those with an abnormal oral glucose tolerance test were excluded form the study. All patients had at least three office BP measurements >140/90 mm Hg after 4 weeks of an unrestricted salt diet and without antihypertensive medication.
Study Protocol
The study was approved by the Ethics Committee of the hospital, and written informed consent was obtained from all participants. A low-calcium diet containing 
500 mg of calcium per day was given to all patients for 4 weeks. The dietary advice was prepared by an expert dietitian and was basically achieved by eliminating dairy products. Patients were visited weekly at the Hypertension Unit, office SBP and DBP were measured, and compliance with the diet was assessed by means of direct interview. Patients were advised to keep their intake of calories, salt, and alcohol, as well as their exercise level, constant for the whole study period.
At the end of this run-in period, patients were randomized in a double-blind fashion to receive placebo tablets (n=10) or calcium tablets (n=10) (Calcium Sandoz; Sandoz Pharma; 1500 mg/d) for an 8-week period, in addition to the same basal lowcalcium diet.
The last day of both run-in and intervention periods, BP was measured by 24-hour ABPM. Serum and 24-hour urinary calcium and phosphate, calcitropic hormones [urinary hydroxyproline, serum osteocalcin, parathormone, and 1,25(OH)2-vitamin D3], plasma glucose, and plasma insulin levels were measured. Intraplatelet free calcium concentration was measured by the FURA-2 technique, and the insulin sensitivity index was estimated by the euglycemic-hyperinsulinemic clamp technique.
Blood Pressure Measurements
Office BP Measurement
Every week throughout the study, a mercury-in-glass sphygmomanometer was used to measure BP three times in succession at 3-minute intervals, after a 10-minute rest in the sitting position, with the arm supported on a cushion and the cuff at heart level. SBP was recorded at the appearance of the Korotkoff sounds (phase I) and DBP at their disappearance (phase V). BP values were estimated as the mean of the three readings. All measurements were performed by the same nurse using the same manometer.
Noninvasive 24-Hour ABPM
Twenty-four-hour ABPM was performed using an automated, noninvasive, oscillometric device (SpaceLabs 90207, SpaceLabs Inc). The appropriate cuff was placed on the nondominant arm, and BP was registered automatically at 15-minute intervals for a 24-hour period. Mean values and standard deviation of SBP and DBP were obtained from each record in the 24-hour period.
Measurement of Platelet Calcium Concentration
Twenty milliliters of venous blood was drawn into 20% (vol/vol) citrate-dextrose solution (containing 2.5 g sodium citrate, 1.5 g citric acid, 2.0 g dextrose in 100 mL distilled water) and was centrifuged at 200g for 10 minutes at 20°C to obtain the PRP. The PRP was centrifuged at 500g for 20 minutes at 20°C in the presence of (50% vol/vol) adenosine (0.28 g/dL) and theophylline (1 g/dL) dissolved in CCD, and the pellet was resuspended in HBS containing: NaCl 145 mmol/L, KCl 5 mmol/L, MgCl2 1 mmol/L, glucose 6 mmol/L, HEPES 10 mmol/L, and bovine serum albumin 0.2 mg/mL. The pH was adjusted to 7.4 at 37°C. The platelet suspension was incubated for 35 minutes at 37°C in a shaking water bath with 2 mmol/L Fura 2-AM. The labeled platelets were washed by centrifugation and resuspension in HBS, adjusting platelet count to 0.5x108/mL with a Technikon H-1 system Coulter counter (Technikon Instruments Corp). After an equilibration period of 15 minutes at 37°C in the presence of 1 mmol/L of CaCl2, 2 mL of the platelet suspension was placed in a quartz cuvette for fluorescence measurements, which were carried out in a Hitachi F-2000 spectrofluorometer (Hitachi Ltd). The fluorescence signal was obtained once every second with alternate excitation wavelengths (nm), and platelet cytosolic calcium concentration ([Ca]i) was estimated by the ratio of the excitation wavelengths 340/380. The emission wavelength was 510 for Fura-2.
