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(Hypertension. 1997;30:1289-1294.)
© 1997 American Heart Association, Inc.

Articles

Association of Calcitriol and Blood Pressure in Normotensive Men

Estela Kristal-Boneh; Paul Froom; Gil Harari; Joseph Ribak

From the Occupational Health and Rehabilitation Institute (E.K.-B., P.F., G.H., J.R.), Raanana, and the Sackler Faculty of Medicine (P.F., J.R.), Tel Aviv University, Tel Aviv, Israel.

Correspondence to Dr E. Kristal-Boneh, Occupational Health and Rehabilitation Institute, POB 3, Raanana 43100, Israel.

	Abstract

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Abstract The purpose of this study was to clarify the possible associations between the serum 1,25-dihydroxyvitamin D (calcitriol) level and blood pressure. Cross-sectional analysis of data was performed. Data collected included levels of serum calcitriol, parathyroid hormone, serum calcium, and blood lead; blood pressure; dietary history; and demographic and anthropometric variables. One hundred normotensive male industrial employees made up the study population. Systolic blood pressure and diastolic blood pressure were main outcome measures. After possible confounders were controlled for, multivariate analyses yielded an inverse, independent, and statistically significant association between calcitriol level and systolic blood pressure (standardized ß=-0.2704, P=.0051). A similar trend of borderline significance was found for the association between calcitriol and diastolic blood pressure (standardized ß=-0.1814, P=.0611). Parathyroid hormone, serum calcium, and blood lead levels were not associated with blood pressure. When subjects were divided into four groups by calcitriol level, those in the lowest quartile showed significantly higher systolic and diastolic blood pressures than those in the upper quartile (difference=11 mm Hg, P=.007, and difference=4 mm Hg, P=.071, respectively). There is an inverse association between serum calcitriol level and blood pressure. This suggests that in addition to its role in calcium homeostasis, the active metabolite of vitamin D may play a role in determining blood pressure. The differences in both systolic and diastolic blood pressures between the upper and lower quartiles of serum calcitriol were substantial and may be of clinical significance.

Key Words: vitamin D • blood pressure • lead

	Introduction

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Studies conducted over the last decade have suggested that vitamin D may play a role in blood pressure regulation. Receptors for 1,25-dihydroxyvitamin D (calcitriol) have been found in target tissues closely connected with blood pressure regulation.^{1 2 3 4 5 6} There are also indications that hypo- and hypercalcemia affect blood pressure,⁷ and that in both cases, vitamin D metabolism may be involved. Inconclusive, inconsistent results have been obtained in studies of vitamin D metabolites and blood pressure: decreased⁸ and increased^{9 10} levels of calcitriol have been observed in hypertensive humans and in rat models,^{11 12} as have positive and negative associations between serum calcitriol and blood pressure.^{8 13 14} Furthermore, calcitriol has been found to suppress the in vitro secretion of PTH,¹⁵ which has been associated with blood pressure level.¹⁰ These works are of interest not only because of their possible implications for hypertension but also because they can clarify the physiological seasonal changes in blood pressure that are not completely explained by fluctuations in environmental temperature.¹⁶ Because vitamin D status is lowest¹⁷ and blood pressure is highest¹⁶ in winter, given an adequate dietary calcium intake, an inverse association between blood pressure and calcitriol may be expected.

We sought to determine the possible association between calcitriol and blood pressure in a cohort of healthy normotensive men.

	Methods

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Study Population
The study population consisted of industrial employees, some of whom were occupationally exposed to lead and some of whom were not exposed to lead or to any other nephrotoxic chemicals. All subjects performed similar physical work under similar environmental conditions in air-conditioned plants. All subjects in a single workstation were examined in order to prevent discrimination; however, not all fit our inclusion criteria of male sex, age 25 to 64 years, no history of chronic disease, at least 1 year of tenure, no use of medication (other than analgesics) during the month preceding data collection, and no engagement in other activity that involved the possibility of chemical exposure. We also excluded men with implausibly high or low total caloric intakes (800 to 4200 kcal/d). Every employee was offered the examination free of charge. The response rate was 95%. Complete data were available for 100 eligible subjects. Before their enrollment, all were informed about the risks and discomfort involved in participation in the project. It was explained that they were being asked to volunteer for research purposes only and that their sole compensation would be the receipt of the results of the medical tests carried out during the study. All participants signed an informed consent form, and they were able to withdraw from the study at any time they wished. The study was approved by the local Research on Human Subjects Committee (Lowenstein Hospital).

Study Design
The study was cross-sectional in design and was carried out on-site, on regular workdays. To account for possible seasonal effects on vitamin D levels and blood pressure, all data collection and blood sampling were carried out during the winter (January, February) and not after vacation. Blood samples were taken in a single day for 20 employees in a given workstation. Physical examinations were performed on different days, five subjects per day, together with the field tests and personal interview.

Measurements
Height and weight were measured between 6 and 9 AM, with the subject wearing only light industrial clothes and no shoes. Body weight was measured using the Seca electronic scale (Seca Alpha, model 770), accurate to 100 grams; Quetelet's index [weight (kg)/height (m)²] was used as a measure of BMI. Thereafter the subject was asked to remain in repose for 5 minutes while the technician completed the test form. With the subject still seated, four blood pressure measurements were performed using a mercury manometer (sphygmomanometer), accurate to within 2 mm Hg, with 1-minute intervals between measurements. The mean of the last three measurements was used in the analysis. The same technician performed all measurements.

The field test consisted of an examination of the working conditions by an expert hygienist.

Subjects were interviewed about health-related habits (peculiar to the winter), medical history, and demographic information. Smoking habits were determined by the replies to a comprehensive questionnaire. Daily dietary intake of calcium was estimated from a semiquantified food frequency dietary questionnaire (Flora's questionnaire), which included 112 food items; there was also space at the end of each food subgroup for additional (volunteered) information on foods consumed that were not listed. The food items used in the questionnaire had been shown to be those most frequently consumed (>80%) by our population in a more extensive quantified dietary survey covering 260 food items that had been applied in an earlier evaluation of the nutritional intake of a stratified random sample of Israelis.¹⁸ Participants reported how often, on average, over the present season they had eaten the specified portion of each food. We computed nutrient intake by multiplying the frequency of intake of each unit of food by the nutrient composition of the specified portion size. Several types of units were used to quantify portion size, such as standard units, commercial containers, and natural units such as fruits and vegetables. The interview was personal, conducted by a trained interviewer, and lasted about 40 minutes. The present methods were successfully used in a previous study.¹⁹

Venous blood samples were taken with the subject seated in a climate-controlled room before the beginning of a regular workday (between 7 and 9 AM), after a 10-hour fast (subjects were encouraged to drink water during the fasting period). The tourniquet was released immediately after blood began to enter the tube to avoid venostasis. The samples were placed in vacuum-type test tubes without additives and with lithium heparin (for measuring lead). Serum was separated from whole blood in the tubes without additive within 30 minutes of being drawn, and the tube for endocrine measurement was covered with tinfoil and stored at -20°C. Fresh serum samples were analyzed in the Kodak Ektachem Automated Clinical Chemistry Analyzer (Eastman Kodak Co). Total protein was estimated by the biuret method.²⁰ Albumin was determined by the bromcresol green method.²¹ Total calcium was determined by spectrophotometry.²² Blood samples were sent to Bio-Rad Laboratories for external control, and a satisfactory rating was obtained. In addition, every 3 months, samples were sent to the College of American Pathologists for control, and satisfactory ratings were obtained. Blood lead levels were measured by atomic absorption spectroscopy using a modification of the method described previously.²³ The coefficient of variation was 5%. Assay quality control was assured by participation in the UK National External Quality Assessment Schemes for clinical chemistry, with satisfactory results. Intact PTH levels were measured by a solid-phase, two-site chemiluminescent enzyme immunometric assay (Immulite intact PTH, Diagnostic Products Corp), with intra-assay and interassay coefficients of variation of 5.4% and 5.0%, respectively. Plasma levels of 25-OH-D and calciferol were measured by competitive protein-binding analysis (25-Hydroxyvitamin D ³H Radioimmunoassay Kit and 1,25-Dihydroxyvitamin D ³H Radioligand Receptor Assay Kit, Incstar Corp). Intra-assay and interassay coefficients of variation were 3.9% and 15.2%, respectively, for 25-OH-D and 6.9% and 6.9%, respectively, for calcitriol.