For calculation of [Ca]i, the relationship between fluorescence ratio at 340/380 (R) and [Ca2+]i was obtained using the equation17
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Measurement of Insulin Resistance
The studies were carried out on the last day of both the run-in and intervention periods, beginning at 8:30 AM after an overnight fast (10 to 14 hours), with the subjects lying supine in a quiet room with a constant temperature of 21°C. Polyethylene cannulas were inserted into an antecubital vein (for infusion of test substances) and retrogradely into a wrist vein surrounded by a heated (70°C) box (for blood sampling). Use of the box ensures arterialization of venous blood within 20 to 40 minutes.18
Insulin sensitivity was assessed with the use of the euglycemichyperinsulinemic clamp technique.19 Briefly, a primed constant infusion of insulin (Actrapid HM, Novo Industries) was administered for 120 minutes at a rate of 40 mU per square meter of body-surface area per minute to achieve hyperinsulinemia (an insulin level of 100 µU/mL [700 pmol/L]). Plasma glucose concentration was held constant at baseline by a variable-rate infusion of exogenous glucose, which was adjusted on the basis of frequent blood glucose measurements. The amount of glucose required to maintain isoglycemia equals whole-body disposal of glucose, provided that endogenous glucose production is essentially absent. The quantity of glucose infused during the final 60 minutes, corrected for body-surface area, provided an index of the insulin sensitivity of the whole body (expressed in terms of the number of milligrams of glucose infused per kilogram of body weight per minute).
Blood samples were obtained during the baseline period and then every 20 minutes until the end of the study.
Plasma glucose was assayed by the glucose oxidase method (Beckman Glucose Analyzer, Beckman Instruments). Serum insulin concentrations were determined by radioimmunoassay.
Statistical Analysis
Values are expressed by their mean±SEM. Differences between groups at baseline and at the end of the treatment period were analyzed by means of nonparametric Mann-Whitney and Wilcoxon tests. The relationship between intracellular calcium and insulin sensitivity at baseline was examined by means of nonparametric Spearman’s rank correlation coefficient. The statistical analysis was performed with the aid of the BMDP Statistical Package.
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Results |
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At the end of the 4-week period of low calcium diet, no significant differences were observed between patients randomized to placebo (n=10) or calcium supplementation (n=10) in any of the parameters studied (Tables 1 and 2
). In the entire group of essential hypertensive patients, we observed a significant inverse relationship between platelet free calcium concentration and insulin sensitivity index (Spearman’s rank correlation coefficient, -.5253; P<.05). Conversely, baseline values of calcitropic hormones did not correlate with insulin sensitivity.
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BP Changes Induced by High Calcium Intake
Table 3 shows mean values (±SEM) of office SBP and DBP at 2-week intervals throughout the study. No significant changes were observed in patients receiving oral calcium supplementation with respect to the placebo group.
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Table 1 shows mean values (±SEM) of 24-hour SBP and DBP at the end of the run-in and double-blind periods in both groups of patients studied. Compared with the placebo group, no significant changes in 24-hour SBP or DBP were observed in patients receiving calcium supplementation.
Changes in Calcium Metabolism Induced by High Calcium Intake
Table 1 also shows mean values of the different calcium metabolism parameters studied in both placebo and calcium groups at baseline and at the end of the intervention period. Both serum and urinary calcium and phosphate and urinary hydroxyproline were not modified in the two groups. Conversely, compared with the placebo group, oral calcium supplementation promoted a decrease in serum osteocalcin (from 22.2±1.90 to 17.9±2.0 µg/L; P=.0015), serum parathormone (from 4.20±0.38 to 3.30 ±0.36 pmol/L; P=.0003), and 1,25(OH)2-vitamin D3 (from 98.0±11.0 to 61.6±5.7 pmol/L; P=.0062).
Changes in Intraplatelet Calcium Content Induced by High Calcium Intake
Fig 1 shows individual values of the intraplatelet free calcium concentration before and after double-blind treatment in both placebo and calcium groups. Compared with patients maintained at low calcium diet, high calcium intake promoted a significant decrease in mean values of the intraplatelet free calcium concentration (from 35.9±1.2 to 26.5±0.8 nmol/L; P=.0005) (Table 2).
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Changes in Glucose Metabolism Induced by High Calcium Intake
Fig 2 shows individual changes in the insulin sensitivity index in both placebo and calcium groups. Compared with patients maintained on a low calcium diet, oral calcium supplementation significantly increased the insulin sensitivity index (from 2.89±0.77 to 4.00±0.95 mg·kg-1. min-1; P=.0007) (Table 2). As is also shown in Table 2, this increase in the insulin sensitivity index was accompanied by a decrease in fasting plasma insulin (from 71.8±5.9 to 64.6±6.2 pmol/L; P=.05). Finally, fasting plasma glucose was not significantly affected by the level of calcium intake.