Ionized calcium was calculated as follows: total calcium–[8xalbumin (g/100 mL)+2xglobulin (g/100 mL)+3].

Statistical Analysis
Data analyses were carried out using the SAS software (SAS Institute Inc).²⁴ Calcitriol levels were categorized according to the distribution in the study population. Multiple linear regression analysis was used to test the association between calcitriol level and blood pressure after controlling for potential confounding variables: age, BMI, cigarette smoking, alcohol consumption, family history of hypertension, blood lead level, and engagement in sports activities. Blood lead levels were included in the model because of a possible association with both calcitriol level²⁵ and blood pressure.²⁶ Because blood lead concentrations are typically skewed, analysis was performed on the natural logarithm of blood lead.

Results were considered to be statistically significant at the level of 5%.

	Results

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Characteristics of the study population are given in Table 1. Variables in Table 1 were considered possible confounders and were included in the multivariate analyses.

View this table: [in this window] [in a new window]   Table 1. Characteristics of the Study Population

However, to avoid colinearity, the association between blood pressure and the independent variables that were highly correlated with calcitriol was explored in separate statistical models. Occupationally exposed subjects had blood lead levels higher than those of nonexposed subjects (Table 1). There were no differences between the groups in dietary history: 9% of subjects ate less than 50% of the RDA of calcium, 47% between 50% and 100% of the RDA, and 46% more than 100% of the RDA. Age was positively correlated with systolic blood pressure and BMI to both systolic and diastolic blood pressures. Age and BMI were not correlated to serum calcitriol (P>.2).

There was a statistically significant inverse correlation between serum calcitriol and systolic blood pressure (r=-.24, P=.0167, Fig 1); a similar trend of borderline significance was found for diastolic blood pressure (r=-.19, P=.0603).

View larger version (18K): [in this window] [in a new window]   Figure 1. Correlation between systolic blood pressure (SBP) and serum calcitriol levels.

The standardized coefficients and significance levels for the association between calcitriol and blood pressure after adjustment for possible confounders are given in Table 2. There was an inverse, independent and statistically significant association between calcitriol level and systolic blood pressure (standardized ß=-0.2704, P=.0051) and a similar trend of borderline statistical significance for the association between calcitriol and diastolic blood pressure (standardized ß=-0.1814, P=.0611). Age was significantly associated with systolic blood pressure. BMI was positively associated with both systolic and diastolic blood pressures.

View this table: [in this window] [in a new window]   Table 2. Association Between Calcitriol and Systolic and Diastolic Blood Pressures

Blood lead level was not associated with blood pressure. A possible interaction between blood lead and calcitriol that affected blood pressure was tested in a different statistical model (not shown). No such interaction was found. When the association between calcitriol and blood pressure was tested further in separate statistical models for the subjects who were occupationally exposed to lead and those who were not, results for both groups were consistent with the results for the entire population (not shown).

PTH, serum calcium, and serum ionized calcium were highly correlated with calcitriol (r>.30, P<.05 for all parameters). Therefore, their association with blood pressure was further analyzed in four separate models to avoid colinearity with calcitriol. Univariate analyses yielded no association between PTH, 25-OH-D, serum calcium, or serum ionized calcium with systolic or diastolic blood pressure (P>.2 for all associations). This was also true for multivariate analyses, even when these factors were taken as covariates of calcitriol (P>.2 for the eight statistical models; data not shown in tables).

To further explore the association between calcitriol and blood pressure, calcitriol concentrations were divided into four categories according to the distribution in the study population. Blood pressure levels in the different categories of calcitriol are shown in Fig 2. Within each calcitriol quartile, analyses of the data after adjustment for BMI and age resulted in associations with systolic blood pressure, which were in the same direction as was found for the entire cohort (results not shown). The associations with systolic blood pressure reached statistical significance for three of the four quartiles. In a statistical model similar to that shown in Table 2, calcitriol (linear) was replaced by categorized calcitriol. After possible confounders were controlled for, a statistically significant dose-response was demonstrated for the association between calcitriol and systolic blood pressure (P=.007) and a borderline significance for the association between calcitriol and diastolic blood pressure (P=.071).

View larger version (24K): [in this window] [in a new window]   Figure 2. Blood pressure level at different quartiles of serum calcitriol. SBP indicates systolic blood pressure; DBP, diastolic blood pressure.

	Discussion

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The main finding of this study is an inverse association between calcitriol level and blood pressure in healthy normotensive men. There have been related studies of small groups of hypertensive persons,⁸ of 14 men with impaired glucose tolerance,²⁷ of postmenopausal women,¹³ and of hypertensive rat models.^{11 12} Our results are consistent with those reported for hypertensive humans⁸ and for spontaneously hypertensive rats^{11 12} and disagree with the results for postmenopausal women¹³ and hypertensive patients with low ionized calcium levels.^{9 10} One study of normotensive men showed an inverse association between calcitriol and blood pressure that did not reach statistical significance.¹⁴ The discordant results in studies of hypertensive humans may be because of the small sample sizes or the different clinical characteristics of the various cohorts. It is possible that in subjects with severe hypertension, calcitriol elevations are secondary to renal calcium leak with a compensatory increase in PTH. The sources of the inconsistency between our results and the study of Sowers et al¹³ of postmenopausal women are unclear. The levels of calcitriol we found were substantially higher than those reported by Sowers et al, although we would have expected them to be lower because our data were collected in the winter and the data of Sowers et al were collected from May to August. Our subjects were also of different ages and gender and all were normotensive, whereas some of theirs were under treatment for hypertension. When the postmenopausal women were divided by blood pressure status, there was no association with calcitriol. Finally, nutritional status and serum calcium status were not studied, and these may have explained the effects of calcitriol on blood pressure. These interstudy differences may also point to a differential relationship between indexes of calcium metabolism and blood pressure that are dependent on gender, as reported by Young et al⁸ for hypertensives.

There have been several intervention studies showing that treatment with alphacalcidiol, a synthetic analogue of calcitriol, without calcium supplementation has a hypotensive effect in patients with marginal/intermittent hypercalcemia,²⁸ mild primary hyperparathyroidism,²⁹ and impaired glucose tolerance (both normotensives and hypertensives).²⁷ However, the changes in blood pressure were significantly related to the changes induced by serum calcium and phosphate.²⁷ In another study by Resnick and Laragh,³⁰ an increase in blood pressure (accompanied by an increase in serum ionized calcium) after vitamin D administration was reported in low-renin hypertensive subjects, whereas a decrease in blood pressure was observed in high-renin hypertensive subjects. Thus, in the subjects who showed a positive association between vitamin D treatment and blood pressure measurements, a concomitant increase in serum ionized calcium could have explained the increase in blood pressure.

The hypotensive effects of calcitriol are further but indirectly supported by studies on the effects of ultraviolet radiation on blood pressure. A beneficial influence of a series of ultraviolet B irradiations on cardiovascular regulation was noted in 24 young, healthy men.³¹ In children, ultraviolet irradiation led to a gradual reduction in blood pressure after 24 hours that persisted for several days.²

There are several possible mechanisms underlying the effect of calcitriol on blood pressure. PTH has been found to be associated with an increase in blood pressure,^{9 32 33 34} and the parathyroid glands have receptors for calcitriol.³⁵ In vitro alphacalcidiol can suppress the secretion of PTH,¹⁵ suggesting that calcitriol may act on blood pressure indirectly by reducing the circulatory level of PTH. However, we did not find an association between PTH and blood pressure. Calcitriol has also been reported to suppress plasma renin activity.³⁰ In some studies^{27 29} the hypotensive effect of alphacalcidiol was related to a reduction in body weight and serum ionized calcium level, suggesting that improved calcium absorption causes calciuresis and secondary natriuresis, concomitant with the reduction in body mass (fluid loss). The fact that there was also no association between levels of PTH, 25-OH-D, and serum calcium with blood pressure levels in our normotensive sample implies that the association between calcitriol and blood pressure was not merely a reflection of the effects of calcium on blood pressure but an independent effect. There is also experimental evidence of a direct effect of calcitriol on blood pressure: Long-term exposure of chick skeletal muscle in culture to calcitriol increased the ability of the skeletal muscle membranes to sequester calcium.³⁶ Thus, it is possible that calcitriol could increase the ability of cells to regulate free intracellular calcium more efficiently.³⁷ In a study of patients with moderate hypertension, vascular resistance measured in the calf was found to be inversely and independently associated with calcitriol level.³⁸ Finally, specific receptors for calcitriol have been found in tissues involved in blood pressure regulation, in heart muscles,^{2 39 40 41} and in vascular smooth muscle.^{3 4} Autoradiographic in vivo studies of mice hearts have shown a preferential distribution of calcitriol in cells producing atrial natriuretic factor, and calcitriol receptors have been found in regions of the spinal cord and brain stem that are associated with cardiovascular regulation, in pituicytes (which release vasopressin),¹ and in epinephrine- and norepinephrine-secreting cells in the adrenal medulla.⁵ Further investigations are needed to clarify the calcitriol–blood pressure connection.