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Discussion |
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The present study shows that a short period (8 weeks) of high calcium intake (
2 g/d) reduces intraplatelet free calcium concentration and positively affects glucose metabolism, increasing insulin sensitivity and decreasing fasting plasma insulin, although to a lesser extent. None of these parameters were significantly affected in patients maintained on a low calcium intake (500 mg/d). Several epidemiological studies have demonstrated an inverse relationship between calcium consumption and BP.1–3 Calcium intake in populations at high risk for hypertension, including the elderly and blacks, is usually low. However, interventional studies using calcium supplementation have shown inconsistent results. In 1985, McCarron and Morris20 reported a significant reduction in SBP and DBP in essential hypertensive patients treated with calcium supplements, although the effect in normotensive controls was negligible. A recent meta-analysis of studies conducted in normotensive and hypertensive populations concludes that oral calcium supplementation has a modest effect on SBP but not on DBP.4 Nevertheless, in the present study we did not observe any significant effect of calcium on BP, assessed by means of either weekly office measurements or 24-hour ABPM. It is important to note that this lack of effect of calcium supplementation on BP may be influenced by the well-known heterogeneity of the hypertensive population. In this sense, salt-sensitive patients with low-renin hypertension are more prone to have a calcium-deficient state and, consequently, to respond to oral calcium supplementation with a fall in BP, whereas salt resistance with normal or high-renin hypertension does not respond to changes in calcium intake.21,22
Several mechanisms have been proposed to explain the antihypertensive effect of calcium. These include a natriuretic effect,23 a decrease in calcium-regulating hormones24,25 (which may have a vasoactive effect), and a decrease in intracellular free calcium concentration,8–11 which induces vasorelaxation.
Calcium-regulating hormones are sensitive to changes in dietary calcium consumption and serum ionized calcium. It has been demonstrated that the reduction of dietary calcium increases plasma levels of parathormone,26,27 calcitriol [1,25(OH)2-vitamin D3],26,28 osteocalcin,28 and the urinary excretion of hydroxyproline.27,28 On the other hand, the increase in dietary calcium reduces parathormone24,25 and calcitriol.26 There is emerging evidence that these hormones may play a role in BP regulation. It has been reported that parathormone may increase calcium entry in heart cells,29 and increased levels of this hormone have been found in essential hypertensive patients.30 Moreover, calcitriol has been shown to enhance contractile properties in resistance arteries of both normotensive and hypertensive animals,31 and increased plasma levels have also been found in essential hypertensive patients.30 In our study, we have observed a significant decrease in both parathormone and calcitriol in patients receiving oral calcium supplementation. However, on the basis of the present evidence, a relationship between the decrease in the plasma levels of these hormones and intraplatelet free calcium concentration is merely speculative.
Increased intracellular free calcium concentration is a common feature in essential hypertensive patients that has been proposed as the responsible mechanism of increased vascular peripheral resistance and BP.5–7 Oshima et al8 reported that calcium supplementation in stroke-prone spontaneously hypertensive rats decreased intracellular free calcium concentration in both circulating platelets and lymphocytes. Furthermore, in black hypertensive patients, it has been reported that high calcium intake prevents the increase in intracellular calcium promoted by high salt diet.11 Our results are in agreement with those previously reported. Essential hypertensive patients treated with oral calcium supplementation decreased intraplatelet free calcium concentration in 25% of their basal values, whereas patients receiving placebo did not exhibit any significant change. As shown in Fig 1, intraplatelet calcium decreased in all but one patient treated with calcium supplements.
The existence of a relationship between intracellular calcium concentration and insulin metabolism has been proposed.14 In experimental studies, insulin-mediated glucose transport is affected by increasing the intracellular level of calcium.15,16 Furthermore, hypertensive non-insulin-dependent diabetics, who are insulin resistant, exhibit a reduction in Ca2+-ATPase and an increase in intracellular calcium compared with nondiabetic hypertensives.32 This relationship has been confirmed in the present work. We have observed a correlation between intraplatelet free calcium concentration and insulin sensitivity index in the entire group of hypertensive patients studied after a 4-week period of low calcium diet. Furthermore, we hypothesized that reducing intraplatelet calcium would affect insulin metabolism. Our results confirmed this hypothesis. In fact, the reduction of intraplatelet calcium achieved with oral calcium supplementation was associated with an increase in the insulin sensitivity index and a decrease in plasma fasting insulin levels. None of these parameters were affected in patients maintained at low calcium intake, who did not reduce intraplatelet calcium. These results are in agreement with those obtained by Resnick and Laragh.33 Those authors observed that patients who presented a fall in BP after 1 month of oral calcium supplementation exhibited an amelioration of carbohydrate metabolism with both a decrease in the area under the curve of glucose and an increase in the insulin response after an oral glucose tolerance test.
In conclusion, oral calcium supplementation reduces intraplatelet calcium concentration, even without a significant effect on BP, assessed by means of 24-hour ABPM. This reduction in intraplatelet calcium is associated with a reduction in the insulin resistance and in circulating fasting plasma insulin levels.
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