Because of the reported association between blood lead level and calcitriol²⁵ and the possible association between blood lead level and blood pressure,²⁶ subjects occupationally exposed to lead were intentionally included in this study. Blood lead level was not found to be associated with blood pressure, and there was no interaction between blood lead level and calcitriol affecting blood pressure. Thus, our results do not support the hypothesis that there is an effect of blood lead level on blood pressure that is mediated by the calcium homeostatic hormones.

Some authors have suggested that calcitriol has hypertensive effects⁹ and that the hypotensive effect of dietary calcium supplementation may be mediated by reductions in calcitriol levels.⁴² Our results did not support this hypothesis, which may be true when elevations of calcitriol level are secondary to severe calcium deficiency.

There have been several studies linking changes in dairy product intake to changes in blood pressure level.⁴³ Dairy products are among the main dietary sources of vitamin D. From the present results, it seems possible that the effects of increased dairy product intake on blood pressure⁴³ may be at least partially related to changes in availability of 25-OH-D, the precursor of serum calcitriol. This is plausible given an initially inadequate vitamin D consumption or sunlight exposure. Under adequate nutrition and sun exposure conditions, an inverse association between dietary calcium intake (dairy products) and serum calcitriol because of the effects of serum calcium on calcitriol level have been reported.⁴⁴ However, in the present study 25-OH-D levels (which could be affected by nutrition) were relatively higher than those reported in other studies and were not associated with blood pressure, suggesting that at least in our cohort the effects of calcitriol on blood pressure are not indirect markers of the effects of vitamin D intake.

Our results should be interpreted with caution. First, our calcitriol levels were higher than those reported in other studies, such that extrapolations of these findings to other populations in countries with less sunny winters, to women, or to older subjects who spend more time indoors may be unwarranted. Furthermore (as discussed earlier), the effect of calcitriol on blood pressure may be renin-dependent, and kidney damage may also influence the results. Our study group had normal values of PTH, 25-OH-D, and serum calcium, had normal blood pressure, had normal creatinine level, and were apparently healthy.

The physiological importance of our findings is unclear. In previous reports we have demonstrated that as a result of heat acclimatization, blood volume is higher in summer than in winter.^{45 46} This suggests that there may be seasonal changes in the capacity of the vascular system; that is, an increase in calcitriol levels in summer caused by high levels of sunlight exposure may enable the increase in blood volume during heat acclimatization. This hypothesis deserves further investigation.

We conclude that there is an inverse association between serum calcitriol level and blood pressure. This suggests that in addition to its role in calcium homeostasis, the active metabolite of vitamin D may be a factor determining blood pressure level. The presence of receptors for calcitriol in blood vessels indicates a possible vasodilator effect that could be either direct or indirect. The substantial differences in both systolic and diastolic blood pressure levels between the upper and lower quartiles of serum calcitriol may be of clinical significance, and the causation and pharmacological implications should be further investigated.

	Selected Abbreviations and Acronyms

 

BMI = body mass index calcitriol = 1,25-dihydroxyvitamin D 25-OH-D = 25-hydroxyvitamin D PTH = parathyroid hormone RDA = recommended daily allowance

	Acknowledgments

 
This study was supported by the Committee for Preventive Action and Research in Occupational Health, The Ministry of Labor and Social Affairs, Jerusalem, Israel.

Received March 31, 1997; first decision April 25, 1997; accepted May 21, 1997.

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